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Sample records for population pharmacokinetic parameters

  1. Estimation of population pharmacokinetic parameters of saquinavir in HIV patients with the MONOLIX software.

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    Lavielle, Marc; Mentré, France

    2007-04-01

    In nonlinear mixed-effects models, estimation methods based on a linearization of the likelihood are widely used although they have several methodological drawbacks. Kuhn and Lavielle (Comput. Statist. Data Anal. 49:1020-1038 (2005)) developed an estimation method which combines the SAEM (Stochastic Approximation EM) algorithm, with a MCMC (Markov Chain Monte Carlo) procedure for maximum likelihood estimation in nonlinear mixed-effects models without linearization. This method is implemented in the Matlab software MONOLIX which is available at http://www.math.u-psud.fr/~lavielle/monolix/logiciels. In this paper we apply MONOLIX to the analysis of the pharmacokinetics of saquinavir, a protease inhibitor, from concentrations measured after single dose administration in 100 HIV patients, some with advance disease. We also illustrate how to use MONOLIX to build the covariate model using the Bayesian Information Criterion. Saquinavir oral clearance (CL/F) was estimated to be 1.26 L/h and to increase with body mass index, the inter-patient variability for CL/F being 120%. Several methodological developments are ongoing to extend SAEM which is a very promising estimation method for population pharmacockinetic/pharmacodynamic analyses.

  2. Cost-constrained optimal sampling for system identification in pharmacokinetics applications with population priors and nuisance parameters.

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    Sorzano, Carlos Oscars S; Pérez-De-La-Cruz Moreno, Maria Angeles; Burguet-Castell, Jordi; Montejo, Consuelo; Ros, Antonio Aguilar

    2015-06-01

    Pharmacokinetics (PK) applications can be seen as a special case of nonlinear, causal systems with memory. There are cases in which prior knowledge exists about the distribution of the system parameters in a population. However, for a specific patient in a clinical setting, we need to determine her system parameters so that the therapy can be personalized. This system identification is performed many times by measuring drug concentrations in plasma. The objective of this work is to provide an irregular sampling strategy that minimizes the uncertainty about the system parameters with a fixed amount of samples (cost constrained). We use Monte Carlo simulations to estimate the average Fisher's information matrix associated to the PK problem, and then estimate the sampling points that minimize the maximum uncertainty associated to system parameters (a minimax criterion). The minimization is performed employing a genetic algorithm. We show that such a sampling scheme can be designed in a way that is adapted to a particular patient and that it can accommodate any dosing regimen as well as it allows flexible therapeutic strategies. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  3. Population Pharmacokinetics of Intranasal Scopolamine

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    Wu, L.; Chow, D. S. L.; Putcha, L.

    2013-01-01

    Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS).The bioavailability and pharmacokinetics (PK) was evaluated using data collected in Phase II IND protocols. We reported earlier statistically significant gender differences in PK parameters of INSCOP at a dose level of 0.4 mg. To identify covariates that influence PK parameters of INSCOP, we examined population covariates of INSCOP PK model for 0.4 mg dose. Methods: Plasma scopolamine concentrations versus time data were collected from 20 normal healthy human subjects (11 male/9 female) after a 0.4 mg dose. Phoenix NLME was employed for PK analysis of these data using gender, body weight and age as covariates for model selection. Model selection was based on a likelihood ratio test on the difference of criteria (-2LL). Statistical significance for base model building and individual covariate analysis was set at P less than 0.05{delta(-2LL)=3.84}. Results: A one-compartment pharmacokinetic model with first-order elimination best described INSCOP concentration ]time profiles. Inclusion of gender, body weight and age as covariates individually significantly reduced -2LL by the cut-off value of 3.84(P less than 0.05) when tested against the base model. After the forward stepwise selection and backward elimination steps, gender was selected to add to the final model which had significant influence on absorption rate constant (ka) and the volume of distribution (V) of INSCOP. Conclusion: A population pharmacokinetic model for INSCOP has been identified and gender was a significant contributing covariate for the final model. The volume of distribution and Ka were significantly higher in males than in females which confirm gender-dependent pharmacokinetics of scopolamine after administration of a 0.4 mg dose.

  4. Population pharmacokinetics and relationship between demographic and clinical variables and pharmacokinetics of gentamicin in neonates

    NARCIS (Netherlands)

    Stolk, L M L; Degraeuwe, P L J; Nieman, F H M; de Wolf, M C; de Boer, A|info:eu-repo/dai/nl/075097346

    Population pharmacokinetic parameter estimates were calculated from 725 routine plasma gentamicin concentrations obtained in 177 neonates of 24 to 42 weeks' gestational age in their first week of life. Kel increases and V/W decreases with increasing gestational age. Almost identical results were

  5. Population pharmacokinetics of olprinone in healthy male volunteers

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    Kunisawa T

    2014-03-01

    Full Text Available Takayuki Kunisawa,1 Hidefumi Kasai,2 Makoto Suda,2 Manabu Yoshimura,3 Ami Sugawara,3 Yuki Izumi,3 Takafumi Iida,3 Atsushi Kurosawa,3 Hiroshi Iwasaki3 1Surgical Operation Department, Asahikawa Medical University Hospital, Hokkaido, Japan; 2Clinical Study Management Division, Bell Medical Solutions Inc, Tokyo, Japan; 3Department of Anesthesiology and Critical Care Medicine, Asahikawa Medical University, Hokkaido, Japan Background: Olprinone decreases the cardiac preload and/or afterload because of its vasodilatory effect and increases myocardial contractility by inhibiting phosphodiesterase III. Purpose: The objective of this study was to characterize the population pharmacokinetics of olprinone after a single continuous infusion in healthy male volunteers. Methods: We used 500 plasma concentration data points collected from nine healthy male volunteers for the study. The population pharmacokinetic analysis was performed using the nonlinear mixed effect model (NONMEM® software. Results: The time course of plasma concentration of olprinone was best described using a two-compartment model. The final pharmacokinetic parameters were total clearance (7.37 mL/minute/kg, distribution volume of the central compartment (134 mL/kg, intercompartmental clearance (7.75 mL/minute/kg, and distribution volume of the peripheral compartment (275 mL/kg. The interindividual variability in the total clearance was 12.4%, and the residual error variability (exponential and additive were 22.2% and 0.129 (standard deviation. The final pharmacokinetic model was assessed using a bootstrap method and visual predictive check. Conclusion: We developed a population pharmacokinetic model of olprinone in healthy male adults. The bootstrap method and visual predictive check showed that this model was appropriate. Our results might be used to develop the population pharmacokinetic model in patients. Keywords: phosphodiesterase III inhibitor, men, pharmacokinetic model

  6. Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach.

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    Betts, Alison; Keunecke, Anne; van Steeg, Tamara J; van der Graaf, Piet H; Avery, Lindsay B; Jones, Hannah; Berkhout, Jan

    2018-04-10

    The linear pharmacokinetics (PK) of therapeutic monoclonal antibodies (mAbs) can be considered a class property with values that are similar to endogenous IgG. Knowledge of these parameters across species could be used to avoid unnecessary in vivo PK studies and to enable early PK predictions and pharmacokinetic/pharmacodynamic (PK/PD) simulations. In this work, population-pharmacokinetic (popPK) modeling was used to determine a single set of 'typical' popPK parameters describing the linear PK of mAbs in human, cynomolgus monkey and transgenic mice expressing the human neonatal Fc receptor (hFcRn Tg32), using a rich dataset of 27 mAbs. Non-linear PK was excluded from the datasets and a 2-compartment model was applied to describe mAb disposition. Typical human popPK estimates compared well with data from comparator mAbs with linear PK in the clinic. Outliers with higher than typical clearance were found to have non-specific interactions in an affinity-capture self-interaction nanoparticle spectroscopy assay, offering a potential tool to screen out these mAbs at an early stage. Translational strategies were investigated for prediction of human linear PK of mAbs, including use of typical human popPK parameters and allometric exponents from cynomolgus monkey and Tg32 mouse. Each method gave good prediction of human PK with parameters predicted within 2-fold. These strategies offer alternative options to the use of cynomolgus monkeys for human PK predictions of linear mAbs, based on in silico methods (typical human popPK parameters) or using a rodent species (Tg32 mouse), and call into question the value of completing extensive in vivo preclinical PK to inform linear mAb PK.

  7. Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants, a population pharmacokinetic modelling approach.

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    Marsot, Amélie; Brevaut-Malaty, Véronique; Vialet, Renaud; Boulamery, Audrey; Bruguerolle, Bernard; Simon, Nicolas

    2014-08-01

    Phenobarbital is widely used for treatment of neonatal seizures. Its optimal use in neonates and young infants requires information regarding pharmacokinetics. The objective of this study is to characterize the absolute bioavailability of phenobarbital in neonates and young infants, a pharmacokinetic parameter which has not yet been investigated. Routine clinical pharmacokinetic data were retrospectively collected from 48 neonates and infants (weight: 0.7-10 kg; patient's postnatal age: 0-206 days; GA: 27-42 weeks) treated with phenobarbital, who were administered as intravenous or suspension by oral routes and hospitalized in a paediatric intensive care unit. Total mean dose of 4.6 mg/kg (3.1-10.6 mg/kg) per day was administered by 30-min infusion or by oral route. Pharmacokinetic analysis was performed using a nonlinear mixed-effect population model software). Data were modelled with an allometric pharmacokinetic model, using three-fourths scaling exponent for clearance (CL). The population typical mean [per cent relative standard error (%RSE)] values for CL, apparent volume of distribution (Vd ) and bioavailability (F) were 0.0054 L/H/kg (7%), 0.64 L/kg (15%) and 48.9% (22%), respectively. The interindividual variability of CL, Vd , F (%RSE) and residual variability (%RSE) was 17% (31%), 50% (27%), 39% (27%) and 7.2 mg/L (29%), respectively. The absolute bioavailability of phenobarbital in neonates and infants was estimated. The dose should be increased when switching from intravenous to oral administration. © 2013 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.

  8. Investigating pulmonary and systemic pharmacokinetics of inhaled olodaterol in healthy volunteers using a population pharmacokinetic approach.

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    Borghardt, Jens Markus; Weber, Benjamin; Staab, Alexander; Kunz, Christina; Formella, Stephan; Kloft, Charlotte

    2016-03-01

    Olodaterol, a novel β2-adrenergic receptor agonist, is a long-acting, once-daily inhaled bronchodilator approved for the treatment of chronic obstructive pulmonary disease. The aim of the present study was to describe the plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers by population pharmacokinetic modelling and thereby to infer its pulmonary fate. Plasma and urine data after intravenous administration (0.5-25 μg) and oral inhalation (2.5-70 μg via the Respimat® inhaler) were available from a total of 148 healthy volunteers (single and multiple dosing). A stepwise model building approach was applied, using population pharmacokinetic modelling. Systemic disposition parameters were fixed to estimates obtained from intravenous data when modelling data after inhalation. A pharmacokinetic model, including three depot compartments with associated parallel first-order absorption processes (pulmonary model) on top of a four-compartment body model (systemic disposition model), was found to describe the data the best. The dose reaching the lung (pulmonary bioavailable fraction) was estimated to be 49.4% [95% confidence interval (CI) 46.1, 52.7%] of the dose released from the device. A large proportion of the pulmonary bioavailable fraction [70.1% (95% CI 66.8, 73.3%)] was absorbed with a half-life of 21.8 h (95% CI 19.7, 24.4 h). The plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers were adequately described. The key finding was that a high proportion of the pulmonary bioavailable fraction had an extended pulmonary residence time. This finding was not expected based on the physicochemical properties of olodaterol. © 2015 The British Pharmacological Society.

  9. Compartmental analysis, imaging techniques and population pharmacokinetic. Experiences at CENTIS

    International Nuclear Information System (INIS)

    Hernández, Ignacio; León, Mariela; Leyva, Rene; Castro, Yusniel; Ayra, Fernando E.

    2016-01-01

    Introduction: In pharmacokinetic evaluation small rodents are used in a large extend. Traditional pharmacokinetic evaluations by the two steps approach can be replaced by the sparse data design which may also represent a complicated situation to evaluate satisfactorily from the statistical point of view. In this presentation different situations of sparse data sampling are analyzed based on practical consideration. Non linear mixed effect model was selected in order to estimate pharmacokinetic parameters in simulated data from real experimental results using blood sampling and imaging procedures. Materials and methods: Different scenarios representing several experimental designs of incomplete individual profiles were evaluated. Data sets were simulated based on real data from previous experiments. In all cases three to five blood samples were considered per time point. A combination of compartmental analysis with tumor uptake obtained by gammagraphy of radiolabeled drugs is also evaluated.All pharmacokinetic profiles were analyzed by means of MONOLIX software version 4.2.3. Results: All sampling schedules yield the same results when computed using the MONOLIX software and the SAEM algorithm. Population and individual pharmacokinetic parameters were accurately estimated with three or five determination per sampling point. According with the used methodology and software tool, it can be an expected result, but demonstrating the method performance in such situations, allow us to select a more flexible design using a very small number of animals in preclinical research. The combination with imaging procedures also allows us to construct a completely structured compartmental analysis. Results of real experiments are presented demonstrating the versatility of used methodology in different evaluations. The same sampling approach can be considered in phase I or II clinical trials. (author)

  10. [Diagnostic value of quantitative pharmacokinetic parameters and relative quantitative pharmacokinetic parameters in breast lesions with dynamic contrast-enhanced MRI].

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    Sun, T T; Liu, W H; Zhang, Y Q; Li, L H; Wang, R; Ye, Y Y

    2017-08-01

    Objective: To explore the differential between the value of dynamic contrast-enhanced MRI quantitative pharmacokinetic parameters and relative pharmacokinetic quantitative parameters in breast lesions. Methods: Retrospective analysis of 255 patients(262 breast lesions) who was obtained by clinical palpation , ultrasound or full-field digital mammography , and then all lessions were pathologically confirmed in Zhongda Hospital, Southeast University from May 2012 to May 2016. A 3.0 T MRI scanner was used to obtain the quantitative MR pharmacokinetic parameters: volume transfer constant (K(trans)), exchange rate constant (k(ep))and extravascular extracellular volume fraction (V(e)). And measured the quantitative pharmacokinetic parameters of normal glands tissues which on the same side of the same level of the lesions; and then calculated the value of relative pharmacokinetic parameters: rK(rans)、rk(ep) and rV(e).To explore the diagnostic value of two pharmacokinetic parameters in differential diagnosis of benign and malignant breast lesions using receiver operating curves and model of logistic regression. Results: (1)There were significant differences between benign lesions and malignant lesions in K(trans) and k(ep) ( t =15.489, 15.022, respectively, P 0.05). The areas under the ROC curve(AUC)of K(trans), k(ep) and V(e) between malignant and benign lesions were 0.933, 0.948 and 0.387, the sensitivity of K(trans), k(ep) and V(e) were 77.1%, 85.0%, 51.0% , and the specificity of K(trans), k(ep) and V(e) were 96.3%, 93.6%, 60.8% for the differential diagnosis of breast lesions if taken the maximum Youden's index as cut-off. (2)There were significant differences between benign lesions and malignant lesions in rK(trans), rk(ep) and rV(e) ( t =14.177, 11.726, 2.477, respectively, P quantitative pharmacokinetic parameters and the prediction probability of relative quantitative pharmacokinetic parameters( Z =0.867, P =0.195). Conclusion: There was no significant

  11. Clinical Population Pharmacokinetics and Toxicodynamics of Linezolid

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    Boak, Lauren M.; Rayner, Craig R.; Grayson, M. Lindsay; Paterson, David L.; Spelman, Denis; Khumra, Sharmila; Capitano, Blair; Forrest, Alan; Li, Jian

    2014-01-01

    Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxicodynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10- to 28-day therapy for platelet nadirs of linezolid therapy and large between-patient variability, close monitoring of patients for development of toxicity is important. Dose individualization based on plasma linezolid concentration profiles and platelet counts should be considered to minimize linezolid-associated thrombocytopenia. Overall, oxazolidinone therapy over 5 to 7 days even at relatively high doses was predicted to be as safe as 10-day therapy of 600 mg linezolid every 12 h. PMID:24514086

  12. CARVEDILOL POPULATION PHARMACOKINETIC ANALYSIS – APPLIED VALIDATION PROCEDURE

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    Aleksandra Catić-Đorđević

    2013-09-01

    Full Text Available Carvedilol is a nonselective beta blocker/alpha-1 blocker, which is used for treatment of essential hypertension, chronic stable angina, unstable angina and ischemic left ventricular dysfunction. The aim of this study was to describe carvedilol population pharmacokinetic (PK analysis as well as the validation of analytical procedure, which is an important step regarding this approach. In contemporary clinical practice, population PK analysis is often more important than standard PK approach in setting a mathematical model that describes the PK parameters. Also, it includes the variables that have particular importance in the drugs pharmacokinetics such as sex, body mass, dosage, pharmaceutical form, pathophysiological state, disease associated with the organism or the presence of a specific polymorphism in the isoenzyme important for biotransformation of the drug. One of the most frequently used approach in population PK analysis is the Nonlinear Modeling of Mixed Effects - NONMEM modeling. Analytical methods used in the data collection period is of great importance for the implementation of a population PK analysis of carvedilol in order to obtain reliable data that can be useful in clinical practice. High performance liquid chromatography (HPLC analysis of carvedilol is used to confirm the identity of a drug and provide quantitative results and also to monitor the efficacy of the therapy. Analytical procedures used in other studies could not be fully implemented in our research as it was necessary to perform certain modification and validation of the method with the aim of using the obtained results for the purpose of a population pharmacokinetic analysis. Validation process is a logical terminal phase of analytical procedure development that provides applicability of the procedure itself. The goal of validation is to ensure consistency of the method and accuracy of results or to confirm the selection of analytical method for a given sample

  13. The Influence of Normalization Weight in Population Pharmacokinetic Covariate Models.

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    Goulooze, Sebastiaan C; Völler, Swantje; Välitalo, Pyry A J; Calvier, Elisa A M; Aarons, Leon; Krekels, Elke H J; Knibbe, Catherijne A J

    2018-03-23

    In covariate (sub)models of population pharmacokinetic models, most covariates are normalized to the median value; however, for body weight, normalization to 70 kg or 1 kg is often applied. In this article, we illustrate the impact of normalization weight on the precision of population clearance (CL pop ) parameter estimates. The influence of normalization weight (70, 1 kg or median weight) on the precision of the CL pop estimate, expressed as relative standard error (RSE), was illustrated using data from a pharmacokinetic study in neonates with a median weight of 2.7 kg. In addition, a simulation study was performed to show the impact of normalization to 70 kg in pharmacokinetic studies with paediatric or obese patients. The RSE of the CL pop parameter estimate in the neonatal dataset was lowest with normalization to median weight (8.1%), compared with normalization to 1 kg (10.5%) or 70 kg (48.8%). Typical clearance (CL) predictions were independent of the normalization weight used. Simulations showed that the increase in RSE of the CL pop estimate with 70 kg normalization was highest in studies with a narrow weight range and a geometric mean weight away from 70 kg. When, instead of normalizing with median weight, a weight outside the observed range is used, the RSE of the CL pop estimate will be inflated, and should therefore not be used for model selection. Instead, established mathematical principles can be used to calculate the RSE of the typical CL (CL TV ) at a relevant weight to evaluate the precision of CL predictions.

  14. Population pharmacokinetics of amikacin in neonatal intensive care unit patients

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    Paulo Caceres Guido

    2017-02-01

    Full Text Available Background Amikacin treatment requires close monitoring of blood concentrations to increase the probability that levels achieved are both effective and safe. Aims We described population pharmacokinetics parameters of amikacin in newborns from a Neonatal Intensive Care Unit with suspected or documented sepsis. Methods A nonlinear mixed-effect model approach was used to analyse the data. Results Twenty seven neonates were enrolled. Final parameter estimates were: Ke(h-1=0.232x(CR Exp-0.85; V(mL/kg=497. Conclusion Weight and serum creatinine are associated with neonatal amikacin volume of distribution and elimination constant rate, respectively. The presence of sepsis may decrease amikacin elimination, although this observation should be further explored. These results could help to individualize amikacin dosage for neonates.

  15. Population Pharmacokinetics of Tracers: A New Tool for Medical Imaging?

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    Gandia, Peggy; Jaudet, Cyril; Chatelut, Etienne; Concordet, Didier

    2017-02-01

    Positron emission tomography-computed tomography is a medical imaging method measuring the activity of a radiotracer chosen to accumulate in cancer cells. A recent trend of medical imaging analysis is to account for the radiotracer's pharmacokinetic properties at a voxel (three-dimensional-pixel) level to separate the different tissues. These analyses are closely linked to population pharmacokinetic-pharmacodynamic modelling. Kineticists possess the cultural background to improve medical imaging analysis. This article stresses the common points with population pharmacokinetics and highlights the methodological locks that need to be lifted.

  16. Population pharmacokinetics of adefovir dipivoxil tablets in healthy Chinese volunteers.

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    Huang, Jihan; Zhang, Yaping; Huang, Xiaohui; Li, Lujin; Li, Yunfei; Wang, Kun; Yang, Juan; He, Yingchun; Lv, Yinghua; Zheng, Qingshan

    2014-01-01

    To develop a population pharmacokinetic model of adefovir dipivoxil in healthy volunteers and evaluate the effect of individual factors on the pharmacokinetics of adefovir dipivoxil. Plasma concentration data collected from 32 healthy Chinese subjects in a Phase I clinical study was pooled. Subjects received a single oral dose of 10 mg, 20 mg, or 30 mg adefovir dipivoxil, or multiple doses of 10 mg once a day for 9 days. Plasma concentrations of adefovir dipivoxil were measured using a validated liquid chromatography-mass spectrometric method. A nonlinear mixed-effect model was used to analyze the plasma concentration data of adefovir dipivoxil in healthy volunteers and to calculate the relevant parameters as well as inter- and intra-individual variability. The time course of adefovir dipivoxil concentration is best described by a first-order absorption and first-order elimination two-compartment model with lag time. The final estimate of total body clearance (CL) is 56.9 L/h and 78.7 L/h for single and multiple dosing regimen, respectively; the volume distribution of the central compartment (V2) is 106 L; inter-compartmental clearance (Q) is 220 L/h; volume distribution of the peripheral compartment (V3) is 498 L and 800 L for single and multiple dosing regimen, respectively; absorption rate is 0.509 h-1; and lag time is 0.315 hours. The inter-individual variabilities of CL and V2 were 22.4% and 58.9%, respectively. The proportional error of residual variability is 14.1% and the additive error is 0.30 ng/L. The final pharmacokinetic model was evaluated using a bootstrap method. A nonlinear mixed effect model for oral adefovir dipivoxil formulations was developed in healthy Chinese subjects. A multiple dosing regimen may significantly increase the body clearance and volume distribution of the peripheral compartment compared to a single dosing regimen. *These authors contribute equally to this work.

  17. Influence of Differing Analgesic Formulations of Aspirin on Pharmacokinetic Parameters

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    Kunal Kanani

    2015-08-01

    Full Text Available Aspirin has been used therapeutically for over 100 years. As the originator and an important marketer of aspirin-containing products, Bayer’s clinical trial database contains numerous reports of the pharmacokinetics of various aspirin formulations. These include evaluations of plain tablets, effervescent tablets, granules, chewable tablets, and fast-release tablets. This publication seeks to expand upon the available pharmacokinetic information concerning aspirin formulations. In the pre-systemic circulation, acetylsalicylic acid (ASA is rapidly converted into its main active metabolite, salicylic acid (SA. Therefore, both substances are measured in plasma and reported in the results. The 500 mg strength of each formulation was chosen for analysis as this is the most commonly used for analgesia. A total of 22 studies were included in the analysis. All formulations of 500 mg aspirin result in comparable plasma exposure to ASA and SA as evidenced by AUC. Tablets and dry granules provide a consistently lower Cmax compared to effervescent, granules in suspension and fast release tablets. Effervescent tablets, fast release tablets, and granules in suspension provide a consistently lower median Tmax compared to dry granules and tablets for both ASA and SA. This report reinforces the importance of formulation differences and their impact on pharmacokinetic parameters.

  18. Effect of co-medication on the pharmacokinetic parameters of phenobarbital in asphyxiated newborns.

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    Šíma, M; Pokorná, P; Hronová, K; Slanař, O

    2015-01-01

    Phenobarbital is an anticonvulsive drug widely used in newborns with hypoxic-ischemic encephalopathy. The objective of our study was to describe possible effect of frequently co-administered medications (dopamine, dobutamine, norepinephrine, furosemide, phenytoin, and analgesics) on the phenobarbital pharmacokinetics in full term newborns with hypoxic-ischemic encephalopathy. Phenobarbital pharmacokinetic parameters (standardized intravenous loading dose was 10-20 mg/kg, maintenance dose 2-6 mg/kg/day) were computed using non-compartmental analysis. Co-medication was evaluated throughout the whole treatment period up to 5 days. Volume of distribution, clearance, and half-life median values (95 % CI) for phenobarbital in the whole study population (n=37) were 0.48 (0.41-0.56) l/kg, 0.0034 (0.0028-0.0040) l/h/kg, and 93.7 (88.1-99.2) h, respectively. Phenobarbital pharmacokinetic parameters were not significantly affected by vasoactive drugs (dopamine, dobutamine, and norepinephrine), furosemide, phenytoin, or analgesics. Furthermore, no dose-dependent alteration of phenobarbital pharmacokinetic parameters was noted for vasoactive medication at doses equivalent to cumulative vasoactive-inotropic score (area under the curve in a plot of vasoactive-inotropic score against time) 143.2-8473.6, furosemide at cumulative doses of 0.2-42.9 mg/kg, or phenytoin at cumulative doses of 10.3-46.2 mg/kg. Phenobarbital pharmacokinetics was not affected by investigated co-administered drugs used in newborns with hypoxic-ischemic encephalopathy in real clinical settings.

  19. Dynamic Contrast-enhanced MR Imaging in Renal Cell Carcinoma: Reproducibility of Histogram Analysis on Pharmacokinetic Parameters

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    Wang, Hai-yi; Su, Zi-hua; Xu, Xiao; Sun, Zhi-peng; Duan, Fei-xue; Song, Yuan-yuan; Li, Lu; Wang, Ying-wei; Ma, Xin; Guo, Ai-tao; Ma, Lin; Ye, Hui-yi

    2016-01-01

    Pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) have been increasingly used to evaluate the permeability of tumor vessel. Histogram metrics are a recognized promising method of quantitative MR imaging that has been recently introduced in analysis of DCE-MRI pharmacokinetic parameters in oncology due to tumor heterogeneity. In this study, 21 patients with renal cell carcinoma (RCC) underwent paired DCE-MRI studies on a 3.0 T MR system. Extended Tofts model and population-based arterial input function were used to calculate kinetic parameters of RCC tumors. Mean value and histogram metrics (Mode, Skewness and Kurtosis) of each pharmacokinetic parameter were generated automatically using ImageJ software. Intra- and inter-observer reproducibility and scan–rescan reproducibility were evaluated using intra-class correlation coefficients (ICCs) and coefficient of variation (CoV). Our results demonstrated that the histogram method (Mode, Skewness and Kurtosis) was not superior to the conventional Mean value method in reproducibility evaluation on DCE-MRI pharmacokinetic parameters (K trans & Ve) in renal cell carcinoma, especially for Skewness and Kurtosis which showed lower intra-, inter-observer and scan-rescan reproducibility than Mean value. Our findings suggest that additional studies are necessary before wide incorporation of histogram metrics in quantitative analysis of DCE-MRI pharmacokinetic parameters. PMID:27380733

  20. Bayesian Population Physiologically-Based Pharmacokinetic (PBPK Approach for a Physiologically Realistic Characterization of Interindividual Variability in Clinically Relevant Populations.

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    Markus Krauss

    Full Text Available Interindividual variability in anatomical and physiological properties results in significant differences in drug pharmacokinetics. The consideration of such pharmacokinetic variability supports optimal drug efficacy and safety for each single individual, e.g. by identification of individual-specific dosings. One clear objective in clinical drug development is therefore a thorough characterization of the physiological sources of interindividual variability. In this work, we present a Bayesian population physiologically-based pharmacokinetic (PBPK approach for the mechanistically and physiologically realistic identification of interindividual variability. The consideration of a generic and highly detailed mechanistic PBPK model structure enables the integration of large amounts of prior physiological knowledge, which is then updated with new experimental data in a Bayesian framework. A covariate model integrates known relationships of physiological parameters to age, gender and body height. We further provide a framework for estimation of the a posteriori parameter dependency structure at the population level. The approach is demonstrated considering a cohort of healthy individuals and theophylline as an application example. The variability and co-variability of physiological parameters are specified within the population; respectively. Significant correlations are identified between population parameters and are applied for individual- and population-specific visual predictive checks of the pharmacokinetic behavior, which leads to improved results compared to present population approaches. In the future, the integration of a generic PBPK model into an hierarchical approach allows for extrapolations to other populations or drugs, while the Bayesian paradigm allows for an iterative application of the approach and thereby a continuous updating of physiological knowledge with new data. This will facilitate decision making e.g. from preclinical to

  1. Population pharmacokinetics of ticagrelor in patients with acute coronary syndromes.

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    Li, Jianguo; Tang, Weifeng; Storey, Robert F; Husted, Steen; Teng, Renli

    2016-09-01

    Ticagrelor is an orally administered antiplatelet agent used to reduce thrombotic events in patients with acute coronary syndromes. Data from two studies in patients with acute coronary syndromes with large amounts of pharmacokinetic (PK) data (phase IIb DISPERSE-2 study (n = 609)); phase III PLATO PK substudy (n = 6,381)), along with non-linear mixed effects modeling software, were used to develop population PK models for ticagrelor and its metabolite, AR-C124910XX, and to evaluate the impact of demographic and clinical factors on the PK of ticagrelor and AR-C124910XX. 32 covariates relating to disease history, biomarkers, clinical chemistry, and concomitant medications were assessed. A one-compartment model with population mean PK parameters of firstorder absorption rate constant (0.67/h), apparent systemic clearance (14 L/h), and apparent volume of distribution (221 L) was shown to best describe the PK profile of ticagrelor. Patients co-administered moderate CYP3A inducers or inhibitors increased (by 110%, 95% confidence interval (CI), 52 - 192%) or decreased (by 64%, 95% CI, 39 - 73%) apparent ticagrelor clearance, respectively, while habitual smoking decreased apparent ticagrelor clearance by 22% (95% CI, 19 - 25%). Ticagrelor bioavailability was 21% (95% CI, 19 - 22%) lower at treatment initiation (visit 1) versus subsequent visits. Compared with Caucasian patients, ticagrelor bioavailability was 39% (95% CI, 33 - 46%) higher in Asian patients and 18% (95% CI, 6 - 28%) lower in Black patients. In the current analyses, the population PK models developed for ticagrelor and AR-C124910XX described the data obtained in the DISPERSE-2 and PLATO studies well, and were consistent with previous phase I PK studies.

  2. Selected pharmacokinetic parameters for Cefovecin in hens and green iguanas.

    Science.gov (United States)

    Thuesen, L R; Bertelsen, M F; Brimer, L; Skaanild, M T

    2009-12-01

    The third generation cephalosporin cefovecin has been shown to have an exceptionally long elimination half-life in dogs and cats, making it suitable for antibacterial treatment with a 14-day dosing interval in these species. Pharmacokinetic parameters for cefovecin were investigated in juvenile hens and green iguanas, following subcutaneous injections with 10 mg cefovecin/kg bodyweight. Preliminary studies in eight additional species of birds and reptiles were performed and results were compared with the parameters found in hens and green iguanas. The kinetics were characterized by rapid absorption with peak plasma concentration of 6 +/- 2 microg/mL in hens and 35 +/- 12 microg/mL in green iguanas. The mean plasma half-life for cefovecin was 0.9 +/- 0.3 h for hens and 3.9 h in green iguanas. Volume of distribution was 1.6 +/- 0.5 L/kg for hens and 0.3 L/kg for green iguanas and clearance was 1252 +/- 185 mL.h/kg for hens and 53 mL.h/kg for green iguanas. Results from preliminary studies did not differ notably from those seen in hens and green iguanas. Cefovecin is not suitable for the treatment of bacterial infections with a 14-day dosing interval in hens or green iguanas and seems not to be in a number of other bird and retile species either.

  3. Population pharmacokinetics of phenobarbital in infants with neonatal encephalopathy treated with therapeutic hypothermia.

    Science.gov (United States)

    Shellhaas, Renée A; Ng, Chee M; Dillon, Christina H; Barks, John D E; Bhatt-Mehta, Varsha

    2013-02-01

    Phenobarbital is the first-line treatment for neonatal seizures. Many neonates with hypoxic ischemic encephalopathy are treated with therapeutic hypothermia, and about 40% have clinical seizures. Little is known about the pharmacokinetics of phenobarbital in infants with hypoxic ischemic encephalopathy who undergo therapeutic hypothermia. The objective of this study was to determine the effect of therapeutic hypothermia on phenobarbital pharmacokinetics, taking into account maturational changes. Level 3 neonatal ICU. Infants with hypoxic ischemic encephalopathy and suspected seizures, all treated with phenobarbital. Some of these infants also received treatment with therapeutic hypothermia. None. A retrospective cohort study of 39 infants with hypoxic ischemic encephalopathy treated with phenobarbital (20 were treated with therapeutic hypothermia and 19 were not). Data on phenobarbital plasma concentrations were collected in 39 subjects with hypoxic ischemic encephalopathy with or without therapeutic hypothermia. Using nonlinear mixed-effects modeling, population pharmacokinetics of phenobarbital were developed with a total of 164 plasma concentrations. A one-compartment model best described the pharmacokinetics. The clearance of phenobarbital was linearly related to body weight and matured with increasing age with a maturation half-life of 22.1 days. Therapeutic hypothermia did not influence the pharmacokinetic parameters of phenobarbital. Therapeutic hypothermia does not influence the clearance of phenobarbital after accounting for weight and age. Standard phenobarbital dosing is appropriate for the initial treatment of seizures in neonates with hypoxic ischemic encephalopathy treated with therapeutic hypothermia.

  4. [A study of population pharmacokinetics of linezolid in Chinese].

    Science.gov (United States)

    Zhang, L; Bai, N; Liu, Y N; Wang, R

    2016-12-12

    Objective: To study the population pharmacokinetic (PPK) profiles of linezolid in Chinese healthy volunteers and infected patients. Methods: Linezolid 600 mg was administered to 31 Chinese healthy volunteers with a single dose and to 57 infected patients every 12 h for at least 5 doses. High performance liquid chromatography was applied to determine the plasma concentration of linezolid. Nonlinear mixed-effects modeling method was applied to analyze the PPK profiles. Results: For healthy volunteers with single dose of linezolid, 2-compartment with linear elimination model was the most appropriate structural pharmacokinetic model. The population typical value of apparent volume of central compartment was 26.99 L, volume of peripheral compartment was 22.22 L, apparent clearance of central compartment was 7.99 L/h, and clearance of peripheral compartment was 101.28 L/h. For each 1 kg deviation of weight from the mean value, 0.62 L of volume of peripheral compartment was correlated. For Chinese infected patients with multiple doses of linezolid, 1-compartment with linear elimination model was the most appropriate structural pharmacokinetic model. The population typical value of apparent volume was 38.85 L, and apparent clearance was 4.70 L/h. For each 1 kg deviation of weight from the mean value, 0.79 L of volume, as well as 0.04 L/h of clearance were correlated. For each 1 year deviation of age from the mean value, -0.045 L/h of clearance was correlated. Conclusions: The pharmacokinetic profiles of linezolid in Chinese simulate a 2-compartment with linear elimination model when single dose is administrated, and the weight is linearly positive-correlated to volume. While a 1-compartment with linear elimination model is appropriate when multiple doses are administrated, and the weight is linearly positive-correlated to volume and clearance, but the age is linearly negative-correlated to clearance.

  5. Population Pharmacokinetics of Fentanyl in the Critically Ill

    Science.gov (United States)

    Choi, Leena; Ferrell, Benjamin A; Vasilevskis, Eduard E; Pandharipande, Pratik P; Heltsley, Rebecca; Ely, E Wesley; Stein, C Michael; Girard, Timothy D

    2016-01-01

    Objective To characterize fentanyl population pharmacokinetics in patients with critical illness and identify patient characteristics associated with altered fentanyl concentrations. Design Prospective cohort study. Setting Medical and surgical ICUs in a large tertiary care hospital in the United States. Patients Patients with acute respiratory failure and/or shock who received fentanyl during the first five days of their ICU stay. Measurements and Main Results We collected clinical and hourly drug administration data and measured fentanyl concentrations in plasma collected once daily for up to five days after enrollment. Among 337 patients, the mean duration of infusion was 58 hours at a median rate of 100 µg/hr. Using a nonlinear mixed-effects model implemented by NONMEM, we found fentanyl pharmacokinetics were best described by a two-compartment model in which weight, severe liver disease, and congestive heart failure most affected fentanyl concentrations. For a patient population with a mean weight of 92 kg and no history of severe liver disease or congestive heart failure, the final model, which performed well in repeated 10-fold cross-validation, estimated total clearance (CL), intercompartmental clearance (Q), and volumes of distribution for the central (V1) and peripheral compartments (V2) to be 35 (95% confidence interval: 32 to 39) L/hr, 55 (42 to 68) L/hr, 203 (140 to 266) L, and 523 (428 to 618) L, respectively. Severity of illness was marginally associated with fentanyl pharmacokinetics but did not improve the model fit after liver and heart disease were included. Conclusions In this study, fentanyl pharmacokinetics during critical illness were strongly influenced by severe liver disease, congestive heart failure, and weight, factors that should be considered when dosing fentanyl in the ICU. Future studies are needed to determine if data-driven fentanyl dosing algorithms can improve outcomes for ICU patients. PMID:26491862

  6. Population pharmacokinetics of artesunate and amodiaquine in African children

    Directory of Open Access Journals (Sweden)

    Ouedraogo Alphonse

    2009-08-01

    Full Text Available Abstract Background Pharmacokinetic (PK data on amodiaquine (AQ and artesunate (AS are limited in children, an important risk group for malaria. The aim of this study was to evaluate the PK properties of a newly developed and registered fixed dose combination (FDC of artesunate and amodiaquine. Methods A prospective population pharmacokinetic study of AS and AQ was conducted in children aged six months to five years. Participants were randomized to receive the new artesunate and amodiaquine FDC or the same drugs given in separate tablets. Children were divided into two groups of 70 (35 in each treatment arm to evaluate the pharmacokinetic properties of AS and AQ, respectively. Population pharmacokinetic models for dihydroartemisinin (DHA and desethylamodiaquine (DeAq, the principal pharmacologically active metabolites of AS and AQ, respectively, and total artemisinin anti-malarial activity, defined as the sum of the molar equivalent plasma concentrations of DHA and artesunate, were constructed using the non-linear mixed effects approach. Relative bioavailability between products was compared by estimating the ratios (and 95% CI between the areas under the plasma concentration-time curves (AUC. Results The two regimens had similar PK properties in young children with acute malaria. The ratio of loose formulation to fixed co-formulation AUCs, was estimated as 1.043 (95% CI: 0.956 to 1.138 for DeAq. For DHA and total anti-malarial activity AUCs were estimated to be the same. Artesunate was rapidly absorbed, hydrolysed to DHA, and eliminated. Plasma concentrations were significantly higher following the first dose, when patients were acutely ill, than after subsequent doses when patients were usually afebrile and clinically improved. Amodiaquine was converted rapidly to DeAq, which was then eliminated with an estimated median (range elimination half-life of 9 (7 to 12 days. Efficacy was similar in the two treatments groups, with cure rates of 0

  7. Population pharmacokinetics and pharmacodynamics of cysteamine in nephropathic cystinosis patients

    Directory of Open Access Journals (Sweden)

    Bouazza Naïm

    2011-12-01

    Full Text Available Abstract Background Nephropathic cystinosis is an autosomal recessive disorder resulting in an impaired transport of cystine trough the lysosomal membrane causing an accumulation of free cystine in lysosomes. The only specific treatment for nephropathic cystinosis is cysteamine bitartrate. This study was aimed to describe the relationship between cysteamine plasma concentrations and white blood cell cystine levels, and to simulate an optimized administration scheme to improve the management of patients with cystinosis. Methods Cysteamine and cystine concentrations were measured in 69 nephropathic cystinosis patients. A total of 250 cysteamine plasma concentrations and 243 intracellular cystine concentrations were used to perform a population pharmacokinetic and pharmacodynamic analysis. An optimized administration scheme was simulated in order to maintain cystine levels below 1 nmol half-cystine/mg of protein and to investigate the possibility of administrating the treatment less than 4 times a day (QID, recommended. The current dosing recommendations are 1.3 g/m2/day for less than 50 kg BW and 2 g/day thereafter; the maximum dose should not exceed 1.95 g/m2/day. Results Cysteamine concentrations were satisfactorily described by a one-compartment model. Parameter estimates were standardized for a mean standard bodyweight using an allometric model. WBC cystine levels were adequately described by an indirect response model where the first-order removal rate constant is stimulated by the cysteamine concentrations. Conclusions According to simulations, in order to increase the percentage of patient with cystine levels below 1 nmol half-cystine/mg of protein, the current dosages could be changed as follows: 80 mg/kg/day (QID from 10 to 17 kg, 70 mg/kg/day (QID from 17 to 25 kg, 60 mg/kg/day (QID from 25 to 40 kg and 50 mg/kg/day (QID from 40 to 70 kg (these dosages remain under the maximum recommended dose. However an 8-hourly daily treatment (TID

  8. Estimation of pharmacokinetic parameters from non-compartmental variables using Microsoft Excel.

    Science.gov (United States)

    Dansirikul, Chantaratsamon; Choi, Malcolm; Duffull, Stephen B

    2005-06-01

    This study was conducted to develop a method, termed 'back analysis (BA)', for converting non-compartmental variables to compartment model dependent pharmacokinetic parameters for both one- and two-compartment models. A Microsoft Excel spreadsheet was implemented with the use of Solver and visual basic functions. The performance of the BA method in estimating pharmacokinetic parameter values was evaluated by comparing the parameter values obtained to a standard modelling software program, NONMEM, using simulated data. The results show that the BA method was reasonably precise and provided low bias in estimating fixed and random effect parameters for both one- and two-compartment models. The pharmacokinetic parameters estimated from the BA method were similar to those of NONMEM estimation.

  9. Population pharmacokinetics model of THC used by pulmonary route in occasional cannabis smokers.

    Science.gov (United States)

    Marsot, A; Audebert, C; Attolini, L; Lacarelle, B; Micallef, J; Blin, O

    Cannabis is the most widely used illegal drug in the world. Delta-9-tetrahydrocannabinol (THC) is the main source of the pharmacological effect. Some studies have been carried out and showed significant variability in the described models as the values of the estimated pharmacokinetic parameters. The objective of this study was to develop a population pharmacokinetic model for THC in occasional cannabis smokers. Twelve male volunteers (age: 20-28years, body weight: 62.5-91.0kg), tobacco (3-8 cigarette per day) and cannabis occasional smokers were recruited from the local community. After ad libitum smoking cannabis cigarette according a standardized procedure, 16 blood samples up to 72h were collected. Population pharmacokinetic analysis was performed using a non-linear mixed effects model, with NONMEM software. Demographic and biological data were investigated as covariates. A three-compartment model with first-order elimination fitted the data. The model was parameterized in terms of micro constants and central volume of distribution (V 1 ). Normal ALT concentration (6.0 to 45.0IU/l) demonstrated a statistically significant correlation with k 10 . The mean values (%Relative Standard Error (RSE)) for k 10 , k 12 , k 21 , k 23 , k 32 and V 1 were 0.408h -1 (48.8%), 4.070h -1 (21.4%), 0.022h -1 (27.0%), 1.070h -1 (14.3%), 1.060h -1 (16.7%) and 19.10L (39.7%), respectively. We have developed a population pharmacokinetic model able to describe the quantitative relationship between administration of inhaled doses of THC and the observed plasma concentrations after smoking cannabis. In addition, a linear relationship between ALT concentration and value of k 10 has been described and request further investigation. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Population pharmacokinetics of intravenous Erwinia asparaginase in pediatric acute lymphoblastic leukemia patients.

    Science.gov (United States)

    Sassen, Sebastiaan D T; Mathôt, Ron A A; Pieters, Rob; Kloos, Robin Q H; de Haas, Valérie; Kaspers, Gertjan J L; van den Bos, Cor; Tissing, Wim J E; Te Loo, Maroeska; Bierings, Marc B; Kollen, Wouter J W; Zwaan, Christian M; van der Sluis, Inge M

    2017-03-01

    Erwinia asparaginase is an important component in the treatment of pediatric acute lymphoblastic leukemia. A large variability in serum concentrations has been observed after intravenous Erwinia asparaginase. Currently, Dutch Childhood Oncology Group protocols dose alterations are based on trough concentrations to ensure adequate asparaginase activity (≥100 IU/L). The aim of this study was to describe the population pharmacokinetics of intravenous Erwinia asparaginase to quantify and gather insight into inter-individual and inter-occasion variability. The starting dose was evaluated on the basis of the derived population pharmacokinetic parameters. In a multicenter prospective observational study, a total of 714 blood samples were collected from 51 children (age 1-17 years) with acute lymphoblastic leukemia. The starting dose was 20,000 IU/m 2 three times a week and adjusted according to trough levels from week three onwards. A population pharmacokinetic model was developed using NONMEM ® A 2-compartment linear model with allometric scaling best described the data. Inter-individual and inter-occasion variability of clearance were 33% and 13%, respectively. Clearance in the first month of treatment was 14% higher ( P <0.01). Monte Carlo simulations with our pharmacokinetic model demonstrated that patients with a low weight might require higher doses to achieve similar concentrations compared to patients with high weight. The current starting dose of 20,000 IU/m 2 might result in inadequate concentrations, especially for smaller, lower weight patients, hence dose adjustments based on individual clearance are recommended. The protocols were approved by the institutional review boards. (Registered at NTR 3379 Dutch Trial Register; www.trialregister.nl). Copyright© Ferrata Storti Foundation.

  11. A general method to determine sampling windows for nonlinear mixed effects models with an application to population pharmacokinetic studies.

    Science.gov (United States)

    Foo, Lee Kien; McGree, James; Duffull, Stephen

    2012-01-01

    Optimal design methods have been proposed to determine the best sampling times when sparse blood sampling is required in clinical pharmacokinetic studies. However, the optimal blood sampling time points may not be feasible in clinical practice. Sampling windows, a time interval for blood sample collection, have been proposed to provide flexibility in blood sampling times while preserving efficient parameter estimation. Because of the complexity of the population pharmacokinetic models, which are generally nonlinear mixed effects models, there is no analytical solution available to determine sampling windows. We propose a method for determination of sampling windows based on MCMC sampling techniques. The proposed method attains a stationary distribution rapidly and provides time-sensitive windows around the optimal design points. The proposed method is applicable to determine sampling windows for any nonlinear mixed effects model although our work focuses on an application to population pharmacokinetic models. Copyright © 2012 John Wiley & Sons, Ltd.

  12. Population pharmacokinetics of oral diclofenac for acute pain in children.

    Science.gov (United States)

    Standing, Joseph F; Howard, Richard F; Johnson, Atholl; Savage, Imogen; Wong, Ian C K

    2008-12-01

    To develop a population pharmacokinetic model for a new diclofenac suspension (50 mg 5 ml(-1)) in adult volunteers and paediatric patients, and recommend a dose for acute pain in children. Blood samples were drawn at the start and end of surgery, and on removal of the venous cannula from 70 children (aged 1 to 12 years, weight 9 to 37 kg) who received a preoperative oral 1 mg kg(-1) dose; these were pooled with rich (14 post-dose samples) data from 30 adult volunteers. Population pharmacokinetic modelling was undertaken with NONMEM. The optimum adult dose of diclofenac for acute pain is 50 mg. Simulation from the final model was performed to predict a paediatric dose to achieve a similar AUC to 50 mg in adults. A total of 558 serum diclofenac concentrations from 100 subjects was used in the pooled analysis. A single disposition compartment model with first order elimination and dual absorption compartments was used. The estimates of CL/F and V(D)/F were 53.98 l h(-1) 70 kg(-1) and 4.84 l 70 kg(-1) respectively. Allometric size models appeared to predict adequately changes in CL and V(D) with age. Of the simulated doses investigated, 1 mg kg(-1) gave paediatric AUC((0,12 h)) to adult 50 mg AUC((0,12 h)) ratios of 1.00, 1.08 and 1.18 for ages 1-3, 4-6 and 7-12 years respectively. This study has shown 1 mg kg(-1) diclofenac to produce similar exposure in children aged 1 to 12 years as 50 mg in adults, and is acceptable for clinical practice; patients are unlikely to obtain further benefit from higher doses.

  13. Population pharmacokinetics of proguanil in patients with acute P. falciparum malaria after combined therapy with atovaquone.

    Science.gov (United States)

    Hussein, Z; Eaves, C J; Hutchinson, D B; Canfield, C J

    1996-11-01

    1. The pharmacokinetics of proguanil were evaluated in patients with acute P. falciparum malaria receiving concomitantly proguanil hydrochloride and atovaquone. The population consisted of 203 Blacks, 112 Orientals and 55 Malays; 274 males and 96 females. Of the 370 patients, 114 and 256 patients were classified as 'poor' and 'extensive' metabolizers of proguanil, respectively. Body weight and age ranged between 11-110 kg and 3-65 years, respectively. 2. A one compartment model with first-order absorption and elimination was fitted to proguanil plasma concentration-time profiles, using non-linear mixed effect modelling (NONMEM). 3. Oral clearance (CLo) showed a 0.785 power relationship with body weight and was 13% higher in Orientals than Blacks and Malays and 17% lower in 'poor' than 'extensive' metabolizers. According to the mean weight of each population, the final population estimates of CLo in Blacks, Orientals and Malays who are 'extensive' metabolizers were 54.0, 61.5 and 64.3 l h-1, respectively. Age, gender and dose had no significant effects on CLo. 4. Apparent volume of distribution (V/F) showed a 0.88 power relationship with body weight. The final population estimates were 562 and 1629 l in children ( 15 years, respectively, who had a mean body weight of 22.6 and 54.8 kg, respectively. The effect of other covariates on V/F was not examined. 5. The final magnitudes of interpatient variability in CLo and V/F were relatively low at 22.5 and 17.0%, respectively. 6. Population pharmacokinetic parameter estimates in Black, Oriental and Malay patients with acute P. falciparum malaria are in good agreement with results of pharmacokinetic studies in healthy Caucasian volunteers. In view of the 30-50% residual variability in proguanil plasma concentrations, the slight effects of Orientals and 'poor' metabolizers on CLo are unlikely to be clinically significant. Hence, dose recommendation will be solely based on body weight.

  14. Population Pharmacokinetics and Pharmacodynamics of Meropenem in Nonobese, Obese, and Morbidly Obese Patients.

    Science.gov (United States)

    Chung, Eun Kyoung; Cheatham, S Christian; Fleming, Megan R; Healy, Daniel P; Kays, Michael B

    2017-03-01

    The study objective was to evaluate meropenem population pharmacokinetics and pharmacodynamics in nonobese, obese, and morbidly obese patients. Forty adult patients-11 nonobese (body mass index [BMI] calculate probability of target attainment (PTA) for 5 dosing regimens, infused over 0.5 and 3 hours, using fT>MIC of 40%, 54%, and 100% of the dosing interval. A 2-compartment linear-elimination model best described the serum concentration-time data, and creatinine clearance was significantly associated with systemic clearance. Pharmacokinetic parameters were not significantly different among patient groups. In patients with creatinine clearances ≥50 mL/min, all simulated dosing regimens achieved >90% PTA at 40% fT>MIC in all patient groups at MICs ≤2 mg/L. Only 500 mg q8h, infused over 0.5 hour, did not achieve >90% PTA at 54% fT>MIC in nonobese and morbidly obese patients. At 100% fT>MIC, 1 g q6h and 2 g q8h, infused over 3 hours, reliably achieved >90% PTA in all patient groups. Meropenem pharmacokinetics are comparable among nonobese, obese, and morbidly obese patients. Standard dosing regimens provide adequate pharmacodynamic exposures for susceptible pathogens at 40% and 54% fT>MIC, but prolonged infusions of larger doses are needed for adequate exposures at 100% fT>MIC. Dosage adjustments based solely on body weight are unnecessary. © 2016, The American College of Clinical Pharmacology.

  15. Population pharmacokinetics of caffeine and its metabolites theobromine, paraxanthine and theophylline after inhalation in combination with diacetylmorphine.

    Science.gov (United States)

    Zandvliet, Anthe S; Huitema, Alwin D R; de Jonge, Milly E; den Hoed, Rob; Sparidans, Rolf W; Hendriks, Vincent M; van den Brink, Wim; van Ree, Jan M; Beijnen, Jos H

    2005-01-01

    The stimulant effect of caffeine, as an additive in diacetylmorphine preparations for study purposes, may interfere with the pharmacodynamic effects of diacetylmorphine. In order to obtain insight into the pharmacology of caffeine after inhalation in heroin users, the pharmacokinetics of caffeine and its dimethylxanthine metabolites were studied. The objectives were to establish the population pharmacokinetics under these exceptional circumstances and to compare the results to published data regarding intravenous and oral administration in healthy volunteers. Diacetylmorphine preparations containing 100 mg of caffeine were used by 10 persons by inhalation. Plasma concentrations of caffeine, theobromine, paraxanthine and theophylline were measured by high performance liquid chromatography. Non-linear mixed effects modelling was used to estimate population pharmacokinetic parameters. The model was evaluated by the jack-knife procedure. Caffeine was rapidly and effectively absorbed after inhalation. Population pharmacokinetics of caffeine and its dimethylxanthine metabolites could adequately and simultaneously be described by a linear multi-compartment model. The volume of distribution for the central compartment was estimated to be 45.7 l and the apparent elimination rate constant of caffeine at 8 hr after inhalation was 0.150 hr(-1) for a typical individual. The bioavailability was approximately 60%. The presented model adequately describes the population pharmacokinetics of caffeine and its dimethylxanthine metabolites after inhalation of the caffeine sublimate of a 100 mg tablet. Validation proved the stability of the model. Pharmacokinetics of caffeine after inhalation and intravenous administration are to a large extent similar. The bioavailability of inhaled caffeine is approximately 60% in experienced smokers.

  16. Pharmacokinetic parameters derived from dynamic contrast enhanced MRI of cervical cancers predict chemoradiotherapy outcome

    International Nuclear Information System (INIS)

    Andersen, Erlend K.F.; Hole, Knut Håkon; Lund, Kjersti V.; Sundfør, Kolbein; Kristensen, Gunnar B.; Lyng, Heidi; Malinen, Eirik

    2013-01-01

    Purpose: To assess the prognostic value of pharmacokinetic parameters derived from pre-chemoradiotherapy dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) of cervical cancer patients. Materials and methods: Seventy-eight patients with locally advanced cervical cancer underwent DCE-MRI with Gd-DTPA before chemoradiotherapy. The pharmacokinetic Brix and Tofts models were fitted to contrast enhancement curves in all tumor voxels, providing histograms of several pharmacokinetic parameters (Brix: A Brix , k ep , k el , Tofts: K trans , ν e ). A percentile screening approach including log-rank survival tests was undertaken to identify the clinically most relevant part of the intratumoral parameter distribution. Clinical endpoints were progression-free survival (PFS) and locoregional control (LRC). Multivariate analysis including FIGO stage and tumor volume was used to assess the prognostic significance of the imaging parameters. Results: A Brix , k el , and K trans were significantly (P e was significantly positively correlated with PFS only. k ep showed no association with any endpoint. A Brix was positively correlated with K trans and ν e , and showed the strongest association with endpoint in the log-rank testing. k el and K trans were independent prognostic factors in multivariate analysis with LRC as endpoint. Conclusions: Parameters estimated by pharmacokinetic analysis of DCE-MR images obtained prior to chemoradiotherapy may be used for identifying patients at risk of treatment failure

  17. Phenobarbital in intensive care unit pediatric population: predictive performances of population pharmacokinetic model.

    Science.gov (United States)

    Marsot, Amélie; Michel, Fabrice; Chasseloup, Estelle; Paut, Olivier; Guilhaumou, Romain; Blin, Olivier

    2017-10-01

    An external evaluation of phenobarbital population pharmacokinetic model described by Marsot et al. was performed in pediatric intensive care unit. Model evaluation is an important issue for dose adjustment. This external evaluation should allow confirming the proposed dosage adaptation and extending these recommendations to the entire intensive care pediatric population. External evaluation of phenobarbital published population pharmacokinetic model of Marsot et al. was realized in a new retrospective dataset of 35 patients hospitalized in a pediatric intensive care unit. The published population pharmacokinetic model was implemented in nonmem 7.3. Predictive performance was assessed by quantifying bias and inaccuracy of model prediction. Normalized prediction distribution errors (NPDE) and visual predictive check (VPC) were also evaluated. A total of 35 infants were studied with a mean age of 33.5 weeks (range: 12 days-16 years) and a mean weight of 12.6 kg (range: 2.7-70.0 kg). The model predicted the observed phenobarbital concentrations with a reasonable bias and inaccuracy. The median prediction error was 3.03% (95% CI: -8.52 to 58.12%), and the median absolute prediction error was 26.20% (95% CI: 13.07-75.59%). No trends in NPDE and VPC were observed. The model previously proposed by Marsot et al. in neonates hospitalized in intensive care unit was externally validated for IV infusion administration. The model-based dosing regimen was extended in all pediatric intensive care unit to optimize treatment. Due to inter- and intravariability in pharmacokinetic model, this dosing regimen should be combined with therapeutic drug monitoring. © 2017 Société Française de Pharmacologie et de Thérapeutique.

  18. Population pharmacokinetics of bupivacaine in combined lumbar and sciatic nerve block

    Science.gov (United States)

    Eljebari, Hanene; Jebabli, Nadia; Salouage, Issam; Gaies, Emna; Lakhal, Mohamed; Boussofara, Mehdi; Klouz, Anis

    2014-01-01

    Objectives: The primary aim of this study was to establish the population pharmacokinetic (PPK) model of bupivacaine after combined lumbar plexus and sciatic nerve blocks and secondary aim is to assess the effect of patient's characteristics including age, body weight and sex on pharmacokinetic parameters. Materials and Methods: A total of 31 patients scheduled for elective lower extremity surgery with combined lumbar and sciatic nerve block using plain bupivacaine 0.5% were included. The total bupivacaine plasma concentrations were measured before injection and after two blocks placement and at selected time points. Monitoring of bupivacaine was made by high performance liquid chromatography (HPLC) with ultraviolet detection. Non-linear mixed effects modeling was used to analyze the PPK of bupivacaine. Results: One compartment model with first order absorption, two input compartments and a central elimination was selected. The Shapiro-Wilks test of normality for normalized prediction distribution errors for this model (P = 0.156) showed this as a valid model. The selected model predicts a population clearance of 930 ml/min (residual standard error [RSE] = 15.48%, IC 95% = 930 ± 282.24) with inter individual variability of 75.29%. The central volume of distribution was 134 l (RSE = 12.76%, IC = 134 ± 33.51 L) with inter individual variability of 63.40%. The absorption of bupivacaine in two sites Ka1 and Ka2 were 0.00462/min for the lumbar site and 0.292/min for the sciatic site. Age, body weight and sex have no effect on the bupivacaine pharmacokinetics in this studied population. Conclusion: The developed model helps us to assess the systemic absorption of bupivacaine at two injections sites. PMID:24741194

  19. Solid state NMR and bioequivalence comparison of the pharmacokinetic parameters of two formulations of clindamycin

    KAUST Repository

    Al-Talla, Zeyad; Akrawi, Sabah H.; Emwas, Abdul-Hamid M.

    2011-01-01

    Objective: The purpose of this study was to compare the pharmacokinetic parameters and determine the bioequivalence of a generic formulation of clindamycin that is sold in the local markets in the Middle East (Clindox® 150 mg capsule; test) with a

  20. Obesity and drug pharmacology: a review of the influence of obesity on pharmacokinetic and pharmacodynamic parameters

    NARCIS (Netherlands)

    Smit, C.; Hoogd, S. De; Bruggemann, R.J.M.; Knibbe, C.A.

    2018-01-01

    INTRODUCTION: The rising prevalence of obesity confronts clinicians with dosing problems in the (extreme) overweight population. Obesity has a great impact on key organs that play a role in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, however the ultimate impact of these changes on

  1. Population Pharmacokinetics of Tenofovir in Human Immunodeficiency Virus-Infected Patients Taking Highly Active Antiretroviral Therapy

    OpenAIRE

    Jullien, Vincent; Tréluyer, Jean-Marc; Rey, Elisabeth; Jaffray, Patrick; Krivine, Anne; Moachon, Laurence; Lillo-Le Louet, Agnès; Lescoat, Anne; Dupin, Nicolas; Salmon, Dominique; Pons, Gérard; Urien, Saïk

    2005-01-01

    The influence of renal function on tenofovir pharmacokinetics was investigated in 193 human immunodeficiency virus (HIV)-infected patients by the use of a population approach performed with the nonlinear mixed effects modeling program NONMEM. Tenofovir pharmacokinetics was well described by a two-compartment open model in which the absorption and the distribution rate constants are equal. Typical population estimates of apparent central distribution volume (Vc/F), peripheral distribution volu...

  2. Population pharmacokinetics of buprenorphine following a two-stage intravenous infusion in healthy volunteers

    DEFF Research Database (Denmark)

    Jensen, Mette Lykke; Foster, David J.R.; Upton, Richard N.

    2007-01-01

    The aim of this investigation was to characterize the pharmacokinetics of buprenorphine following administration of an intravenous (i.v.) infusion. To date, the population kinetics of buprenorphine has been described for bolus administration only.......The aim of this investigation was to characterize the pharmacokinetics of buprenorphine following administration of an intravenous (i.v.) infusion. To date, the population kinetics of buprenorphine has been described for bolus administration only....

  3. Population pharmacokinetic model of transdermal nicotine delivered from a matrix-type patch.

    Science.gov (United States)

    Linakis, Matthew W; Rower, Joseph E; Roberts, Jessica K; Miller, Eleanor I; Wilkins, Diana G; Sherwin, Catherine M T

    2017-12-01

    Nicotine addiction is an issue faced by millions of individuals worldwide. As a result, nicotine replacement therapies, such as transdermal nicotine patches, have become widely distributed and used. While the pharmacokinetics of transdermal nicotine have been extensively described using noncompartmental methods, there are few data available describing the between-subject variability in transdermal nicotine pharmacokinetics. The aim of this investigation was to use population pharmacokinetic techniques to describe this variability, particularly as it pertains to the absorption of nicotine from the transdermal patch. A population pharmacokinetic parent-metabolite model was developed using plasma concentrations from 25 participants treated with transdermal nicotine. Covariates tested in this model included: body weight, body mass index, body surface area (calculated using the Mosteller equation) and sex. Nicotine pharmacokinetics were best described with a one-compartment model with absorption based on a Weibull distribution and first-order elimination and a single compartment for the major metabolite, cotinine. Body weight was a significant covariate on apparent volume of distribution of nicotine (exponential scaling factor 1.42). After the inclusion of body weight in the model, no other covariates were significant. This is the first population pharmacokinetic model to describe the absorption and disposition of transdermal nicotine and its metabolism to cotinine and the pharmacokinetic variability between individuals who were administered the patch. © 2017 The British Pharmacological Society.

  4. Selected pharmacokinetic parameters for cefovecin in hens and green iguanas

    DEFF Research Database (Denmark)

    Thuesen, Line Risager; Bertelsen, Mads Frost; Brimer, Leon

    2009-01-01

    hens and green iguanas, following subcutaneous injections with 10 mg cefovecin / kg bodyweight. Preliminary studies in eight additional species of birds and reptiles were performed and results were compared with the parameters found in hens and green iguanas. The kinetics were characterized by rapid...

  5. Population Pharmacokinetics of Cladribine in Patients with Multiple Sclerosis.

    Science.gov (United States)

    Savic, Radojka M; Novakovic, Ana M; Ekblom, Marianne; Munafo, Alain; Karlsson, Mats O

    2017-10-01

    The aims of this study were to characterize the concentration-time course of cladribine (CdA) and its main metabolite 2-chloroadenine (CAde), estimate interindividual variability in pharmacokinetics (PK), and identify covariates explaining variability in the PK of CdA. This population PK analysis was based on the combined dataset from four clinical studies in patients with multiple sclerosis (MS): three phase I studies, including one food and one drug-drug interaction study, and one phase III clinical study. Plasma and urine concentration data of CdA and CAde were modeled simultaneously. The analysis comprised a total of 2619 CdA and CAde plasma and urine concentration observations from 173 patients with MS who received an intravenous infusion or oral tablet doses of CdA as a single agent or in combination with interferon (IFN) β-1a. CdA PK data were best described by a three-compartment model, while a one-compartment model best described the PK of CAde. CdA renal clearance (CL R ) was correlated with creatinine clearance (CL CR ), predicting a decrease in the total clearance of 19%, 30% and 40% for patients with mild (CL CR  = 65 ml/min), moderate (CL CR  = 40 ml/min) and severe (CL CR  = 20 ml/min) renal impairment, respectively. Food decreased the extent of CdA absorption by 11.2% and caused an absorption delay. Coadministration with IFNβ-1a was found to increase non-CL R (CL NR ) by 21%, resulting in an increase of 11% in total clearance. Both CdA and CAde displayed linear PK after intravenous and oral administration of CdA, with CdA renal function depending on CL CR . Trial registration number for study 25643: NCT00213135.

  6. Population Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Malaria

    OpenAIRE

    Tarning, Joel; Rijken, Marcus J.; McGready, Rose; Phyo, Aung Pyae; Hanpithakpong, Warunee; Day, Nicholas P. J.; White, Nicholas J.; Nosten, François; Lindegardh, Niklas

    2012-01-01

    Pregnant women are particularly vulnerable to malaria. The pharmacokinetic properties of antimalarial drugs are often affected by pregnancy, resulting in lower drug concentrations and a consequently higher risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of piperaquine and dihydroartemisinin in pregnant and nonpregnant women with uncomplicated malaria. Twenty-four pregnant and 24 matched nonpregnant women on the Thai-Myanmar boar...

  7. [Application of Fourier amplitude sensitivity test in Chinese healthy volunteer population pharmacokinetic model of tacrolimus].

    Science.gov (United States)

    Guan, Zheng; Zhang, Guan-min; Ma, Ping; Liu, Li-hong; Zhou, Tian-yan; Lu, Wei

    2010-07-01

    In this study, we evaluated the influence of different variance from each of the parameters on the output of tacrolimus population pharmacokinetic (PopPK) model in Chinese healthy volunteers, using Fourier amplitude sensitivity test (FAST). Besides, we estimated the index of sensitivity within whole course of blood sampling, designed different sampling times, and evaluated the quality of parameters' and the efficiency of prediction. It was observed that besides CL1/F, the index of sensitivity for all of the other four parameters (V1/F, V2/F, CL2/F and k(a)) in tacrolimus PopPK model showed relatively high level and changed fast with the time passing. With the increase of the variance of k(a), its indices of sensitivity increased obviously, associated with significant decrease in sensitivity index for the other parameters, and obvious change in peak time as well. According to the simulation of NONMEM and the comparison among different fitting results, we found that the sampling time points designed according to FAST surpassed the other time points. It suggests that FAST can access the sensitivities of model parameters effectively, and assist the design of clinical sampling times and the construction of PopPK model.

  8. Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria

    Directory of Open Access Journals (Sweden)

    Bose Carl

    2011-05-01

    Full Text Available Abstract Background The World Health Organization endorses the use of artemisinin-based combination therapy for treatment of acute uncomplicated falciparum malaria in the second and third trimesters of pregnancy. However, the effects of pregnancy on the pharmacokinetics of artemisinin derivatives, such as artesunate (AS, are poorly understood. In this analysis, the population pharmacokinetics of oral AS, and its active metabolite dihydroartemisinin (DHA, were studied in pregnant and non-pregnant women at the Kingasani Maternity Clinic in the DRC. Methods Data were obtained from 26 pregnant women in the second (22 - 26 weeks or the third (32 - 36 weeks trimester of pregnancy and from 25 non-pregnant female controls. All subjects received 200 mg AS. Plasma AS and DHA were measured using a validated LC-MS method. Estimates for pharmacokinetic and variability parameters were obtained through nonlinear mixed effects modelling. Results A simultaneous parent-metabolite model was developed consisting of mixed zero-order, lagged first-order absorption of AS, a one-compartment model for AS, and a one-compartment model for DHA. Complete conversion of AS to DHA was assumed. The model displayed satisfactory goodness-of-fit, stability, and predictive ability. Apparent clearance (CL/F and volume of distribution (V/F estimates, with 95% bootstrap confidence intervals, were as follows: 195 L (139-285 L for AS V/F, 895 L/h (788-1045 L/h for AS CL/F, 91.4 L (78.5-109 L for DHA V/F, and 64.0 L/h (55.1-75.2 L/h for DHA CL/F. The effect of pregnancy on DHA CL/F was determined to be significant, with a pregnancy-associated increase in DHA CL/F of 42.3% (19.7 - 72.3%. Conclusions In this analysis, pharmacokinetic modelling suggests that pregnant women have accelerated DHA clearance compared to non-pregnant women receiving orally administered AS. These findings, in conjunction with a previous non-compartmental analysis of the modelled data, provide further evidence that

  9. Correction for photobleaching in dynamic fluorescence microscopy: application in the assessment of pharmacokinetic parameters in ultrasound-mediated drug delivery

    International Nuclear Information System (INIS)

    Derieppe, M; Bos, C; De Greef, M; Moonen, C; Denis de Senneville, B

    2016-01-01

    We have previously demonstrated the feasibility of monitoring ultrasound-mediated uptake of a hydrophilic model drug in real time with dynamic confocal fluorescence microscopy. In this study, we evaluate and correct the impact of photobleaching to improve the accuracy of pharmacokinetic parameter estimates. To model photobleaching of the fluorescent model drug SYTOX Green, a photobleaching process was added to the current two-compartment model describing cell uptake. After collection of the uptake profile, a second acquisition was performed when SYTOX Green was equilibrated, to evaluate the photobleaching rate experimentally. Photobleaching rates up to 5.0 10 −3 s −1 were measured when applying power densities up to 0.2 W.cm −2 . By applying the three-compartment model, the model drug uptake rate of 6.0 10 −3 s −1 was measured independent of the applied laser power. The impact of photobleaching on uptake rate estimates measured by dynamic fluorescence microscopy was evaluated. Subsequent compensation improved the accuracy of pharmacokinetic parameter estimates in the cell population subjected to sonopermeabilization. (paper)

  10. Influence of Erroneous Patient Records on Population Pharmacokinetic Modeling and Individual Bayesian Estimation

    NARCIS (Netherlands)

    van der Meer, Aize Franciscus; Touw, Daniel J.; Marcus, Marco A. E.; Neef, Cornelis; Proost, Johannes H.

    2012-01-01

    Background: Observational data sets can be used for population pharmacokinetic (PK) modeling. However, these data sets are generally less precisely recorded than experimental data sets. This article aims to investigate the influence of erroneous records on population PK modeling and individual

  11. Direct reconstruction of pharmacokinetic parameters in dynamic fluorescence molecular tomography by the augmented Lagrangian method

    Science.gov (United States)

    Zhu, Dianwen; Zhang, Wei; Zhao, Yue; Li, Changqing

    2016-03-01

    Dynamic fluorescence molecular tomography (FMT) has the potential to quantify physiological or biochemical information, known as pharmacokinetic parameters, which are important for cancer detection, drug development and delivery etc. To image those parameters, there are indirect methods, which are easier to implement but tend to provide images with low signal-to-noise ratio, and direct methods, which model all the measurement noises together and are statistically more efficient. The direct reconstruction methods in dynamic FMT have attracted a lot of attention recently. However, the coupling of tomographic image reconstruction and nonlinearity of kinetic parameter estimation due to the compartment modeling has imposed a huge computational burden to the direct reconstruction of the kinetic parameters. In this paper, we propose to take advantage of both the direct and indirect reconstruction ideas through a variable splitting strategy under the augmented Lagrangian framework. Each iteration of the direct reconstruction is split into two steps: the dynamic FMT image reconstruction and the node-wise nonlinear least squares fitting of the pharmacokinetic parameter images. Through numerical simulation studies, we have found that the proposed algorithm can achieve good reconstruction results within a small amount of time. This will be the first step for a combined dynamic PET and FMT imaging in the future.

  12. Optimal designs for population pharmacokinetic studies of oral artesunate in patients with uncomplicated falciparum malaria

    Directory of Open Access Journals (Sweden)

    Lindegardh Niklas

    2011-07-01

    Full Text Available Abstract Background Currently, population pharmacokinetic (PK studies of anti-malarial drugs are designed primarily by the logistical and ethical constraints of taking blood samples from patients, and the statistical models that are fitted to the data are not formally considered. This could lead to imprecise estimates of the target PK parameters, and/or designs insufficient to estimate all of the parameters. Optimal design methodology has been developed to determine blood sampling schedules that will yield precise parameter estimates within the practical constraints of sampling the study populations. In this work optimal design methods were used to determine sampling designs for typical future population PK studies of dihydroartemisinin, the principal biologically active metabolite of oral artesunate. Methods Optimal designs were derived using freely available software and were based on appropriate structural PK models from an analysis of data or the literature and key sampling constraints identified in a questionnaire sent to active malaria researchers (3-4 samples per patient, at least 15 minutes between samples. The derived optimal designs were then evaluated via simulation-estimation. Results The derived optimal sampling windows were 17 to 29 minutes, 30 to 57 minutes, 2.5 to 3.7 hours and 5.8 to 6.6 hours for non-pregnant adults; 16 to 29 minutes, 31 minutes to 1 hour, 2.0 to 3.4 hours and 5.5 to 6.6 hours for designs with non-pregnant adults and children and 35 to 59 minutes, 1.2 to 3.4 hours, 3.4 to 4.9 hours and 6.0 to 8.0 hours for pregnant women. The optimal designs resulted in acceptable precision of the PK parameters. Conclusions The proposed sampling designs in this paper are robust and efficient and should be considered in future PK studies of oral artesunate where only three or four blood samples can be collected.

  13. Gaussian process inference for estimating pharmacokinetic parameters of dynamic contrast-enhanced MR images.

    Science.gov (United States)

    Wang, Shijun; Liu, Peter; Turkbey, Baris; Choyke, Peter; Pinto, Peter; Summers, Ronald M

    2012-01-01

    In this paper, we propose a new pharmacokinetic model for parameter estimation of dynamic contrast-enhanced (DCE) MRI by using Gaussian process inference. Our model is based on the Tofts dual-compartment model for the description of tracer kinetics and the observed time series from DCE-MRI is treated as a Gaussian stochastic process. The parameter estimation is done through a maximum likelihood approach and we propose a variant of the coordinate descent method to solve this likelihood maximization problem. The new model was shown to outperform a baseline method on simulated data. Parametric maps generated on prostate DCE data with the new model also provided better enhancement of tumors, lower intensity on false positives, and better boundary delineation when compared with the baseline method. New statistical parameter maps from the process model were also found to be informative, particularly when paired with the PK parameter maps.

  14. Population pharmacokinetics of artesunate and dihydroartemisinin following single- and multiple-dosing of oral artesunate in healthy subjects

    Directory of Open Access Journals (Sweden)

    Kirsch Lee E

    2009-12-01

    Full Text Available Abstract Background The population pharmacokinetics of artesunate (AS and its active metabolite dihydroartemisinin (DHA were studied in healthy subjects receiving single- or multiple-dosing of AS orally either in combination with pyronaridine (PYR or as a monotherapy with or without food. Methods Data from 118 concentration-time profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects received 2-5 mg/kg of single- and multiple-dosing of oral AS either in combination with PYR or as a monotherapy with or without food. Plasma AS and DHA were measured simultaneously using a validated liquid chromatography- mass spectrometric method with a lower limit of quantification of 1 ng/mL for both AS and DHA. Nonlinear mixed-effect modelling was used to obtain the pharmacokinetic and variability (inter-individual and residual variability parameter estimates. Results A novel parent-metabolite pharmacokinetic model consisting of a dosing compartment, a central compartment for AS, a central compartment and a peripheral compartment for DHA was developed. AS and DHA data were modelled simultaneously assuming stoichiometric conversion to DHA. AS was rapidly absorbed with a population estimate of absorption rate constant (Ka of 3.85 h-1. The population estimates of apparent clearance (CL/F and volume of distribution (V2/F for AS were 1190 L/h with 36.2% inter-individual variability (IIV and 1210 L with 57.4% IIV, respectively. For DHA, the population estimates of apparent clearance (CLM/F and central volume of distribution (V3/F were 93.7 L/h with 28% IIV and 97.1 L with 30% IIV, respectively. The population estimates of apparent inter-compartmental clearance (Q/F and peripheral volume of distribution (V4/F for DHA were 5.74 L/h and 18.5 L, respectively. Intake of high-fat and high-caloric meal prior to the drug administration resulted in 84% reduction in Ka. Body weight impacted CLM/F, such that a unit change in

  15. Population pharmacokinetic model of THC integrates oral, intravenous, and pulmonary dosing and characterizes short- and long-term pharmacokinetics.

    Science.gov (United States)

    Heuberger, Jules A A C; Guan, Zheng; Oyetayo, Olubukayo-Opeyemi; Klumpers, Linda; Morrison, Paul D; Beumer, Tim L; van Gerven, Joop M A; Cohen, Adam F; Freijer, Jan

    2015-02-01

    Δ(9)-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately describe the terminal phase of THC to describe accumulation of the drug. In early clinical research, the THC challenge test can be optimized through more accurate predictions of the dosing sequence and the wash-out between occasions in a crossover setting, which is mainly determined by the terminal half-life of the compound. The purpose of this study is to better quantify the long-term pharmacokinetics of THC. A population-based PK model for THC was developed describing the profile up to 48 h after an oral, intravenous, and pulmonary dose of THC in humans. In contrast to earlier models, the current model integrates all three major administration routes and covers the long terminal phase of THC. Results show that THC has a fast initial and intermediate half-life, while the apparent terminal half-life is long (21.5 h), with a clearance of 38.8 L/h. Because the current model characterizes the long-term pharmacokinetics, it can be used to assess the accumulation of THC in a multiple-dose setting and to forecast concentration profiles of the drug under many different dosing regimens or administration routes. Additionally, this model could provide helpful insights into the THC challenge test used for the development of (novel) compounds targeting the cannabinoid system for different therapeutic applications and could improve decision making in future clinical trials.

  16. Population pharmacokinetics of tamsulosin hydrochloride in paediatric patients with neuropathic and non-neuropathic bladder

    Science.gov (United States)

    Tsuda, Yasuhiro; Tatami, Shinji; Yamamura, Norio; Tadayasu, Yusuke; Sarashina, Akiko; Liesenfeld, Karl-Heinz; Staab, Alexander; Schäfer, Hans-Günter; Ieiri, Ichiro; Higuchi, Shun

    2010-01-01

    AIMS The main objective of this study was to characterize the population pharmacokinetics of tamsulosin hydrochloride (HCl) in paediatric patients with neuropathic and non-neuropathic bladder. A secondary objective was to compare the pharmacokinetics in paediatric patients and adults. METHODS Tamsulosin HCl plasma concentrations in 1082 plasma samples from 189 paediatric patients (age range 2–16 years) were analyzed with NONMEM, applying a one compartment model with first-order absorption. Based on the principles of allometry, body weight was incorporated in the base model, along with fixed allometric exponents. Covariate analysis was performed by means of a stepwise forward inclusion and backward elimination procedure. Simulations based on the final model were used to compare the pharmacokinetics with those in adults. RESULTS Beside the priori-implemented body weight, only α1-acid glycoprotein had an effect on both apparent clearance and apparent volume of distribution. No other investigated covariates, including gender, age, race, patient population and concomitant therapy with anti-cholinergics, significantly affected the pharmacokinetics of tamsulosin HCl (P tamsulosin HCl in paediatric patients was established and it described the data well. There was no major difference in the pharmacokinetics of tamsulosin HCl between paediatric patients (age range 2–16 years) and adults when the effect of body weight was taken into consideration. PMID:20642551

  17. Pragmatic pharmacology: population pharmacokinetic analysis of fentanyl using remnant samples from children after cardiac surgery

    Science.gov (United States)

    Van Driest, Sara L.; Marshall, Matthew D.; Hachey, Brian; Beck, Cole; Crum, Kim; Owen, Jill; Smith, Andrew H.; Kannankeril, Prince J.; Woodworth, Alison; Caprioli, Richard M.

    2016-01-01

    Aims One barrier contributing to the lack of pharmacokinetic (PK) data in paediatric populations is the need for serial sampling. Analysis of clinically obtained specimens and data may overcome this barrier. To add evidence for the feasibility of this approach, we sought to determine PK parameters for fentanyl in children after cardiac surgery using specimens and data generated in the course of clinical care, without collecting additional blood samples. Methods We measured fentanyl concentrations in plasma from leftover clinically‐obtained specimens in 130 paediatric cardiac surgery patients and successfully generated a PK dataset using drug dosing data extracted from electronic medical records. Using a population PK approach, we estimated PK parameters for this population, assessed model goodness‐of‐fit and internal model validation, and performed subset data analyses. Through simulation studies, we compared predicted fentanyl concentrations using model‐driven weight‐adjusted per kg vs. fixed per kg fentanyl dosing. Results Fentanyl clearance for a 6.4 kg child, the median weight in our cohort, is 5.7 l h–1 (2.2–9.2 l h–1), similar to values found in prior formal PK studies. Model assessment and subset analyses indicated the model adequately fit the data. Of the covariates studied, only weight significantly impacted fentanyl kinetics, but substantial inter‐individual variability remained. In simulation studies, model‐driven weight‐adjusted per kg fentanyl dosing led to more consistent therapeutic fentanyl concentrations than fixed per kg dosing. Conclusions We show here that population PK modelling using sparse remnant samples and electronic medical records data provides a powerful tool for assessment of drug kinetics and generation of individualized dosing regimens. PMID:26861166

  18. A mechanism-based binding model for the population pharmacokinetics and pharmacodynamics of omalizumab

    Science.gov (United States)

    Hayashi, Naoto; Tsukamoto, Yuko; Sallas, William M; Lowe, Philip J

    2007-01-01

    Aim Omalizumab, a humanized IgG monoclonal antibody that binds to human immunoglobulin E (IgE), interrupts the allergic cascade in asthmatic patients. The aim was to compare simultaneously drug exposure and IgE biomarker responses in Japanese and White patient populations. Methods An instantaneous equilibrium drug–ligand binding and turnover population model was built from 202 Japanese patients. A posterior predictive evaluation for the steady-state distributions of omalizumab and IgE was then carried out against 531 White patients. Results The mean parameters estimated from the Japanese patients were as follows: omalizumab clearance 7.32 ± 0.153 ml h−1, IgE clearance 71.0 ± 4.68 ml h−1 and the difference between that for omalizumab and the complex 5.86 ± 0.920 ml h−1, the volume of distribution for omalizumab and IgE 5900 ± 107 ml, and that for the complex 3630 ± 223 ml, the rate of IgE production 30.3 ± 2.04 µg h−1. Half-lives of IgG (23 days) and IgE (2.4 days) were close to previous reports. The dissociation constant for binding, 1.07 nM, was similar to in vitro values. Clearance and volume of distribution for omalizumab varied with bodyweight, whereas the clearance and rate of production of IgE were predicted accurately by baseline IgE. Overall, these covariates explained much of the interindividual variability. Conclusions The predictiveness of the Japanese model was confirmed by Monte-Carlo simulations for a White population, also providing evidence that the pharmacokinetics of omalizumab and IgE were similar in these two populations. Furthermore, the model enabled the estimation of not only omalizumab disposition parameters, but also the binding with and the rate of production, distribution and elimination of its target, IgE. PMID:17096680

  19. Population pharmacokinetics of exendin-(9-39) and clinical dose selection in patients with congenital hyperinsulinism.

    Science.gov (United States)

    Ng, Chee M; Tang, Fei; Seeholzer, Steven H; Zou, Yixuan; De León, Diva D

    2018-03-01

    Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycaemia in infants and children. Exendin-(9-39), an inverse glucagon-like peptide 1 (GLP-1) agonist, is a novel therapeutic agent for HI that has demonstrated glucose-raising effect. We report the first population pharmacokinetic (PopPK) model of the exendin-(9-39) in patients with HI and propose the optimal dosing regimen for future clinical trials in neonates with HI. A total of 182 pharmacokinetic (PK) observations from 26 subjects in three clinical studies were included for constructing the PopPK model using first order conditional estimation (FOCE) with interaction method in nonlinear mixed-effects modelling (NONMEM). Exposure metrics (area under the curve [AUC] and maximum plasma concentration [C max ]) at no observed adverse effect levels (NOAELs) in rats and dogs were determined in toxicology studies. Observed concentration-time profiles of exendin-(9-39) were described by a linear two-compartmental PK model. Following allometric scaling of PK parameters, age and creatinine clearance did not significantly affect clearance. The calculated clearance and elimination half-life for adult subjects with median weight of 69 kg were 11.8 l h -1 and 1.81 h, respectively. The maximum recommended starting dose determined from modelling and simulation based on the AUC 0-last at the NOAEL and predicted AUC 0-inf using the PopPK model was 27 mg kg -1  day -1 intravenously. This is the first study to investigate the PopPK of exendin-(9-39) in humans. The final PopPK model was successfully used with preclinical toxicology findings to propose the optimal dosing regimen of exendin-(9-39) for clinical studies in neonates with HI, allowing for a more targeted dosing approach to achieve desired glycaemic response. © 2017 The British Pharmacological Society.

  20. Population Pharmacokinetics of Pyrimethamine and Sulfadoxine in Children Treated for Congenital Toxoplasmosis

    Science.gov (United States)

    Corvaisier, Stéphane; Charpiat, Bruno; Mounier, Cyril; Wallon, Martine; Leboucher, Gilles; Al Kurdi, Mounzer; Chaulet, Jean-François; Peyron, François

    2004-01-01

    The population pharmacokinetics of pyrimethamine (PYR) and sulfadoxine (SDX) for a group of 32 children with congenital toxoplasmosis was investigated by nonparametric modeling analysis. A one-compartment model was used as the structural model, and individual pharmacokinetic parameters were estimated by Bayesian modeling. PYR (1.25 mg/kg of body weight) and SDX (25 mg/kg) were administered orally every 10 days for 1 year, with adjustment of the dose to body weight every 3 months. Drug concentrations were measured by high-performance liquid chromatography. A total of 101 measurements in serum were available for both drugs. Mean absorption rate constants, volumes of distribution, elimination rate constants, and half-lives were 0.915 h−1, 4.379 liters/kg, 0.00839 h−1, and 5.5 days for PYR and 1.659 h−1, 0.392 liters/kg, 0.00526 h−1, and 6.6 days for SDX, respectively. Wide interindividual variability was observed. The estimated minimum and maximum concentrations of PYR in serum differed 8- and 25-fold among patients, respectively, and those of SDX differed 4- and 5-fold, respectively. Increases in the concentration of PYR were observed for eight children, and increases in the SDX concentration were observed for seven children. Serum PYR-SDX concentrations are unpredictable even when the dose is standardized for body weight. The concentrations of the PYR-SDX combination that are most efficacious for children have not yet been established. A model such as ours, associated with long-term follow-up, is needed to study the correlation between exposure to these two drugs and clinical outcome in children. PMID:15388436

  1. [Pharmacokinetic monitoring of 24-hour infusion of methotrexate in an adult population with non-Hodgkin lymphoma].

    Science.gov (United States)

    Fernández Megía, M J; Alós Almiñana, M; Esquer Borrás, J

    2004-01-01

    To describe the behavior and variability of methotrexate (MTX) pharmacokinetic parameters in patients with non-Hodgkin lymphoma (NHL) and to suggest a monitoring system to optimize sample collection using a bayesian method. Two adult patient groups diagnosed with different NHL types were studied. Group I was made up of 9 patients aged 53 +/- 16 years who received MTX at a mean dose of 1.652 +/- 327 mg per course. Group II was made up of 7 patients aged 53 +/- 14 years who received MTX at a mean dose of 1.862 +/- 220 mg per course. No statistically significant differences between groups were seen. Serum MTX measurements were performed using polarized immunofluorescence (TDx system). The pharmacokinetic analysis was performed using Abbottbase Pharmacokinetics Systems (PKS) software, adjusting experimental data according to a bicompartmental linear model for intravenous delivery using non-linear regression in Group I and Bayesian estimates in Group II. By estimating mean square error and linear regression between predicted and experimental concentrations, the capability of the Bayesian method implemented in PKS to predict plasma MTX concentration at 48 hours post-infusion was evaluated. The safety of MTX therapy was assessed using patient medical histories and then scoring toxicity using the WHO scale. Pharmacokinetic parameters obtained for group I included: alpha (h(-1)) = 0.38 +/- 0.12; beta (h(-1)) = 0.07 +/- 0.03; K12 (h(-1)) = 0.02 +/- 0.02; K21 (h(-1)) = 0.09 +/- 0.09; K13 (h(-1)) = 0.34 +/- 0.12; Vc (l/kg) = 0.53 +/- 0.23; Vss (l/kg) = 0.62 +/- 0.26; Cl (l/kg.h) = 0.16 +/- 0.06. The error for the PKS population model in measuring plasma MTX concentration at 48 hours post-infusion in Group II was calculated in accordance with three sampling schemes -12 h, 24 h, and both. It was -14.58 x 10(-3), -15.70 x 10(-3) and -14.67 x 10(-3), respectively. Eqm was 9.58 x 10(-3), 2.39 x 10(-3), and 1.02 x 10(-3), respectively. An MTX monitoring scheme is suggested based on

  2. Relative sensitivities of DCE-MRI pharmacokinetic parameters to arterial input function (AIF) scaling.

    Science.gov (United States)

    Li, Xin; Cai, Yu; Moloney, Brendan; Chen, Yiyi; Huang, Wei; Woods, Mark; Coakley, Fergus V; Rooney, William D; Garzotto, Mark G; Springer, Charles S

    2016-08-01

    Dynamic-Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) has been used widely for clinical applications. Pharmacokinetic modeling of DCE-MRI data that extracts quantitative contrast reagent/tissue-specific model parameters is the most investigated method. One of the primary challenges in pharmacokinetic analysis of DCE-MRI data is accurate and reliable measurement of the arterial input function (AIF), which is the driving force behind all pharmacokinetics. Because of effects such as inflow and partial volume averaging, AIF measured from individual arteries sometimes require amplitude scaling for better representation of the blood contrast reagent (CR) concentration time-courses. Empirical approaches like blinded AIF estimation or reference tissue AIF derivation can be useful and practical, especially when there is no clearly visible blood vessel within the imaging field-of-view (FOV). Similarly, these approaches generally also require magnitude scaling of the derived AIF time-courses. Since the AIF varies among individuals even with the same CR injection protocol and the perfect scaling factor for reconstructing the ground truth AIF often remains unknown, variations in estimated pharmacokinetic parameters due to varying AIF scaling factors are of special interest. In this work, using simulated and real prostate cancer DCE-MRI data, we examined parameter variations associated with AIF scaling. Our results show that, for both the fast-exchange-limit (FXL) Tofts model and the water exchange sensitized fast-exchange-regime (FXR) model, the commonly fitted CR transfer constant (K(trans)) and the extravascular, extracellular volume fraction (ve) scale nearly proportionally with the AIF, whereas the FXR-specific unidirectional cellular water efflux rate constant, kio, and the CR intravasation rate constant, kep, are both AIF scaling insensitive. This indicates that, for DCE-MRI of prostate cancer and possibly other cancers, kio and kep may be more suitable imaging

  3. Simultaneous versus sequential pharmacokinetic-pharmacodynamic population analysis using an iterative two-stage Bayesian technique

    NARCIS (Netherlands)

    Proost, Johannes H.; Schiere, Sjouke; Eleveld, Douglas J.; Wierda, J. Mark K. H.

    A method for simultaneous pharmacokinetic-pharmacodynamic (PK-PD) population analysis using an Iterative Two-Stage Bayesian (ITSB) algorithm was developed. The method was evaluated using clinical data and Monte Carlo simulations. Data from a clinical study with rocuronium in nine anesthetized

  4. Population pharmacokinetics of levamisole in children with steroid-sensitive nephrotic syndrome

    NARCIS (Netherlands)

    Kreeftmeijer-Vegter, A.R.; Dorlo, T.P.C.; Gruppen, M.P.; De Boer, A.; De Vries, P.J.

    2015-01-01

    Aim The aim was to investigate the population pharmacokinetics of levamisole in children with steroid-sensitive nephrotic syndrome. Methods Non-linear mixed effects modelling was performed on samples collected during a randomized controlled trial. Samples were collected from children who were

  5. Population pharmacokinetics of levamisole in children with steroid-sensitive nephrotic syndrome

    NARCIS (Netherlands)

    Kreeftmeijer-Vegter, A. R.; Dorlo, T. P. C.; Gruppen, M. P.; de Boer, A. [=Anthonius; de Vries, P. J.

    2015-01-01

    The aim was to investigate the population pharmacokinetics of levamisole in children with steroid-sensitive nephrotic syndrome. Non-linear mixed effects modelling was performed on samples collected during a randomized controlled trial. Samples were collected from children who were receiving 2.5 mg

  6. Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients

    NARCIS (Netherlands)

    Simpson, Julie A.; Agbenyega, Tsiri; Barnes, Karen I.; Di Perri, Gianni; Folb, Peter; Gomes, Melba; Krishna, Sanjeev; Krudsood, Srivicha; Looareesuwan, Sornchai; Mansor, Sharif; McIlleron, Helen; Miller, Raymond; Molyneux, Malcolm; Mwenechanya, James; Navaratnam, Visweswaran; Nosten, Francois; Olliaro, Piero; Pang, Lorrin; Ribeiro, Isabela; Tembo, Madalitso; van Vugt, Michele; Ward, Steve; Weerasuriya, Kris; Win, Kyaw; White, Nicholas J.

    2006-01-01

    Intra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with

  7. Population pharmacokinetics of dihydroartemisinin and piperaquine in pregnant and nonpregnant women with uncomplicated malaria.

    Science.gov (United States)

    Tarning, Joel; Rijken, Marcus J; McGready, Rose; Phyo, Aung Pyae; Hanpithakpong, Warunee; Day, Nicholas P J; White, Nicholas J; Nosten, François; Lindegardh, Niklas

    2012-04-01

    Pregnant women are particularly vulnerable to malaria. The pharmacokinetic properties of antimalarial drugs are often affected by pregnancy, resulting in lower drug concentrations and a consequently higher risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of piperaquine and dihydroartemisinin in pregnant and nonpregnant women with uncomplicated malaria. Twenty-four pregnant and 24 matched nonpregnant women on the Thai-Myanmar boarder were treated with a standard fixed oral 3-day treatment, and venous plasma concentrations of both drugs were measured frequently for pharmacokinetic evaluation. Population pharmacokinetics were evaluated with nonlinear mixed-effects modeling. The main pharmacokinetic finding was an unaltered total exposure to piperaquine but reduced exposure to dihydroartemisinin in pregnant compared to nonpregnant women with uncomplicated malaria. Piperaquine was best described by a three-compartment disposition model with a 45% higher elimination clearance and a 47% increase in relative bioavailability in pregnant women compared with nonpregnant women. The resulting net effect of pregnancy was an unaltered total exposure to piperaquine but a shorter terminal elimination half-life. Dihydroartemisinin was best described by a one-compartment disposition model with a 38% lower relative bioavailability in pregnant women than nonpregnant women. The resulting net effect of pregnancy was a decreased total exposure to dihydroartemisinin. The shorter terminal elimination half-life of piperaquine and lower exposure to dihydroartemisinin will shorten the posttreatment prophylactic effect and might affect cure rates. The clinical impact of these pharmacokinetic findings in pregnant women with uncomplicated malaria needs to be evaluated in larger series.

  8. Role of quantitative pharmacokinetic parameter (transfer constant: Ktrans in the characterization of breast lesions on MRI

    Directory of Open Access Journals (Sweden)

    Jena Amarnath

    2013-01-01

    Full Text Available Background: The semi-quantitative analysis of the time-intensity curves in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI has a limited specificity due to overlapping enhancement patterns after gadolinium administration. With the advances in technology and faster sequences, imaging of the entire breast can be done in a few seconds, which allows measuring the transit of contrast (transfer constant: K trans through the vascular bed at capillary level that reflects quantitative measure of porosity/permeability of tumor vessels. Aim: Our study aims to evaluate the pharmacokinetic parameter K trans for enhancing breast lesions and correlate it with histopathology, and assess accuracy, sensitivity, and specificity of this parameter in discriminating benign and malignant breast lesions. Materials and Methods: One hundred and fifty-one women with 216 histologically proved enhancing breast lesions underwent high temporal resolution DCE-MRI for the early dynamic analysis for calculation of pharmacokinetic parameters (K trans using standard two compartment model. The calculated values of K trans were correlated with histopathology to calculate the sensitivity, specificity, and accuracy. Results: Receiver operating characteristic (ROC curve analysis revealed a mean K trans value of 0.56, which reliably distinguished benign and malignant breast lesions with a sensitivity of 91.1% and specificity of 90.3% with an overall accuracy of 89.3%. The area under curve (AUC was 0.907. Conclusion: K trans is a reliable quantitative parameter for characterizing benign and malignant lesions in routine DCE-MRI of breasts.

  9. Population pharmacokinetics of oxaliplatin (85 mg/m(2)) in combination with 5-fluorouracil in patients with advanced colorectal cancer

    NARCIS (Netherlands)

    Kho, Y.H.; Jansman, F.G.A.; Prins, N.H.; Neef, C.; Brouwers, J.R.B.J.

    Pharmacokinetic (PK) studies of oxaliplatin, using a dose regimen of 85mg/m(2) are lacking. A PK model may be used in future studies to investigate the relationship between pharmacokinetics and dose limiting toxicity. The purpose of this study was to construct a population PK model to describe

  10. Obesity and drug pharmacology: a review of the influence of obesity on pharmacokinetic and pharmacodynamic parameters.

    Science.gov (United States)

    Smit, Cornelis; De Hoogd, Sjoerd; Brüggemann, Roger J M; Knibbe, Catherijne A J

    2018-03-01

    The rising prevalence of obesity confronts clinicians with dosing problems in the (extreme) overweight population. Obesity has a great impact on key organs that play a role in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, however the ultimate impact of these changes on how to adapt the dose may not always be known. Areas covered: In this review, physiological changes associated with obesity are discussed. An overview is provided on the alterations in absorption, distribution, drug metabolism and clearance in (morbid) obesity focusing on general principles that can be extracted from pharmacokinetic studies. Also, relevant pharmacodynamic considerations in obesity are discussed. Expert opinion: Over the last two decades, increased knowledge is generated on PK and PD in obesity. Future research should focus on filling in the knowledge gaps that remain, especially in connecting obesity-related physiological changes with changes in PK and/or PD and vice versa. Ultimately, this knowledge can be used to develop physiologically based PK and PD models on the basis of quantitative systems pharmacology principles. Moreover, efforts should focus on thorough prospective evaluation of developed model-based doses with subsequent implementation of these dosing recommendations in clinical practice.

  11. The effect of breed and sex on sulfamethazine, enrofloxacin, fenbendazole and flunixin meglumine pharmacokinetic parameters in swine.

    Science.gov (United States)

    Howard, J T; Baynes, R E; Brooks, J D; Yeatts, J L; Bellis, B; Ashwell, M S; Routh, P; O'Nan, A T; Maltecca, C

    2014-12-01

    Drug use in livestock has received increased attention due to welfare concerns and food safety. Characterizing heterogeneity in the way swine populations respond to drugs could allow for group-specific dose or drug recommendations. Our objective was to determine whether drug clearance differs across genetic backgrounds and sex for sulfamethazine, enrofloxacin, fenbendazole and flunixin meglumine. Two sires from each of four breeds were mated to a common sow population. The nursery pigs generated (n = 114) were utilized in a random crossover design. Drugs were administered intravenously and blood collected a minimum of 10 times over 48 h. A non-compartmental analysis of drug and metabolite plasma concentration vs. time profiles was performed. Within-drug and metabolite analysis of pharmacokinetic parameters included fixed effects of drug administration date, sex and breed of sire. Breed differences existed for flunixin meglumine (P-value<0.05; Cl, Vdss ) and oxfendazole (P-value<0.05, AUC0→∞ ). Sex differences existed for oxfendazole (P-value < 0.05; Tmax ) and sulfamethazine (P-value < 0.05, Cl). Differences in drug clearance were seen, and future work will determine the degree of additive genetic variation utilizing a larger population. © 2014 John Wiley & Sons Ltd.

  12. POPULATION PHARMACOKINETICS OF ENROFLOXACIN AND ITS METABOLITE CIPROFLOXACIN IN THE GREEN SEA URCHIN (STRONGYLOCENTROTUS DROEBACHIENSIS) FOLLOWING INTRACOELOMIC AND IMMERSION ADMINISTRATION.

    Science.gov (United States)

    Phillips, Brianne E; Harms, Craig A; Lewbart, Gregory A; Lahner, Lesanna L; Haulena, Martin; Rosenberg, Justin F; Papich, Mark G

    2016-03-01

    Sea urchin mass mortality events have been attributed to both infectious and noninfectious etiologies. Bacteria, including Vibrio spp. and Pseudoalteromonas spp., have been isolated during specific mortality events. Aquarium collection sea urchins are also subject to bacterial infections and could benefit from antimicrobial treatment, but pharmacokinetic studies have been lacking for this invertebrate group until recently. This study evaluated the pharmacokinetics of enrofloxacin and its active metabolite ciprofloxacin in the green sea urchin (Strongylocentrotus droebachiensis) after intracoelomic injection and medicated bath immersion administration. The utility of a population pharmacokinetic method using nonlinear mixed effects modeling (NLME) was also evaluated. Thirty sea urchins were assigned to either the injection or immersion group. Twelve study animals and three untreated controls were utilized for each administration method: enrofloxacin 10 mg/kg intracoelomic injection or a 6-hr enrofloxacin 10 mg/L immersion. Each animal was sampled four times from 0 to 120 hr. Water samples were collected during immersion treatment and posttreatment time points in both groups. Hemolymph and water sample drug concentrations were analyzed using high-performance liquid chromatography, and pharmacokinetic parameters were determined using an NLME population pharmacokinetic method. Enrofloxacin concentrations were fit to a two-compartment model with first-order input for the intracoelomic injection group. The enrofloxacin elimination half-life (t½), peak hemolymph concentration (CMAX), and area under the curve (AUC) were 38.82 hr, 90.92 μg/ml, and 1,199 hr·μg/ml, respectively. Enrofloxacin was modeled to a one-compartment model with first-order input for the immersion treatment. The enrofloxacin t½, CMAX, and AUC were 33.46 hr, 0.48 μg/ml, and 32.88 hr·μg/ml, respectively. Ciprofloxacin was detected in trace concentrations in all hemolymph samples, indicating

  13. Full-direct method for imaging pharmacokinetic parameters in dynamic fluorescence molecular tomography

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Guanglei, E-mail: guangleizhang@bjtu.edu.cn [Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084 (China); Department of Biomedical Engineering, School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044 (China); Pu, Huangsheng; Liu, Fei; Bai, Jing [Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084 (China); He, Wei [China Institute of Sport Science, Beijing 100061 (China); Luo, Jianwen, E-mail: luo-jianwen@tsinghua.edu.cn [Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084 (China); Center for Biomedical Imaging Research, School of Medicine, Tsinghua University, Beijing 100084 (China)

    2015-02-23

    Images of pharmacokinetic parameters (also known as parametric images) in dynamic fluorescence molecular tomography (FMT) can provide three-dimensional metabolic information for biological studies and drug development. However, the ill-posed nature of FMT and the high temporal variation of fluorophore concentration together make it difficult to obtain accurate parametric images in small animals in vivo. In this letter, we present a method to directly reconstruct the parametric images from the boundary measurements based on hybrid FMT/X-ray computed tomography (XCT) system. This method can not only utilize structural priors obtained from the XCT system to mitigate the ill-posedness of FMT but also make full use of the temporal correlations of boundary measurements to model the high temporal variation of fluorophore concentration. The results of numerical simulation and mouse experiment demonstrate that the proposed method leads to significant improvements in the reconstruction quality of parametric images.

  14. Effect of sampling schedule on pharmacokinetic parameter estimates of promethazine in astronauts

    Science.gov (United States)

    Boyd, Jason L.; Wang, Zuwei; Putcha, Lakshmi

    2005-08-01

    Six astronauts on the Shuttle Transport System (STS) participated in an investigation on the pharmacokinetics of promethazine (PMZ), a medication used for the treatment of space motion sickness (SMS) during flight. Each crewmember completed the protocol once during flight and repeated thirty days after returned to Earth. Saliva samples were collected at scheduled times for 72 h after PMZ administration; more frequent samples were collected on the ground than during flight owing to schedule constraints in flight. PMZ concentrations in saliva were determined by a liquid chromatographic/mass spectrometric (LC-MS) assay and pharmacokinetic parameters (PKPs) were calculated using actual flight and ground-based data sets and using time-matched sampling schedule on ground to that during flight. Volume of distribution (Vc) and clearance (Cls) decreased during flight compared to that from time-matched ground data set; however, ClS and Vc estimates were higher for all subjects when partial ground data sets were used for analysis. Area under the curve (AUC) normalized with administered dose was similar in flight and partial ground data; however AUC was significantly lower using time-matched sampling compared with the full data set on ground. Half life (t1/2) was longest during flight, shorter with matched-sampling schedule on ground and shortest when complete data set from ground was used. Maximum concentration (Cmax), time for Cmax (tmax), parameters of drug absorption, depicted a similar trend with lowest and longest respectively, during flight, lower with time- matched ground data and highest and shortest with full ground data.

  15. Solid state NMR and bioequivalence comparison of the pharmacokinetic parameters of two formulations of clindamycin

    KAUST Repository

    Al-Talla, Zeyad

    2011-01-01

    Objective: The purpose of this study was to compare the pharmacokinetic parameters and determine the bioequivalence of a generic formulation of clindamycin that is sold in the local markets in the Middle East (Clindox® 150 mg capsule; test) with a reference formulation (Dalacin C® 150 mg capsule) in healthy adult male volunteers. Methods: A single-dose, open-label, 2-period crossover study was conducted. Healthy male volunteers were randomly assigned to oral administration of a single treatment of the reference and test formulations. The same groups were given the alternate formulation. After dosing, serial blood samples were withdrawn for a period of 24 h. Serum harvested from the blood samples was analyzed for clindamycin by high performance liquid chromatography (HPLC) with ultraviolet detection. Pharmacokinetic parameters, including AUC0-∞, AUC 0-t, Cmax, Ke, tmax and t 1/2 were determined from the serum concentrations for both formulations (test and reference). The products were tested for bioequivalence after log-transformation of the data. Results: 24 healthy adult male volunteers from Jordan (mean [SD] age, 28.8 (7.7) years (range 19-45 years); height, 175.8 (10.6) cm (range 159.0-192.0 cm); weight, 75.6 (11.0) kg (range 58-101 kg); and body mass index, 24.4 (1.8) kg/m2 (range 21.3-28 kg/m2)) were enrolled in and completed the study. The 13C NMR spectra for both Dalacin C® and Clindox® showed 18 distinct lines associated with the 18 different carbon atoms. Conclusion: The statistical comparison suggested that Clindox® capsules are bioequivalent to Dalacin C® capsules. The 13C CPMAS results confirmed that the two drugs exhibit typical clindamycin spectra. ©2011 Dustri-Verlag Dr. K. Feistle.

  16. Population pharmacokinetics and pharmacodynamics of linezolid-induced thrombocytopenia in hospitalized patients.

    Science.gov (United States)

    Tsuji, Yasuhiro; Holford, Nicholas H G; Kasai, Hidefumi; Ogami, Chika; Heo, Young-A; Higashi, Yoshitsugu; Mizoguchi, Akiko; To, Hideto; Yamamoto, Yoshihiro

    2017-08-01

    Thrombocytopenia is among the most important adverse effects of linezolid treatment. Linezolid-induced thrombocytopenia incidence varies considerably but has been associated with impaired renal function. We investigated the pharmacodynamic mechanism (myelosuppression or enhanced platelet destruction) and the role of impaired renal function (RF) in the development of thrombocytopenia. The pharmacokinetics of linezolid were described with a two-compartment distribution model with first-order absorption and elimination. RF was calculated using the expected creatinine clearance. The decrease platelets by linezolid exposure was assumed to occur by one of two mechanisms: inhibition of the formation of platelets (PDI) or stimulation of the elimination (PDS) of platelets. About 50% of elimination was found to be explained by renal clearance (normal RF). The population mean estimated plasma protein binding of linezolid was 18% [95% confidence interval (CI) 16%, 20%] and was independent of the observed concentrations. The estimated mixture model fraction of patients with a platelet count decreased due to PDI was 0.97 (95% CI 0.87, 1.00), so the fraction due to PDS was 0.03. RF had no influence on linezolid pharmacodynamics. We have described the influence of weight, renal function, age and plasma protein binding on the pharmacokinetics of linezolid. This combined pharmacokinetic, pharmacodynamic and turnover model identified that the most common mechanism of thrombocytopenia associated with linezolid is PDI. Impaired RF increases thrombocytopenia by a pharmacokinetic mechanism. The linezolid dose should be reduced in RF. © 2017 The British Pharmacological Society.

  17. Population pharmacokinetic modeling of glibenclamide in poorly controlled South African type 2 diabetic subjects

    Directory of Open Access Journals (Sweden)

    Rambiritch V

    2016-07-01

    Full Text Available Virendra Rambiritch,1 Poobalan Naidoo,2 Breminand Maharaj,1 Goonaseelan Pillai3 1University of KwaZulu-Natal, Durban, 2Department of Internal Medicine, RK Khan Regional Hospital, Chatsworth, South Africa; 3Novartis Pharma AG, Basel, Switzerland Aim: The aim of this study was to describe the pharmacokinetics (PK of glibenclamide in poorly controlled South African type 2 diabetic subjects using noncompartmental and model-based methods. Methods: A total of 24 subjects with type 2 diabetes were administered increasing doses (0 mg/d, 2.5 mg/d, 5 mg/d, 10 mg/d, and 20 mg/d of glibenclamide daily at 2-week intervals. Plasma glibenclamide, glucose, and insulin determinations were performed. Blood sampling times were 0 minute, 30 minutes, 60 minutes, 90 minutes, and 120 minutes (post breakfast sampling and 240 minutes, 270 minutes, 300 minutes, 330 minutes, 360 minutes, and 420 minutes (post lunch sampling on days 14, 28, 42, 56, and 70 for doses of 0 mg, 2.5 mg, 5.0 mg, 10 mg, and 20 mg, respectively. Blood sampling was performed after the steady state was reached.  A total of 24 individuals in the data set contributed to a total of 841 observation records. The PK was analyzed using noncompartmental analysis methods, which were implemented in WinNonLin®, and population PK analysis using NONMEM®. Glibenclamide concentration data were log transformed prior to fitting. Results: A two-compartmental disposition model was selected after evaluating one-, two-, and three-compartmental models to describe the time course of glibenclamide plasma concentration data. The one-compartment model adequately described the data; however, the two-compartment model provided a better fit. The three-compartment model failed to achieve successful convergence. A more complex model, to account for enterohepatic recirculation that was observed in the data, was unsuccessful. Conclusion: In South African diabetic subjects, glibenclamide demonstrates linear PK and was best

  18. Development of a paediatric population-based model of the pharmacokinetics of rivaroxaban.

    Science.gov (United States)

    Willmann, Stefan; Becker, Corina; Burghaus, Rolf; Coboeken, Katrin; Edginton, Andrea; Lippert, Jörg; Siegmund, Hans-Ulrich; Thelen, Kirstin; Mück, Wolfgang

    2014-01-01

    Venous thromboembolism has been increasingly recognised as a clinical problem in the paediatric population. Guideline recommendations for antithrombotic therapy in paediatric patients are based mainly on extrapolation from adult clinical trial data, owing to the limited number of clinical trials in paediatric populations. The oral, direct Factor Xa inhibitor rivaroxaban has been approved in adult patients for several thromboembolic disorders, and its well-defined pharmacokinetic and pharmacodynamic characteristics and efficacy and safety profiles in adults warrant further investigation of this agent in the paediatric population. The objective of this study was to develop and qualify a physiologically based pharmacokinetic (PBPK) model for rivaroxaban doses of 10 and 20 mg in adults and to scale this model to the paediatric population (0-18 years) to inform the dosing regimen for a clinical study of rivaroxaban in paediatric patients. Experimental data sets from phase I studies supported the development and qualification of an adult PBPK model. This adult PBPK model was then scaled to the paediatric population by including anthropometric and physiological information, age-dependent clearance and age-dependent protein binding. The pharmacokinetic properties of rivaroxaban in virtual populations of children were simulated for two body weight-related dosing regimens equivalent to 10 and 20 mg once daily in adults. The quality of the model was judged by means of a visual predictive check. Subsequently, paediatric simulations of the area under the plasma concentration-time curve (AUC), maximum (peak) plasma drug concentration (C max) and concentration in plasma after 24 h (C 24h) were compared with the adult reference simulations. Simulations for AUC, C max and C 24h throughout the investigated age range largely overlapped with values obtained for the corresponding dose in the adult reference simulation for both body weight-related dosing regimens. However

  19. The use of in vitro metabolic parameters and physiologically based pharmacokinetic (PBPK) modeling to explore the risk assessment of trichloroethylene

    NARCIS (Netherlands)

    Hissink, E.M.; Bogaards, J.J.P.; Freidig, A.P.; Commandeur, J.N.M.; Vermeulen, N.P.E.; Bladeren, P.J. van

    2002-01-01

    A physiologically based pharmacokinetic (PBPK) model has been developed for trichloroethylene (1,1,2-trichloroethene, TRI) for rat and humans, based on in vitro metabolic parameters. These were obtained using individual cytochrome P450 and glutathione S-transferase enzymes. The main enzymes involved

  20. Population pharmacokinetic-pharmacodynamic modeling of ketamine-induced pain relief of chronic pain.

    Science.gov (United States)

    Dahan, Albert; Olofsen, Erik; Sigtermans, Marnix; Noppers, Ingeborg; Niesters, Marieke; Aarts, Leon; Bauer, Martin; Sarton, Elise

    2011-03-01

    Pharmacological treatment of chronic (neuropathic) pain is often disappointing. In order to enhance our insight in the complex interaction between analgesic drug and chronic pain relief, we performed a pharmacokinetic-pharmacodynamic (PK-PD) modeling study on the effect of S(+)-ketamine on pain scores in Complex Regional Pain Syndrome type 1 (CRPS-1) patients. Sixty CRPS-1 patients were randomly allocated to received a 100-h infusion of S(+)-ketamine or placebo. The drug infusion rate was slowly increased from 5 mg/h (per 70 kg) to 20 mg/h based upon the effect/side effect profile. Pain scores and drug blood samples were obtained during the treatment phase and pain scores were further obtained weekly for another 11 weeks. A population PK-PD model was developed to analyze the S(+)-ketamine-pain data. Plasma concentrations of S(+)-ketamine and its metabolite decreased rapidly upon the termination of S(+)-ketamine infusion. The chance for an analgesic effect from ketamine and placebo treatment was 67±10% and 23±9% (population value±SE), respectively. The pain data were well described by the PK-PD model with parameters C(50)=10.5±4.8 ng/ml (95% ci 4.37-21.2 ng/ml) and t½ for onset/offset=10.9±4.0 days (5.3-20.5 days). Long-term S(+)-ketamine treatment is effective in causing pain relief in CRPS-1 patients with analgesia outlasting the treatment period by 50 days. These data suggest that ketamine initiated a cascade of events, including desensitization of excitatory receptor systems in the central nervous system, which persisted but slowly abated when ketamine molecules were no longer present. Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.

  1. Population pharmacokinetics of teicoplanin in hospitalized elderly patients using cystatin C as an indicator of renal function.

    Science.gov (United States)

    Kasai, Hidefumi; Tsuji, Yasuhiro; Hiraki, Yoichi; Tsuruyama, Moeko; To, Hideto; Yamamoto, Yoshihiro

    2018-04-01

    Serum cystatin C (CysC) has recently been proposed as an alternative marker to serum creatinine (SCR) for estimating renal clearance. In the present study, we performed a population pharmacokinetic analysis of teicoplanin (TEIC), which is mainly eliminated through the kidneys, using CysC as a predictor for renal clearance. Thirty-six patients with MRSA infections who were administrated to the National Hospital Organization Beppu Medical Center between January 2012 and December 2013 were enrolled and gave 123 sets of blood TEIC concentration data. Renal clearance was estimated by the Hoek equation using CysC, by creatinine clearance predicted by the Cockcroft-Gault equation using SCR, or directly by CysC. One compartment open model with inter-individual variabilities for renal clearance and the volume of distribution as well as an additional residual error model was used to estimate population pharmacokinetic parameters for TEIC. The model with the best predictability was that with CysC as a predictor for renal clearance; it showed better significance than the models using estimated the glomerular filtration rate by the Hoek equation or CLcr. The final model was as follows: CL (L/hr) = 0.510 × (CysC/1.4) -0.68  × Total body weight/60 0.81 , omega (CL) = 19.8% CV, VC (L) = 78.1, omega (V) = 42.7% CV. The present results show the usefulness of CysC to more accurately predict the pharmacokinetics of drugs mainly eliminated through the kidneys, such as TEIC. However, since the sample size in this study was relatively small, further investigations on renal clearance predictability using CysC are needed. Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  2. Nycthemeral variations of 99Tcsup(m)-labelled heparin pharmacokinetic parameters

    International Nuclear Information System (INIS)

    Decousus, M.; Gremillet, E.; Decousus, H.; Champailler, A.; Houzard, C.; Perpoint, B.; Jaubert, J.

    1985-01-01

    Six healthy volunteers received four i.v.boluses of 99 Tcsup(m)-heparin at 8.00, 14.00, 20.00 and 02.00 hours at seven-day intervals. Nine blood samples were taken covering a period of 2 h after administration. Simultaneously urine was collected and diuresis not noted. Plasma and urinary radioactivity were measured and standard pharmacokinetic parameters were calculated. Nycthemeral variations of these kinetic parameters were detected by means of distribution-free tests. Circadian rhythms were analysed by means of the cosinor method and the Gauss-Marquardt method. The mean raw value of the following parameters: apparent volume of distribution, plasmatic clearance and extra-renal metabolic clearance, increased significantly between 8.00 and 14.00 and decreased between 14.00 and 20.00. A circadian rhythm was found for the plasmatic clearance only. On the other hand the elimination half-lives and the renal clearance were unaffected by the time of the injections. These results obtained for low doses of 99 Tcsup(m)-heparin suggest a circadian rhythm of the bio-availability of heparin in man. This fact should be taken into account for the use of 99 Tcsup(m)-heparin in the diagnosis of deep-vein thrombosis and for the safe adjustment of the heparin dosages in the treatment of severe thromboembolism. (author)

  3. Population pharmacokinetics of methadone hydrochloride after a single intramuscular administration in adult Japanese sika deer (Cervus nippon nippon).

    Science.gov (United States)

    Scala, Christopher; Marsot, Amélie; Limoges, Marie-Josée; Locatelli, Yann; Simon, Nicolas; Alvarez, Jean-Claude

    2015-03-01

    To assess the population pharmacokinetics of methadone in deer. Prospective non-randomized experimental trial. Twelve healthy adult sika deer (nine males and three females). Deer received intramuscular administration of racemic methadone hydrochloride at 0.5 mg kg(-1) or 1 mg kg(-1) . Plasma methadone and its metabolite 2-Ethylidene-1,5-Dimethyl-3,3-Diphenyl-Pyrolidine (EDDP) concentrations were determined by validated liquid chromatography coupled to tandem mass spectrometry methods, at times 0, 30 minutes, 1, 2, 3, 4, 5, 6, 8, 12 and 24 hours. Population pharmacokinetics analysis was undertaken using a non-linear mixed effects modelling (NONMEM). A two-compartment linear disposition model best described observed time-concentration profiles of methadone and EDDP. Population parameter estimates of methadone were elimination clearance (17.3 L hour(-1) ), metabolic clearance (34.6 L hour(-1) ), volume of distribution of compartment 1 (216.0 L) and volume of distribution of compartment 2 (384.0 L). Population parameter estimates of EDDP were elimination clearance (121.0 L hour(-1) ), volume of distribution of compartment 3 (1.08 L) and volume of distribution of compartment 4 (499.5 L). The total clearance and total volume of distribution of methadone and EDDP were 51.9 L hour(-1) , 121.0 L hour (-1) , 600.0 L and 500.6 L, respectively. The methadone terminal elimination half-life was 8.19 hours. No adverse effects were observed after methadone administration. Following intramuscular injection, methadone was characterized by a large total volume of distribution, high systemic clearance and intermediate terminal half-life in sika deer. © 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

  4. Development and optimization of carvedilol orodispersible tablets: enhancement of pharmacokinetic parameters in rabbits

    Science.gov (United States)

    Aljimaee, Yazeed HM; El-Helw, Abdel-Rahim M; Ahmed, Osama AA; El-Say, Khalid M

    2015-01-01

    Background Carvedilol (CVD) is used for the treatment of essential hypertension, heart failure, and systolic dysfunction after myocardial infarction. Due to its lower aqueous solubility and extensive first-pass metabolism, the absolute bioavailability of CVD does not exceed 30%. To overcome these drawbacks, the objective of this work was to improve the solubility and onset of action of CVD through complexation with hydroxypropyl-β-cyclodextrin and formulation of the prepared complex as orodispersible tablets (ODTs). Methods Compatibility among CVD and all tablet excipients using differential scanning calorimetry and Fourier transform infrared spectroscopy, complexation of CVD with different polymers, and determination of the solubility of CVD in the prepared complexes were first determined. A Box-Behnken design (BBD) was used to study the effect of tablet formulation variables on the characteristics of the prepared tablets and to optimize preparation conditions. According to BBD design, 15 formulations of CVD-ODTs were prepared by direct compression and then evaluated for their quality attributes. The relative pharmacokinetic parameters of the optimized CVD-ODTs were compared with those of the marketed CVD tablet. A single dose, equivalent to 2.5 mg/kg CVD, was administered orally to New Zealand white rabbits using a double-blind, randomized, crossover design. Results The solubility of CVD was improved from 7.32 to 22.92 mg/mL after complexation with hydroxypropyl-β-cyclodextrin at a molar ratio of 1:2 (CVD to cyclodextrin). The formulated CVD-ODTs showed satisfactory results concerning tablet hardness (5.35 kg/cm2), disintegration time (18 seconds), and maximum amount of CVD released (99.72%). The pharmacokinetic data for the optimized CVD-ODT showed a significant (Ptablet. Conclusion The optimized CVD-ODTs showed improved oral absorption of CVD and a subsequent acceleration of clinical effect, which is favored for hypertensive and cardiac patients. PMID

  5. Population Pharmacokinetics of Gemcitabine and dFdU in Pancreatic Cancer Patients Using an Optimal Design, Sparse Sampling Approach.

    Science.gov (United States)

    Serdjebi, Cindy; Gattacceca, Florence; Seitz, Jean-François; Fein, Francine; Gagnière, Johan; François, Eric; Abakar-Mahamat, Abakar; Deplanque, Gael; Rachid, Madani; Lacarelle, Bruno; Ciccolini, Joseph; Dahan, Laetitia

    2017-06-01

    Gemcitabine remains a pillar in pancreatic cancer treatment. However, toxicities are frequently observed. Dose adjustment based on therapeutic drug monitoring might help decrease the occurrence of toxicities. In this context, this work aims at describing the pharmacokinetics (PK) of gemcitabine and its metabolite dFdU in pancreatic cancer patients and at identifying the main sources of their PK variability using a population PK approach, despite a sparse sampled-population and heterogeneous administration and sampling protocols. Data from 38 patients were included in the analysis. The 3 optimal sampling times were determined using KineticPro and the population PK analysis was performed on Monolix. Available patient characteristics, including cytidine deaminase (CDA) status, were tested as covariates. Correlation between PK parameters and occurrence of severe hematological toxicities was also investigated. A two-compartment model best fitted the gemcitabine and dFdU PK data (volume of distribution and clearance for gemcitabine: V1 = 45 L and CL1 = 4.03 L/min; for dFdU: V2 = 36 L and CL2 = 0.226 L/min). Renal function was found to influence gemcitabine clearance, and body surface area to impact the volume of distribution of dFdU. However, neither CDA status nor the occurrence of toxicities was correlated to PK parameters. Despite sparse sampling and heterogeneous administration and sampling protocols, population and individual PK parameters of gemcitabine and dFdU were successfully estimated using Monolix population PK software. The estimated parameters were consistent with previously published results. Surprisingly, CDA activity did not influence gemcitabine PK, which was explained by the absence of CDA-deficient patients enrolled in the study. This work suggests that even sparse data are valuable to estimate population and individual PK parameters in patients, which will be usable to individualize the dose for an optimized benefit to risk ratio.

  6. Population Pharmacokinetics of Morphine and Morphine-6-Glucuronide following Rectal Administration

    DEFF Research Database (Denmark)

    Brokjær, Anne; Kreilgaard, Mads; Olesen, Anne Estrup

    2015-01-01

    INTRODUCTION: To safely and effectively administer morphine as liquid formulation via the rectal route, a thorough understanding of the pharmacokinetics is warranted. The aims were: 1) to develop a population pharmacokinetic model of liquid rectal morphine and morphine-6-glucoronide (M6G), 2...... cm from the anal verge. A 2 mg morphine hydrochloride dose was administered intravenously as reference. Blood samples were drawn at baseline and at nine time points post dosing. Serum was obtained by centrifugation and assayed for contents of morphine and M6G with a validated high performance liquid...... chromatographic method. Modelling was performed using NONMEM 7.2 and the first order conditional estimation method with interaction. RESULTS: A two compartment distribution model with one absorption transit compartment for rectal administration and systemic clearance from the central compartment best described...

  7. Fully populated VCM or the hidden parameter

    Directory of Open Access Journals (Sweden)

    Kermarrec G.

    2017-11-01

    Full Text Available Least-squares estimates are trustworthy with minimal variance if the correct stochastic model is used. Due to computational burden, diagonal models that neglect correlations are preferred to describe the elevation dependency of the variance of GPS observations. In this contribution, an improved stochastic model based on a parametric function to take correlations between GPS phase observations into account is presented. Built on an adapted and flexible Mátern function accounting for spatiotemporal variabilities, its parameters can be fixed thanks to Maximum Likelihood Estimation or chosen apriori to model turbulent tropospheric refractivity fluctuations. In this contribution, we will show in which cases and under which conditions corresponding fully populated variance covariance matrices (VCM replace the estimation of a tropospheric parameter. For this equivalence “augmented functional versus augmented stochastic model” to hold, the VCM should be made sufficiently largewhich corresponds to computing small batches of observations. A case study with observations from a medium baseline of 80 km divided into batches of 600 s shows improvement of up to 100 mm for the 3Drms when fully populated VCM are used compared with an elevation dependent diagonal model. It confirms the strong potential of such matrices to improve the least-squares solution, particularly when ambiguities are let float.

  8. Automatic individual arterial input functions calculated from PCA outperform manual and population-averaged approaches for the pharmacokinetic modeling of DCE-MR images.

    Science.gov (United States)

    Sanz-Requena, Roberto; Prats-Montalbán, José Manuel; Martí-Bonmatí, Luis; Alberich-Bayarri, Ángel; García-Martí, Gracián; Pérez, Rosario; Ferrer, Alberto

    2015-08-01

    To introduce a segmentation method to calculate an automatic arterial input function (AIF) based on principal component analysis (PCA) of dynamic contrast enhanced MR (DCE-MR) imaging and compare it with individual manually selected and population-averaged AIFs using calculated pharmacokinetic parameters. The study included 65 individuals with prostate examinations (27 tumors and 38 controls). Manual AIFs were individually extracted and also averaged to obtain a population AIF. Automatic AIFs were individually obtained by applying PCA to volumetric DCE-MR imaging data and finding the highest correlation of the PCs with a reference AIF. Variability was assessed using coefficients of variation and repeated measures tests. The different AIFs were used as inputs to the pharmacokinetic model and correlation coefficients, Bland-Altman plots and analysis of variance tests were obtained to compare the results. Automatic PCA-based AIFs were successfully extracted in all cases. The manual and PCA-based AIFs showed good correlation (r between pharmacokinetic parameters ranging from 0.74 to 0.95), with differences below the manual individual variability (RMSCV up to 27.3%). The population-averaged AIF showed larger differences (r from 0.30 to 0.61). The automatic PCA-based approach minimizes the variability associated to obtaining individual volume-based AIFs in DCE-MR studies of the prostate. © 2014 Wiley Periodicals, Inc.

  9. Population pharmacokinetics and dosing regimen design of milrinone in preterm infants

    Science.gov (United States)

    Paradisis, Mary; Jiang, Xuemin; McLachlan, Andrew J; Evans, Nick; Kluckow, Martin; Osborn, David

    2007-01-01

    Aims To define the pharmacokinetics of milrinone in very preterm infants and determine an optimal dose regimen to prevent low systemic blood flow in the first 12 h after birth. Methods A prospective open‐labelled, dose‐escalation pharmacokinetic study was undertaken in two stages. In stage one, infants received milrinone at 0.25 μg/kg/min (n = 8) and 0.5 μg/kg/min (n = 11) infused from 3 to 24 h of age. Infants contributed 4–5 blood samples for concentration–time data which were analysed using a population modelling approach. A simulation study was used to explore the optimal dosing regimen to achieve target milrinone concentrations (180–300 ng/ml). This milrinone regimen was evaluated in stage two (n = 10). Results Infants (n = 29) born before 29 weeks gestation were enrolled. Milrinone pharmacokinetics were described using a one‐compartment model with first‐order elimination rate, with a population mean clearance (CV%) of 35 ml/h (24%) and volume of distribution of 512 ml (21%) and estimated half‐life of 10 h. The 0.25 and 0.5 μg/kg/min dosage regimens did not achieve optimal milrinone concentration‐time profiles to prevent early low systemic blood flow. Simulation studies predicted a loading infusion (0.75 μg/kg/min for 3 h) followed by maintenance infusion (0.2 μg/kg/min until 18 h of age) would provide an optimal milrinone concentration profile. This was confirmed in stage two of the study. Conclusion Population pharmacokinetic modelling in the preterm infant has established an optimal dose regimen for milrinone that increases the likelihood of achieving therapeutic aims and highlights the importance of pharmacokinetic studies in neonatal clinical pharmacology. PMID:16690639

  10. Comparison of predictability for human pharmacokinetics parameters among monkeys, rats, and chimeric mice with humanised liver.

    Science.gov (United States)

    Miyamoto, Maki; Iwasaki, Shinji; Chisaki, Ikumi; Nakagawa, Sayaka; Amano, Nobuyuki; Hirabayashi, Hideki

    2017-12-01

    1. The aim of the present study was to evaluate the usefulness of chimeric mice with humanised liver (PXB mice) for the prediction of clearance (CL t ) and volume of distribution at steady state (Vd ss ), in comparison with monkeys, which have been reported as a reliable model for human pharmacokinetics (PK) prediction, and with rats, as a conventional PK model. 2. CL t and Vd ss values in PXB mice, monkeys and rats were determined following intravenous administration of 30 compounds known to be mainly eliminated in humans via the hepatic metabolism by various drug-metabolising enzymes. Using single-species allometric scaling, human CL t and Vd ss values were predicted from the three animal models. 3. Predicted CL t values from PXB mice exhibited the highest predictability: 25 for PXB mice, 21 for monkeys and 14 for rats were predicted within a three-fold range of actual values among 30 compounds. For predicted human Vd ss values, the number of compounds falling within a three-fold range was 23 for PXB mice, 24 for monkeys, and 16 for rats among 29 compounds. PXB mice indicated a higher predictability for CL t and Vd ss values than the other animal models. 4. These results demonstrate the utility of PXB mice in predicting human PK parameters.

  11. Treatment with subcutaneous and transdermal fentanyl: results from a population pharmacokinetic study in cancer patients.

    Science.gov (United States)

    Oosten, Astrid W; Abrantes, João A; Jönsson, Siv; de Bruijn, Peter; Kuip, Evelien J M; Falcão, Amílcar; van der Rijt, Carin C D; Mathijssen, Ron H J

    2016-04-01

    Transdermal fentanyl is effective for the treatment of moderate to severe cancer-related pain but is unsuitable for fast titration. In this setting, continuous subcutaneous fentanyl may be used. As data on the pharmacokinetics of continuous subcutaneous fentanyl are lacking, we studied the pharmacokinetics of subcutaneous and transdermal fentanyl. Furthermore, we evaluated rotations from the subcutaneous to the transdermal route. Fifty-two patients treated with subcutaneous and/or transdermal fentanyl for moderate to severe cancer-related pain participated. A population pharmacokinetic model was developed and evaluated using non-linear mixed-effects modelling. For rotations from subcutaneous to transdermal fentanyl, a 1:1 dose conversion ratio was used while the subcutaneous infusion was continued for 12 h (with a 50 % tapering after 6 h). A 6-h scheme with 50 % tapering after 3 h was simulated using the final model. A one-compartment model with first-order elimination and separate first-order absorption processes for each route adequately described the data. The estimated apparent clearance of fentanyl was 49.6 L/h; the absorption rate constant for subcutaneous and transdermal fentanyl was 0.0358 and 0.0135 h(-1), respectively. Moderate to large inter-individual and inter-occasion variability was found. Around rotation from subcutaneous to transdermal fentanyl, measured and simulated plasma fentanyl concentrations rose and increasing side effects were observed. We describe the pharmacokinetics of subcutaneous and transdermal fentanyl in one patient cohort and report several findings that are relevant for clinical practice. Further research is warranted to study the optimal scheme for rotations from the subcutaneous to the transdermal route.

  12. Population pharmacokinetic analysis of oxaliplatin in adults and children identifies important covariates for dosing.

    Science.gov (United States)

    Nikanjam, Mina; Stewart, Clinton F; Takimoto, Chris H; Synold, Timothy W; Beaty, Orren; Fouladi, Maryam; Capparelli, Edmund V

    2015-03-01

    To characterize the determinants of variability for oxaliplatin pharmacokinetics including age, renal function, and hepatic function in children and adults. Oxaliplatin pharmacokinetic data were combined from phase I and II clinical trials: three pediatric trials (Peds1-3) and two adult NCI organ dysfunction studies (Hepatic and Renal). A population pharmacokinetic model was developed utilizing platinum ultrafiltrate concentrations to characterize changes in oxaliplatin disposition with age and organ dysfunction along with other potential sources of oxaliplatin pharmacokinetic variability. A total of 1,508 concentrations from 186 children and adults were used in the study. The data were well described by a three-compartment model. Serum creatinine (SCR) was an independent predictor of clearance (CL) while age was an independent predictor of volume of distribution. Although age was a significant covariate on CL in the univariate analysis, age effects on CL were entirely accounted for by SCR. Gender, hepatic function, and race had no effect on CL or volume of distribution. Median CL values were 0.58 (Hepatic), 0.34 (Renal), 0.78 (Peds1), 0.74 (Peds2), and 0.81 (Peds3) (L/h/kg(0.75)). Monte Carlo simulations of the final model with 130 mg/m(2) yielded median AUC values of: 14.2 (2-6 years), 16.8 (6-12 years), 16.5 (12-18 years), and 17.3 (>18 years) (µg h/mL). Renal function had the greatest effect on CL with a small age effect seen on the distribution of oxaliplatin. Young pediatric patients had higher CL values than adults as a result of better renal function.

  13. Population pharmacokinetic (PK) analysis of laromustine, an emerging alkylating agent, in cancer patients.

    Science.gov (United States)

    Nassar, Ala F; Wisnewski, Adam V; King, Ivan

    2017-05-01

    1. Alkylating agents are capable of introducing an alkyl group into nucleophilic sites on DNA or RNA through covalent bond. Laromustine is an active member of a relatively new class of sulfonylhydrazine prodrugs under development as antineoplastic alkylating agents, and displays significant single-agent activity. 2. This is the first report of the population pharmacokinetic analysis of laromustine, 106 patients, 66 with hematologic malignancies and 40 with solid tumors, participated in five clinical trials worldwide. Of these, 104 patients were included in the final NONMEM analysis. 3. The population estimates for total clearance (CL) and volume of distribution of the central compartment (V 1 ) were 96.3 L/h and 45.9 L, associated with high inter-patient variability of 52.9% and 79.8% and inter-occasion variability of 26.7% and 49.3%, respectively. The population estimates for Q and V 2 were 73.2 L/h and 29.9 L, and inter-patient variability in V 2 was 63.1%, respectively. 4. The estimate of V ss (75.8 L) exceeds total body water, indicating that laromustine is distributed to tissues. The half-life is short, less than 1 h, reflecting rapid clearance. Population PK analysis showed laromustine pharmacokinetics to be independent of dose and organ function with no effect on subsequent dosing cycles.

  14. Mechanism-based population pharmacokinetic modelling in diabetes: vildagliptin as a tight binding inhibitor and substrate of dipeptidyl peptidase IV

    Science.gov (United States)

    Landersdorfer, Cornelia B; He, Yan-Ling; Jusko, William J

    2012-01-01

    AIMS To assess the pharmacokinetics of vildagliptin at different doses and build a mechanism-based population model that simultaneously describes vildagliptin pharmacokinetics and its effects on DPP-4 activity based on underlying physiology and biology. METHODS Vildagliptin concentrations and DPP-4 activity vs. time from 13 type 2 diabetic patients after oral vildagliptin 10, 25 or 100 mg and placebo twice daily for 28 days were co-modelled. NONMEM VI and S-ADAPT were utilized for population modelling. RESULTS A target-mediated drug disposition (TMDD) model accounting for capacity-limited high affinity binding of vildagliptin to DPP-4 in plasma and tissues had good predictive performance. Modelling the full time course of the vildagliptin-DPP-4 interaction suggested parallel vildagliptin dissociation from DPP-4 by a slow first-order process and hydrolysis by DPP-4 to an inactive metabolite as a disposition mechanism. Due to limited amounts of DPP-4, vildagliptin concentrations increased slightly more than dose proportionally. This newly proposed model and the parameter estimates are supported by published in vitro studies. Mean parameter estimates (inter-individual coefficient of variation) were: non-saturable clearance 36 l h−1 (25%), central volume of distribution 22 l (37%), half-life of dissociation from DPP-4 1.1 h (94%) and half-life of hydrolysis 6.3 h (81%). CONCLUSIONS Vildagliptin is both an inhibitor and substrate for DPP-4. By utilizing the TMDD approach, slow dissociation of vildagliptin from DPP-4 was found in patients and the half-life of hydrolysis by DPP-4 estimated. This model can be used to predict DPP-4 inhibition effects of other dosage regimens and be modified for other DPP-4 inhibitors to differentiate their properties. PMID:22442826

  15. Factors and Mechanisms for Pharmacokinetic Differences between Pediatric Population and Adults

    Directory of Open Access Journals (Sweden)

    Jose T. Ramos

    2011-02-01

    Full Text Available Many physiologic differences between children and adults may result in age-related changes in pharmacokinetics and pharmacodynamics. Factors such as gastric pH and emptying time, intestinal transit time, immaturity of secretion and activity of bile and pancreatic fluid among other factors determine the oral bioavailability of pediatric and adult populations. Anatomical, physiological and biochemical characteristics in children also affect the bioavailability of other routes of administration. Key factors explaining differences in drug distribution between the pediatric population and adults are membrane permeability, plasma protein binding and total body water. As far as drug metabolism is concerned, important differences have been found in the pediatric population compared with adults both for phase I and phase II metabolic enzymes. Immaturity of glomerular filtration, renal tubular secretion and tubular reabsorption at birth and their maturation determine the different excretion of drugs in the pediatric population compared to adults.

  16. Misonidazole neurotoxicity in the mouse: evaluation of functional, pharmacokinetic, electrophysiologic and morphologic parameters

    International Nuclear Information System (INIS)

    Conroy, P.J.; Von Burg, R.; Passalacqua, W.; Penney, D.P.; Sutherland, R.M.

    1979-01-01

    The neurotoxic effects of chronic administration of misonidazole (0.3 mg/g/day, 5 times weekly) were investigated in Balb/cKa mice over 12 weeks; a variety of measurements were used, including functional and clinical performance, morphologic, electrophysiologic and pharmacokinetic parameters. The half life of drug for a single dose was greater in brain (3 hrs) compared to serum (1.2 hrs); these values decreased to 1.9 hrs and 1.0 hrs respectively after 3 weeks. Misonidazole induced a peripheral lesion after three weeks with a total administered dose of 13.5 g/m 2 or exposure dose of 57 to 75 mM X hrs, which is similar to the doses that cause neuropathy in humans. There was some suggestion of a central neurological deficit related to locomotor control and balance; however, no gross morphological damage was found in the brain. The sequence of effects demonstrated began at 3 to 4 weeks and included: 1) morphologic damage to peripheral nerves; 2) hyperactivity and listlessness; 3) a decrease in rotarod retention time which reached a value 50% of that of saline injected control mice at 8 to 10 weeks; 4) walking on tip-toes with a slightly hunched back (4 to 6 weeks); and 5) an increase in hind foot splay (6 to 7 weeks). The morphologic damage primarily involved the more distal portions of the nerves supplying the interosseous muscles and footpads of the hind limbs. The damage was more severe and progressed more rapidly with time in these distal areas compared to the more proximal regions of the nerves. No marked changes were found in nerve conduction velocity although neuropathy produced by acrylamide produced significant decreases. The changes in neurological parameters reported here may be useful in the further evaluation of hypoxic cell radiosensitizers

  17. A Population Pharmacokinetic Model for Disposition in Plasma, Saliva and Urine of Scopolamine after Intranasal Administration to Healthy Human Subjects

    Science.gov (United States)

    Wu, L.; Tam, V. H.; Chow, D. S. L.; Putcha, L.

    2014-01-01

    An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness. The bioavailability and pharmacokinetics (PK) were evaluated under the Food and Drug Administration guidelines for clinical trials with an Investigative New Drug (IND) protocol. The aim of this project was to develop a PK model that can predict the relationship between plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trials with INSCOP. Methods: Twelve healthy human subjects were administered three dose levels (0.1, 0.2 and 0.4 mg) of INSCOP. Serial blood, saliva and urine samples were collected between 5 min and 24 h after dosing and scopolamine concentrations were measured by using a validated LC-MS-MS assay. Pharmacokinetic Compartmental models, using actual dosing and sampling times, were built using Phoenix (version 1.2). Model selection was based on the likelihood ratio test on the difference of criteria (-2LL) and comparison of the quality of fit plots. Results: The best structural model for INSCOP (minimal -2LL= 502.8) was established. It consisted of one compartment each for plasma, saliva and urine, respectively, which were connected with linear transport processes except the nonlinear PK process from plasma to saliva compartment. The best-fit estimates of PK parameters from individual PK compartmental analysis and Population PK model analysis were shown in Tables 1 and 2, respectively. Conclusion: A population PK model that could predict population and individual PK of scopolamine in plasma, saliva and urine after dosing was developed and validated. Incorporating a non-linear transfer from plasma to saliva compartments resulted in a significantly improved model fitting. The model could be used to predict scopolamine plasma concentrations from salivary and urinary drug levels, allowing non-invasive therapeutic monitoring of scopolamine in space and other remote environments.

  18. Pharmacokinetic studies of neuromuscular blocking agents: Good Clinical Research Practice (GCRP)

    DEFF Research Database (Denmark)

    Viby-Mogensen, J.; Østergaard, D.; Donati, F.

    2000-01-01

    Good Clinical Research Practice (GCRP), neuromuscular blocking agents, pharmacokinetics, pharmacokinetic/pharmacodynamic modeling, population pharmacokinetics, statistics, study design......Good Clinical Research Practice (GCRP), neuromuscular blocking agents, pharmacokinetics, pharmacokinetic/pharmacodynamic modeling, population pharmacokinetics, statistics, study design...

  19. Population pharmacokinetics of imatinib mesylate and its metabolite in children and young adults.

    Science.gov (United States)

    Menon-Andersen, Divya; Mondick, John T; Jayaraman, Bhuvana; Thompson, Patrick A; Blaney, Susan M; Bernstein, Mark; Bond, Mason; Champagne, Martin; Fossler, Michael J; Barrett, Jeffrey S

    2009-01-01

    Imatinib mesylate (Gleevec) is a small molecule tyrosine kinase inhibitor approved for use in the management of chronic myeloid leukemia in adults and children and in gastrointestinal stromal tumors in adults. Population pharmacokinetic (PPK) studies evaluating the effect of population covariates on the pharmacokinetics of imatinib and its active metabolite have been developed in adults with chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). However, this still remains to be described in children. The objectives of the analysis were to develop a PPK model of imatinib and its active metabolite, CGP74588, to describe exposure in children and young adults and to identify covariates that are predictors of variability in disposition. Plasma concentrations from 26 subjects with Philadelphia (Ph+) leukemia (Phase I study) and 15 subjects with refractory solid tumors (Phase II study), who received oral imatinib at doses ranging from 260 to 570 mg/m(2), were available for the PPK analysis in NONMEM. Blood samples were drawn prior to dosing and over 24-48 h on days 1 and 8 of the studies. Covariates studied included weight, age, albumin, alanine aminotransferase and the study population. The pharmacokinetics of imatinib and CGP 74588 were well described by one and two compartment models, respectively. Total body weight was the only covariate found to significantly affect Cl/F and V/F. The final imatinib-CGP 74588 model is summarized as follows: CL/F (imatinib) (L/h) = 10.8 x (WT/70)(0.75), V/F (imatinib) (L) = 284 x (WT/70) and D1(duration of zero order absorption,imatinib) (h) = 1.67 and CL/F (CGP 74588) (L/h) = 9.65 x (WT/70)(0.75), V1/F (CGP 74588) (L) = 11.6 x (WT/70), Q (CGP 74588) (L/h) = 2.9 x (WT/70)(0.75) and V2/F (CGP 74588) (L) = 256*(WT/70). Model evaluation indicated that the final model was robust and satisfactory. Current imatinib dosing guidelines in pediatrics is based on the achievement of exposures consistent with doses known to be

  20. Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda

    Directory of Open Access Journals (Sweden)

    Tarning Joel

    2012-08-01

    Full Text Available Abstract Background Malaria in pregnancy increases the risk of maternal anemia, abortion and low birth weight. Approximately 85.3 million pregnancies occur annually in areas with Plasmodium falciparum transmission. Pregnancy has been reported to alter the pharmacokinetic properties of many anti-malarial drugs. Reduced drug exposure increases the risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin in pregnant women with uncomplicated P. falciparum malaria in Uganda. Methods Twenty-one women with uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy received the fixed oral combination of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Artemether and dihydroartemisinin plasma concentrations after the last dose administration were quantified using liquid chromatography coupled to tandem mass-spectroscopy. A simultaneous drug-metabolite population pharmacokinetic model for artemether and dihydroartemisinin was developed taking into account different disposition, absorption, error and covariate models. A separate modeling approach and a non-compartmental analysis (NCA were also performed to enable a comparison with literature values and different modeling strategies. Results The treatment was well tolerated and there were no cases of recurrent malaria. A flexible absorption model with sequential zero-order and transit-compartment absorption followed by a simultaneous one-compartment disposition model for both artemether and dihydroartemisinin provided the best fit to the data. Artemether and dihydroartemisinin exposure was lower than that reported in non-pregnant populations. An approximately four-fold higher apparent volume of distribution for dihydroartemisinin was obtained by non-compartmental analysis and separate modeling compared to that from simultaneous modeling of the drug

  1. Population pharmacokinetics of a three-day chloroquine treatment in patients with Plasmodium vivax infection on the Thai-Myanmar border.

    Science.gov (United States)

    Höglund, Richard; Moussavi, Younis; Ruengweerayut, Ronnatrai; Cheomung, Anurak; Äbelö, Angela; Na-Bangchang, Kesara

    2016-02-29

    A three-day course of chloroquine remains a standard treatment of Plasmodium vivax infection in Thailand with satisfactory clinical efficacy and tolerability although a continuous decline in in vitro parasite sensitivity has been reported. Information on the pharmacokinetics of chloroquine and its active metabolite desethylchloroquine are required for optimization of treatment to attain therapeutic exposure and thus prevent drug resistance development. The study was conducted at Mae Tao Clinic for migrant worker, Tak province, Thailand. Blood samples were collected from a total of 75 (8 Thais and 67 Burmeses; 36 males and 39 females; aged 17-52 years) patients with mono-infection with P. vivax malaria [median (95 % CI) admission parasitaemia 4898 (1206-29,480)/µL] following treatment with a three-day course of chloroquine (25 mg/kg body weight chloroquine phosphate over 3 days). Whole blood concentrations of chloroquine and desethylchloroquine were measured using high performance liquid chromatography with UV detection. Concentration-time profiles of both compounds were analysed using a population-based pharmacokinetic approach. All patients showed satisfactory response to standard treatment with a three-day course of chloroquine with 100 % cure rate within the follow-up period of 42 days. Neither recurrence of P. vivax parasitaemia nor appearance of P. falciparum occurred. A total of 1045 observations from 75 participants were included in the pharmacokinetic analysis. Chloroquine disposition was most adequately described by the two-compartment model with one transit compartment absorption model into the central compartment and a first-order transformation of chloroquine into desethylchloroquine with an additional peripheral compartment added to desethylchloroquine. First-order elimination from the central compartment of chloroquine and desethylchloroquine was assumed. The model exhibited a strong predictive ability and the pharmacokinetic parameters were

  2. Visceral leishmaniasis relapse hazard is linked to reduced miltefosine exposure in patients from Eastern Africa: a population pharmacokinetic/pharmacodynamic study.

    Science.gov (United States)

    Dorlo, Thomas P C; Kip, Anke E; Younis, Brima M; Ellis, Sally J; Alves, Fabiana; Beijnen, Jos H; Njenga, Simon; Kirigi, George; Hailu, Asrat; Olobo, Joseph; Musa, Ahmed M; Balasegaram, Manica; Wasunna, Monique; Karlsson, Mats O; Khalil, Eltahir A G

    2017-11-01

    Low efficacy of miltefosine in the treatment of visceral leishmaniasis was recently observed in Eastern Africa. To describe the pharmacokinetics and establish a pharmacokinetic/pharmacodynamic relationship for miltefosine in Eastern African patients with visceral leishmaniasis, using a time-to-event approach to model relapse of disease. Miltefosine plasma concentrations from 95 patients (48 monotherapy versus 47 combination therapy) were included in the population pharmacokinetic model using non-linear mixed effects modelling. Subsequently a time-to-event model was developed to model the time of clinical relapse. Various summary pharmacokinetic parameters (various AUCs, Time > EC50, Time > EC90), normalized within each treatment arm to allow simultaneous analysis, were evaluated as relapse hazard-changing covariates. A two-compartment population model with first-order absorption fitted the miltefosine pharmacokinetic data adequately. Relative bioavailability was reduced (-74%, relative standard error 4.7%) during the first week of treatment of the monotherapy arm but only the first day of the shorter combination regimen. Time to the relapse of infection could be described using a constant baseline hazard (baseline 1.8 relapses/year, relative standard error 72.7%). Miltefosine Time > EC90 improved the model significantly when added in a maximum effect function on the baseline hazard (half maximal effect with Time > EC90 6.97 days for monotherapy). Miltefosine drug exposure was found to be decreased in Eastern African patients with visceral leishmaniasis, due to a (transient) initial lower bioavailability. Relapse hazard was inversely linked to miltefosine exposure. Significantly lower miltefosine exposure was observed in children compared with adults, further urging the need for implementation of dose adaptations for children. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

  3. Population pharmacokinetics of nalmefene in healthy subjects and its relation to μ-opioid receptor occupancy.

    Science.gov (United States)

    Kyhl, Lars-Erik Broksoe; Li, Shen; Faerch, Kirstine Ullitz; Soegaard, Birgitte; Larsen, Frank; Areberg, Johan

    2016-02-01

    The aims of this study were to develop a population pharmacokinetic (PK) model to describe the PK of nalmefene in healthy subjects and to relate the exposure of nalmefene to the μ-opioid receptor occupancy by simulations in the target population. Data from nine phase I studies (243 subjects) with extensive blood sampling were pooled and used for the population PK model building. Data from four other phase I studies (85 subjects) were pooled and used as an external validation dataset. Eight subjects from an imaging study contributed occupancy data and the pharmacokinetic/pharmacodynamic (PK/PD) relationship was modelled. Combining the population PK model and the PK/PD relationship enabled simulations to predict μ-opioid occupancy. A two compartment model with first order absorption best described the nalmefene PK data. The typical subject in the population was estimated to have a systemic clearance of 60.4 l h(-1) and a central volume of distribution of 266 l. Absolute oral bioavailability was estimated to 41% without food intake and with food about 53%. Simulation of the μ-opioid receptor occupancy shows that the 95% confidence bound is within or above 60-90% occupancy for up to 22-24 h after a single dose of 20 mg nalmefene. A robust population PK model for nalmefene was developed. Based on the concentration-occupancy model the μ-opioid receptor occupancy after a single 20 mg dose of nalmefene is predicted to be above the target therapeutic occupancy for about 24 h in about 95% of the target population. © 2015 The British Pharmacological Society.

  4. Liraglutide 3.0 mg for Weight Management: A Population Pharmacokinetic Analysis.

    Science.gov (United States)

    Overgaard, Rune V; Petri, Kristin C; Jacobsen, Lisbeth V; Jensen, Christine B

    2016-11-01

    This analysis used a population pharmacokinetic approach to identify covariates that influence plasma exposure of liraglutide 3.0 mg, a glucagon-like peptide-1 (GLP-1) receptor agonist approved for weight management in overweight and obese individuals. Samples for pharmacokinetic analysis were drawn at weeks 2, 12 and 28 of the phase IIIa SCALE Obesity and Prediabetes (N = 2339) and SCALE Diabetes (N = 584) trials. Dose proportionality of liraglutide in obese subjects was investigated using data from a phase II dose-finding study (N = 331). Dose-proportional exposure of liraglutide up to and including 3.0 mg was confirmed. Body weight and sex influenced exposure of liraglutide 3.0 mg, while age ≥70 years, race, ethnicity and baseline glycaemic status did not. Compared with a reference subject weighing 100 kg, exposure of liraglutide 3.0 mg was 44 % lower for a subject weighing 234 kg (90 % CI 41-47), 41 % higher for a subject weighing 60 kg (90 % CI 37-46), and 32 % higher (90 % CI 28-35) in females than males with the same body weight. Neither injection site nor renal function significantly influenced exposure of liraglutide 3.0 mg (post hoc analysis). Population pharmacokinetics of liraglutide up to and including 3.0 mg daily in overweight and obese adults demonstrated dose-proportional exposure, and limited effect of covariates other than sex and body weight. These findings were similar to those previously observed with liraglutide up to 1.8 mg in subjects with type 2 diabetes mellitus. Further analysis of exposure-response relationship and its effect on dose requirements is addressed in a separate publication.

  5. Population pharmacokinetics of enrofloxacin in purple sea stars (Pisaster ochraceus) following an intracoelomic injection or extended immersion.

    Science.gov (United States)

    Rosenberg, Justin F; Haulena, Martin; Phillips, Brianne E; Harms, Craig A; Lewbart, Gregory A; Lahner, Lesanna L; Papich, Mark G

    2016-11-01

    OBJECTIVE To determine population pharmacokinetics of enrofloxacin in purple sea stars (Pisaster ochraceus) administered an intracoelomic injection of enrofloxacin (5 mg/kg) or immersed in an enrofloxacin solution (5 mg/L) for 6 hours. ANIMALS 28 sea stars of undetermined age and sex. PROCEDURES The study had 2 phases. Twelve sea stars received an intracoelomic injection of enrofloxacin (5 mg/kg) or were immersed in an enrofloxacin solution (5 mg/L) for 6 hours during the injection and immersion phases, respectively. Two untreated sea stars were housed with the treated animals following enrofloxacin administration during both phases. Water vascular system fluid samples were collected from 4 sea stars and all controls at predetermined times during and after enrofloxacin administration. The enrofloxacin concentration in those samples was determined by high-performance liquid chromatography. For each phase, noncompartmental analysis of naïve averaged pooled samples was used to obtain initial parameter estimates; then, population pharmacokinetic analysis was performed that accounted for the sparse sampling technique used. RESULTS Injection phase data were best fit with a 2-compartment model; elimination half-life, peak concentration, area under the curve, and volume of distribution were 42.8 hours, 18.9 μg/mL, 353.8 μg•h/mL, and 0.25 L/kg, respectively. Immersion phase data were best fit with a 1-compartment model; elimination half-life, peak concentration, and area under the curve were 56 hours, 36.3 μg•h/mL, and 0.39 μg/mL, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that the described enrofloxacin administration resulted in water vascular system fluid drug concentrations expected to exceed the minimum inhibitory concentration for many bacterial pathogens.

  6. Inference from some pharmacokinetic and pharmacodynamic parameters of busulfan through the analysis of its induction kinetics of micronuclei polychromated erythrocytes

    International Nuclear Information System (INIS)

    Lopez I, M.R.; Vallarino K, T.; Morales R, P.

    2001-01-01

    The induction kinetics of micronuclei polychromated eritrocites (EPC-MN) which is produced by busulfan and compared with that produced by the ionizing radiation, allows to make inferences over the pharmacokinetics and pharmacodynamics of busulfan. Observing two induction mechanisms of MN, this one early at low doses and other later at high doses, this last is presented to a critical dose being very sheer and associated with an increase of the cytotoxicity. The data suggest the transformation or dependence between these two types of leisures, which to determine the narrow therapeutical margin of busulfan. The pharmacokinetic parameters determined in the early mechanisms kinetics indicate a latency period, a time of effective activity and of half life 5.7, 5.2 and 2.6 h respectively. (Author)

  7. Inference of some pharmacokinetic parameters of the C mitomycin, through the analysis of its micro nucleate polychromatic erythrocytes induction kinetics

    International Nuclear Information System (INIS)

    Morales R, P.; Vallarino K, T.; Cruz V, V.; Delgadillo H, A.

    2003-01-01

    The objective of the present work was to establish pharmacokinetic parameters of the C Mitomycin (MMC) in vivo, comparing its kinetics of induction of polychromatic micro nucleate erythrocytes (EPGMN) with that of the gamma radiation. The used doses were of 0.75; 1.5 and 3. 0 μmoles/kg of MMC. It was observed that the MMC produces MN in the first cycle of cellular division and it is independent of the cytotoxic effect. This agent requires of a relatively long period of latency that is not compatible with her great reactivity, for what the pharmacokinetic values obtained in fact reflect the time that takes the processing of leisure in the DNA and the subsequent induction of ruptures that produce MN. (Author)

  8. TC > 0.05 as a Pharmacokinetic Parameter of Paclitaxel for Therapeutic Efficacy and Toxicity in Cancer Patients.

    Science.gov (United States)

    Xin, D S; Zhou, L; Li, C Z; Zhang, S Q; Huang, H Q; Qiu, G D; Lin, L F; She, Y Q; Zheng, J T; Chen, C; Fang, L; Chen, Zhe-Sheng; Zhang, S Y

    2018-03-05

    Paclitaxel (PTX) has remarkable anti-tumor activity, but it causes severe toxicities. There is an urgent need to seek an appropriate pharmacokinetic parameter of PTX to improve treatment efficacy and reduce adverse effects. To evaluate the association of pharmacokinetic parameter TC>0.05 of paclitaxel (PTX) and its therapeutic efficacy and toxicity in patients with solid tumors. A total of 295 patients with ovarian cancer, esophageal cancer, breast cancer, and non-small cell lung cancer (NSCLC), who were admitted to the Tumor Hospital of Shantou University Medical College, China, were recruited for this study. Patients received 3 weeks of PTX chemotherapy. The plasma concentrations of PTX were examined using the MyPaclitaxelTM kit. The patients' PTX TC>0.05 (the time during which PTX plasma concentration exceed 0.05 μmol/L) were calculated based on pharmacokinetic analysis. The results showed that: (1) the concentrations of PTX in these 295 patients ranged from 0.0358-0.127 μmol/L; (2) the PTX TC> 0.05 ranged from 14 to 38 h with a median time of 27 h; (3) among all treatment cycles, there was a statistically significant difference in the PTX TC>0.05 between CR+PR and SD+PD; (4) with the increasing value of TC>0.05, level of leukopenia and leukopenic fever increased; (5) high PTX TC>0.05 led to the occurrence of neutropenia, neutropenic fever, severe anemia, and severe peripheral neurotoxicity. Taken together, our results indicated that the pharmacokinetic parameter PTX TC>0.05 was an effective measure of treatment efficacy and toxicity in patients with solid tumors. Maintaining PTX TC>0.05 at 26 to 30 h could improve its efficacy and reduce the incidence of leukopenia, neutropenia, anemia, and peripheral neurotoxicity in these patients. PTX TC>0.05 is a key pharmacokinetic parameter of PTX which should be monitored to optimize individual treatment in patients with solid tumors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. Population pharmacokinetic modelling of the enterohepatic recirculation of diclofenac and rofecoxib in rats

    Science.gov (United States)

    Huntjens, D R H; Strougo, A; Chain, A; Metcalf, A; Summerfield, S; Spalding, D J M; Danhof, M; Della Pasqua, O

    2008-01-01

    Background and purpose: Enterohepatic recirculation (EHC) is a common pharmacokinetic phenomenon that has been poorly modelled in animals. The presence of EHC leads to the appearance of multiple peaks in the concentration-time profile and increased exposure, which may have implications for drug effect and extrapolation across species. The aim of this investigation was to develop a population pharmacokinetic model for diclofenac and rofecoxib that describes EHC and to assess its consequence for the pharmacodynamics of both drugs. Experimental approach: The pharmacokinetics of diclofenac and rofecoxib was characterized in male rats following intravenous, intraperitoneal and oral administration. Blood samples were collected at pre-defined time points after dosing to determine plasma concentrations over time. A parametric approach using nonlinear mixed effects modelling was applied to describe EHC, whilst simulations were used to evaluate its impact on PGE2 inhibition. Key results: For diclofenac, EHC was described by a compartmental model with periodic transfer rate and metabolite formation rate. For rofecoxib, EHC modelling required a conversion compartment with first-order recycling rate and lag time. Based on model predictions, EHC causes an increase of 95% in the systemic exposure to diclofenac and of 15% in the exposure to rofecoxib. In addition, EHC prolongs the inhibition of PGE2 and increases the duration of the anti-inflammatory effect (24 h for rofecoxib 10 mg kg−1) without affecting maximum inhibition. Conclusions and implications: Our findings show the relevance of exploring EHC in a quantitative manner to accurately interpret pharmacodynamic findings in vivo, in particular when scaling across species. PMID:18193075

  10. Optimisation of the dosage of tranexamic acid in trauma patients with population pharmacokinetic analysis.

    Science.gov (United States)

    Grassin-Delyle, S; Theusinger, O M; Albrecht, R; Mueller, S; Spahn, D R; Urien, S; Stein, P

    2018-06-01

    Tranexamic acid is used both pre-hospital and in-hospital as an antifibrinolytic drug to treat or prevent hyperfibrinolysis in trauma patients; dosing, however, remains empirical. We aimed to measure plasma levels of tranexamic acid in patients receiving pre-hospital anti-hyperfibrinolytic therapy and to build a population pharmacokinetic model to propose an optimised dosing regimen. Seventy-three trauma patients were enrolled and each received tranexamic acid 1 g intravenously pre-hospital. A blood sample was drawn after arrival in the emergency department, and we measured the plasma tranexamic acid concentration using liquid chromatography-mass spectrometry, and modelled the data using non-linear mixed effect modelling. Tranexamic acid was administered at a median (IQR [range]) time of 43 (30-55 [5-135]) min after trauma. Plasma tranexamic acid levels were determined on arrival at hospital, 57 (43-70 [20-148]) min after pre-hospital administration of the drug. The measured concentration was 28.7 (21.5-38.5 [8.7-89.0]) μg.ml -1 . Our subjects had sustained severe trauma; injury severity score 20 (16-29 [5-75]), including penetrating injury in 2.8% and isolated traumatic brain injury in 19.7%. The pharmacokinetics were ascribed a two-compartment open model with body-weight as the main covariate. As tranexamic acid concentrations may fall below therapeutic levels during initial hospital treatment, we propose additional dosing schemes to maintain a specific target blood concentration for as long as required. This is the first study to investigate plasma level and pharmacokinetics of tranexamic acid after pre-hospital administration in trauma patients. Our proposed dosing regimen could be used in subsequent clinical trials to better study efficacy and tolerance profiles with controlled blood concentrations. © 2018 The Association of Anaesthetists of Great Britain and Ireland.

  11. Population Pharmacokinetics of Meropenem in Plasma and Subcutis in Patients on Extracorporeal Membrane Oxygenation Treatment

    DEFF Research Database (Denmark)

    Hanberg, Pelle; Öbrink-Hansen, Kristina; Thorsted, Anders

    2018-01-01

    The objectives of this study were to describe meropenem pharmacokinetics (PK) in plasma and/or subcutaneous adipose tissue (SCT) in critically ill patients receiving ECMO treatment, and to develop a population PK model to simulate alternative dosing regimens and modes of administration. We...... conducted a prospective observational study. Ten patients on ECMO treatment received meropenem (1 or 2 g) intravenously over 5 min every 8 hours. Serial SCT concentrations were determined using microdialysis and compared with plasma concentrations. A population PK model of SCT and plasma data was developed...... infusion would be needed for 100%fT>MIC and 100%fT>4xMIC to be obtained. Meropenem plasma and SCT concentrations were associated with estimated creatinine-clearance (eCLCr). Simulations showed that in patients with increased eCLCr, dose increment or continuous infusion may be needed to obtain therapeutic...

  12. Population Pharmacokinetics of Artesunate and Dihydroartemisinin following Intra-Rectal Dosing of Artesunate in Malaria Patients

    Science.gov (United States)

    Simpson, Julie A; Agbenyega, Tsiri; Barnes, Karen I; Perri, Gianni Di; Folb, Peter; Gomes, Melba; Krishna, Sanjeev; Krudsood, Srivicha; Looareesuwan, Sornchai; Mansor, Sharif; McIlleron, Helen; Miller, Raymond; Molyneux, Malcolm; Mwenechanya, James; Navaratnam, Visweswaran; Nosten, Francois; Olliaro, Piero; Pang, Lorrin; Ribeiro, Isabela; Tembo, Madalitso; van Vugt, Michele; Ward, Steve; Weerasuriya, Kris; Win, Kyaw; White, Nicholas J

    2006-01-01

    Background Intra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with parasitological responses in patients with moderately severe falciparum malaria. Methods and Findings Adults and children in Africa and Southeast Asia with moderately severe malaria were recruited in two Phase II studies (12 adults from Southeast Asia and 11 children from Africa) with intensive sampling protocols, and three Phase III studies (44 children from Southeast Asia, and 86 children and 26 adults from Africa) with sparse sampling. All patients received 10 mg/kg artesunate as a single intra-rectal dose of suppositories. Venous blood samples were taken during a period of 24 h following dosing. Plasma artesunate and dihydroartemisinin (DHA, the main biologically active metabolite) concentrations were measured by high-performance liquid chromatography with electrochemical detection. The pharmacokinetic properties of DHA were determined using nonlinear mixed-effects modelling. Artesunate is rapidly hydrolysed in vivo to DHA, and this contributes the majority of antimalarial activity. For DHA, a one-compartment model assuming complete conversion from artesunate and first-order appearance and elimination kinetics gave the best fit to the data. The mean population estimate of apparent clearance (CL/F) was 2.64 (l/kg/h) with 66% inter-individual variability. The apparent volume of distribution (V/F) was 2.75 (l/kg) with 96% inter-individual variability. The estimated DHA population mean elimination half-life was 43 min. Gender was associated with increased mean CL/F by 1.14 (95% CI: 0.36–1.92) (l/kg/h) for a male compared with a female, and weight was positively associated with V/F. Larger V/Fs were observed for the patients requiring early rescue treatment compared

  13. Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients.

    Directory of Open Access Journals (Sweden)

    Julie A Simpson

    2006-11-01

    Full Text Available Intra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with parasitological responses in patients with moderately severe falciparum malaria.Adults and children in Africa and Southeast Asia with moderately severe malaria were recruited in two Phase II studies (12 adults from Southeast Asia and 11 children from Africa with intensive sampling protocols, and three Phase III studies (44 children from Southeast Asia, and 86 children and 26 adults from Africa with sparse sampling. All patients received 10 mg/kg artesunate as a single intra-rectal dose of suppositories. Venous blood samples were taken during a period of 24 h following dosing. Plasma artesunate and dihydroartemisinin (DHA, the main biologically active metabolite concentrations were measured by high-performance liquid chromatography with electrochemical detection. The pharmacokinetic properties of DHA were determined using nonlinear mixed-effects modelling. Artesunate is rapidly hydrolysed in vivo to DHA, and this contributes the majority of antimalarial activity. For DHA, a one-compartment model assuming complete conversion from artesunate and first-order appearance and elimination kinetics gave the best fit to the data. The mean population estimate of apparent clearance (CL/F was 2.64 (l/kg/h with 66% inter-individual variability. The apparent volume of distribution (V/F was 2.75 (l/kg with 96% inter-individual variability. The estimated DHA population mean elimination half-life was 43 min. Gender was associated with increased mean CL/F by 1.14 (95% CI: 0.36-1.92 (l/kg/h for a male compared with a female, and weight was positively associated with V/F. Larger V/Fs were observed for the patients requiring early rescue treatment compared with the remainder

  14. Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients.

    Science.gov (United States)

    Simpson, Julie A; Agbenyega, Tsiri; Barnes, Karen I; Di Perri, Gianni; Folb, Peter; Gomes, Melba; Krishna, Sanjeev; Krudsood, Srivicha; Looareesuwan, Sornchai; Mansor, Sharif; McIlleron, Helen; Miller, Raymond; Molyneux, Malcolm; Mwenechanya, James; Navaratnam, Visweswaran; Nosten, Francois; Olliaro, Piero; Pang, Lorrin; Ribeiro, Isabela; Tembo, Madalitso; van Vugt, Michele; Ward, Steve; Weerasuriya, Kris; Win, Kyaw; White, Nicholas J

    2006-11-01

    Intra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with parasitological responses in patients with moderately severe falciparum malaria. Adults and children in Africa and Southeast Asia with moderately severe malaria were recruited in two Phase II studies (12 adults from Southeast Asia and 11 children from Africa) with intensive sampling protocols, and three Phase III studies (44 children from Southeast Asia, and 86 children and 26 adults from Africa) with sparse sampling. All patients received 10 mg/kg artesunate as a single intra-rectal dose of suppositories. Venous blood samples were taken during a period of 24 h following dosing. Plasma artesunate and dihydroartemisinin (DHA, the main biologically active metabolite) concentrations were measured by high-performance liquid chromatography with electrochemical detection. The pharmacokinetic properties of DHA were determined using nonlinear mixed-effects modelling. Artesunate is rapidly hydrolysed in vivo to DHA, and this contributes the majority of antimalarial activity. For DHA, a one-compartment model assuming complete conversion from artesunate and first-order appearance and elimination kinetics gave the best fit to the data. The mean population estimate of apparent clearance (CL/F) was 2.64 (l/kg/h) with 66% inter-individual variability. The apparent volume of distribution (V/F) was 2.75 (l/kg) with 96% inter-individual variability. The estimated DHA population mean elimination half-life was 43 min. Gender was associated with increased mean CL/F by 1.14 (95% CI: 0.36-1.92) (l/kg/h) for a male compared with a female, and weight was positively associated with V/F. Larger V/Fs were observed for the patients requiring early rescue treatment compared with the remainder, independent

  15. Population pharmacokinetic study of benznidazole in pediatric Chagas disease suggests efficacy despite lower plasma concentrations than in adults.

    Directory of Open Access Journals (Sweden)

    Jaime Altcheh

    2014-05-01

    Full Text Available Chagas disease, caused by the parasite Trypanosoma cruzi, can lead to long term cardiac morbidity. Treatment of children with benznidazole is effective, but no pediatric pharmacokinetics data are available and clinical pharmacology information on the drug is scarce.Prospective population pharmacokinetic (PK cohort study in children 2-12 years old with Chagas disease treated with oral benznidazole 5-8 mg/kg/day BID for 60 days. (clinicaltrials.gov #NCT00699387.Forty children were enrolled in the study. Mean age was 7.3 years. A total of 117 samples were obtained from 38 patients for PK analysis. A one compartment model best fit the data. Weight-corrected clearance rate (CL/F showed a good correlation with age, with younger patients having a significantly higher CL/F than older children and adults. Simulated median steady-state benznidazole concentrations, based on model parameters, were lower for children in our study than for adults and lowest for children under 7 years of age. Treatment was efficacious in the 37 patients who completed the treatment course, and well tolerated, with few, and mild, adverse drug reactions (ADRs.Observed benznidazole plasma concentrations in children were markedly lower than those previously reported in adults (treated with comparable mg/kg doses, possibly due to a higher CL/F in smaller children. These lower blood concentrations were nevertheless associated to a high therapeutic response in our cohort. Unlike adults, children have few adverse reactions to the drug, suggesting that there may be a direct correlation between drug concentrations and incidence of ADRs. Our results suggest that studies with lower doses in adults may be warranted.ClinicalTrials.gov NCT00699387.

  16. Performance of an iterative two-stage bayesian technique for population pharmacokinetic analysis of rich data sets

    NARCIS (Netherlands)

    Proost, Johannes H.; Eleveld, Douglas J.

    2006-01-01

    Purpose. To test the suitability of an Iterative Two-Stage Bayesian (ITSB) technique for population pharmacokinetic analysis of rich data sets, and to compare ITSB with Standard Two-Stage (STS) analysis and nonlinear Mixed Effect Modeling (MEM). Materials and Methods. Data from a clinical study with

  17. Exposure-safety and efficacy response relationships and population pharmacokinetics of eslicarbazepine acetate.

    Science.gov (United States)

    Gidal, B E; Jacobson, M P; Ben-Menachem, E; Carreño, M; Blum, D; Soares-da-Silva, P; Falcão, A; Rocha, F; Moreira, J; Grinnell, T; Ludwig, E; Fiedler-Kelly, J; Passarell, J; Sunkaraneni, S

    2018-05-06

    Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED) for focal-onset seizures (FOS). Pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to assess dose selection, identify significant AED drug interactions, and quantitate relationships between exposure and safety and efficacy outcomes from Phase 3 trials of adjunctive ESL. Eslicarbazepine (the primary active metabolite of ESL) population PK was evaluated using data from 1351 subjects enrolled in 14 studies (11 Phase 1 and three Phase 3 studies) after multiple oral doses ranging from 400 to 1200 mg. Population PK and PD models related individual eslicarbazepine exposures to safety outcomes and efficacy responses. Eslicarbazepine PK was described by a one-compartment model with linear absorption and elimination. The probability of a treatment-emergent adverse event (TEAE; dizziness, headache, or somnolence) was higher with an initial dose of ESL 800 mg than with an initial dose of ESL 400 mg QD. Body weight, sex, region, and baseline use of carbamazepine (CBZ) or lamotrigine were also found to influence the probability of TEAEs. Eslicarbazepine exposure influenced serum sodium concentration, standardized seizure frequency, and probability of response; better efficacy outcomes were predicted in patients not from Western Europe (WE; vs WE patients) and those not taking CBZ (vs taking CBZ) at baseline. Pharmacokinetic and PK/PD modeling were implemented during the development of ESL for adjunctive treatment of FOS in adults. This quantitative approach supported decision-making during the development of ESL, and contributed to dosing recommendations and labeling information related to drug interactions. © 2018 The Authors. Acta Neurologica Scandinavica Published by John Wiley & Sons Ltd.

  18. Population Pharmacokinetics of Intravenous Paracetamol (Acetaminophen) in Preterm and Term Neonates: Model Development and External Evaluation.

    Science.gov (United States)

    Cook, Sarah F; Roberts, Jessica K; Samiee-Zafarghandy, Samira; Stockmann, Chris; King, Amber D; Deutsch, Nina; Williams, Elaine F; Allegaert, Karel; Wilkins, Diana G; Sherwin, Catherine M T; van den Anker, John N

    2016-01-01

    The aims of this study were to develop a population pharmacokinetic model for intravenous paracetamol in preterm and term neonates and to assess the generalizability of the model by testing its predictive performance in an external dataset. Nonlinear mixed-effects models were constructed from paracetamol concentration-time data in NONMEM 7.2. Potential covariates included body weight, gestational age, postnatal age, postmenstrual age, sex, race, total bilirubin, and estimated glomerular filtration rate. An external dataset was used to test the predictive performance of the model through calculation of bias, precision, and normalized prediction distribution errors. The model-building dataset included 260 observations from 35 neonates with a mean gestational age of 33.6 weeks [standard deviation (SD) 6.6]. Data were well-described by a one-compartment model with first-order elimination. Weight predicted paracetamol clearance and volume of distribution, which were estimated as 0.348 L/h (5.5 % relative standard error; 30.8 % coefficient of variation) and 2.46 L (3.5 % relative standard error; 14.3 % coefficient of variation), respectively, at the mean subject weight of 2.30 kg. An external evaluation was performed on an independent dataset that included 436 observations from 60 neonates with a mean gestational age of 35.6 weeks (SD 4.3). The median prediction error was 10.1 % [95 % confidence interval (CI) 6.1-14.3] and the median absolute prediction error was 25.3 % (95 % CI 23.1-28.1). Weight predicted intravenous paracetamol pharmacokinetics in neonates ranging from extreme preterm to full-term gestational status. External evaluation suggested that these findings should be generalizable to other similar patient populations.

  19. Semiphysiological versus Empirical Modelling of the Population Pharmacokinetics of Free and Total Cefazolin during Pregnancy

    Directory of Open Access Journals (Sweden)

    J. G. Coen van Hasselt

    2014-01-01

    Full Text Available This work describes a first population pharmacokinetic (PK model for free and total cefazolin during pregnancy, which can be used for dose regimen optimization. Secondly, analysis of PK studies in pregnant patients is challenging due to study design limitations. We therefore developed a semiphysiological modeling approach, which leveraged gestation-induced changes in creatinine clearance (CrCL into a population PK model. This model was then compared to the conventional empirical covariate model. First, a base two-compartmental PK model with a linear protein binding was developed. The empirical covariate model for gestational changes consisted of a linear relationship between CL and gestational age. The semiphysiological model was based on the base population PK model and a separately developed mixed-effect model for gestation-induced change in CrCL. Estimates for baseline clearance (CL were 0.119 L/min (RSE 58% and 0.142 L/min (RSE 44% for the empirical and semiphysiological models, respectively. Both models described the available PK data comparably well. However, as the semiphysiological model was based on prior knowledge of gestation-induced changes in renal function, this model may have improved predictive performance. This work demonstrates how a hybrid semiphysiological population PK approach may be of relevance in order to derive more informative inferences.

  20. Genetic parameters in a Swine Population

    Directory of Open Access Journals (Sweden)

    Dana Popa

    2010-05-01

    Full Text Available The estimation of the variance-covariance components is a very important step in animal breeding because these components are necessary for: estimation of the genetic parameters, prediction of the breeding value and design of animal breeding programs. The estimation of genetic parameters is the first step in the development of a swine breeding program, using artificial insemination. Various procedures exist for estimation of heritability. There are three major procedures used for estimating heritability: analysis of variance (ANOVA, parents-offspring regression and restricted maximum likelihood (REML. By using ANOVA methodology or regression method it is possible to obtain aberrant values of genetic parameters (negative or over unit value of heritability coefficient, for example which can not be interpreting because is out of biological limits.

  1. Pharmacokinetic study of atorvastain after single dose administration among pakistani population

    International Nuclear Information System (INIS)

    Maqsood, I.; Najmi, M. H.; Mazhar, W.; Janjua, A.; Tayyaba, B.; Sabah, S.; Bader, Z.

    2017-01-01

    Objective: To obtain pharmacokinetic data of Orvastin, a newly launched formulation of atorvastatin, in healthy males of Pakistan. Study Design: It was quasi-experimental design. Place and Duration of Study: Study was conducted at Centre for Research in Experimental and Applied Medicine (CREAM) Army Medical College, Rawalpindi and duration of study was about ten months. Material and Methods: Twenty-four healthy male subjects were taken conveniently from Pakistani population. Two tablets of Orvastin, each containing atorvastatin 40mg, were administered orally as a single dose. Multiple blood samples were taken with small gaps in between up to the period of 48hrs. High Performance Liquid Chromatography (HPLC) with UV-detector was used for quantification of atorvastatin in plasma; wavelength of UV-detector was adjusted at 247nm. Mobile phase was made up of 60 percent acetonitrile and 40 percent 0.05M sodium phosphate buffer. Flow rate of mobile phase was maintained at 1.5ml/min with 5.5 pH. Progesterone was used as an internal standard. Stock solutions of atorvastatin were made by dissolving it into methanol and acetonitrile was used for making stock solution of progesterone. Calibration curves were made for atorvastatin and internal standard from oncentration time data, values for time to achieve maximum plasma concentration. (Tmax) and maximum plasma concentration (Cmax) were directly calculated. Computer program (APO, MW PHARM, and Ver. 3.60) was used for calculation of pharmacokinetic profile of atorvastatin. Results: Atorvastatin was detected in plasma samples of all volunteers. The absorption rate constant (Ka) was 0.41 l/hr. Cmax was 26.69 ± 6.67 µg/l and Tmax was 3.33 ± 0.41 hrs. Apparent volume of distribution (Vd), of atorvastatin, was 3244.84 ± 1237.36 liters. The elimination rate constant was 0.15 l/hr. Elimination half-life of atorvastatin was 6.14 hours. Trapezoidal rule was used for calculation of AUC /sub 0-48/ and AUC /sub 0-∞/ and it was found

  2. Population pharmacokinetics of hydroxyurea for children and adolescents with sickle cell disease.

    Science.gov (United States)

    Wiczling, Paweł; Liem, Robert I; Panepinto, Julie A; Garg, Uttam; Abdel-Rahman, Susan M; Kearns, Gregory L; Neville, Kathleen A

    2014-09-01

    The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe hydroxyurea (HU) concentrations in serum and urine following oral drug administration in pediatric patients with sickle cell disease. Additionally, the measured hydroxyurea concentrations for particular sampling time were correlated with exposure measures (AUC) to find the most predictive relationship. Hydroxyurea concentrations were determined in 21 subjects. Using a population nonlinear mixed-effect modeling, the HU PK was best described by a one-compartment model with two elimination pathways (metabolic and renal) and a transit compartment absorption. The typical mean absorption time was 0.222 hour. The typical apparent volume of distribution was 21.8 L and the apparent systemic clearance was 6.88 L/h for an average weight patient of 30.7 kg. The 50% of the HU dose was renally excreted. Linear correlations were apparent between the plasma HU concentration at 1, 1.5, 2, 4, and 6 hours post-dose and AUC with the most significant (R(2)  = 0.71) observed at 1.5 hours. A population PK model was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5 hours after an oral dose of the drug were highly predictive of systemic drug exposure. © 2014, The American College of Clinical Pharmacology.

  3. Population Pharmacokinetics of Telapristone (CDB-4124) and its Active Monodemethylated Metabolite CDB-4453, with a Mixture Model for Total Clearance

    OpenAIRE

    Morris, Denise; Podolski, Joseph; Kirsch, Alan; Wiehle, Ronald; Fleckenstein, Lawrence

    2011-01-01

    Telapristone is a selective progesterone antagonist that is being developed for the long-term treatment of symptoms associated with endometriosis and uterine fibroids. The population pharmacokinetics of telapristone (CDB-4124) and CDB-4453 was investigated using nonlinear mixed-effects modeling. Data from two clinical studies (n?=?32) were included in the analysis. A two-compartment (parent) one compartment (metabolite) mixture model (with two populations for apparent clearance) with first-or...

  4. Population Pharmacokinetics of Hydroxychloroquine in Japanese Patients With Cutaneous or Systemic Lupus Erythematosus.

    Science.gov (United States)

    Morita, Shigemichi; Takahashi, Toshiya; Yoshida, Yasushi; Yokota, Naohisa

    2016-04-01

    Hydroxychloroquine (HCQ) is an effective treatment for patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) and has been used for these patients in more than 70 nations. However, in Japan, HCQ has not been approved for CLE or SLE. To establish an appropriate therapeutic regimen and to clarify the pharmacokinetics (PK) of HCQ in Japanese patients with CLE with or without SLE (CLE/SLE), a population pharmacokinetic (PopPK) analysis was performed. In a clinical study of Japanese patients with a diagnosis of CLE irrespective of the presence of SLE, blood and plasma drug concentration-time data receiving multiple oral doses of HCQ sulfate (200-400 mg daily) were analyzed using nonlinear mixed-effects model software. The blood and plasma concentrations of HCQ were analyzed using a high-performance liquid chromatography tandem mass spectrometry method. Model evaluation and validation were performed using goodness-of-fit (GOF) plots, visual predictive check, and a bootstrap. The PopPKs of HCQ in the blood and plasma of 90 Japanese patients with CLE/SLE were well described by a 1-compartment model with first-order absorption and absorption lag time. Body weight was a significant (P < 0.001) covariate of oral clearance of HCQ. The final model was assessed using GOF plots, a bootstrap, and visual predictive check, and this model was appropriate. Simulations based on the final model suggested that the recommended daily doses of HCQ sulfate (200-400 mg) based on the ideal body weight in Japanese patients with CLE/SLE were in the similar concentration ranges. The PopPK models derived from both blood and plasma HCQ concentrations of Japanese patients with CLE/SLE were developed and validated. Based on this study, the dosage regimens of HCQ sulfate for Japanese patients with CLE/SLE should be calculated using the individual ideal body weight.

  5. Population pharmacokinetics and pharmacodynamics of escitalopram in overdose and the effect of activated charcoal

    Science.gov (United States)

    van Gorp, Freek; Duffull, Stephen; Hackett, L Peter; Isbister, Geoffrey K

    2012-01-01

    AIMS To describe the pharmacokinetics and pharmacodynamics (PKPD) of escitalopram in overdose and its effect on QT prolongation, including the effectiveness of single dose activated charcoal (SDAC). METHODS The data set included 78 escitalopram overdose events (median dose, 140 mg [10–560 mg]). SDAC was administered 1.0 to 2.6 h after 12 overdoses (15%). A fully Bayesian analysis was undertaken in WinBUGS 1.4.3, first for a population pharmacokinetic (PK) analysis followed by a PKPD analysis. The developed PKPD model was used to predict the probability of having an abnormal QT as a surrogate for torsade de pointes. RESULTS A one compartment model with first order input and first-order elimination described the PK data, including uncertainty in dose and a baseline concentration for patients taking escitalopram therapeutically. SDAC reduced the fraction absorbed by 31% and reduced the individual predicted area under the curve adjusted for dose (AUCi/dose). The absolute QT interval was related to the observed heart rate with an estimated individual heart rate correction factor (α = 0.35). The heart rate corrected QT interval (QTc) was linearly dependent on predicted escitalopram concentration [slope = 87 ms/(mg l–1)], using a hypothetical effect-compartment (half-life of effect-delay, 1.0h). Administration of SDAC significantly reduced QT prolongation and was shown to reduce the risk of having an abnormal QT by approximately 35% for escitalopram doses above 200 mg. CONCLUSIONS There was a dose-related lengthening of the QT interval that lagged the increase in drug concentration. SDAC resulted in a moderate reduction in fraction of escitalopram absorbed and reduced the risk of the QT interval being abnormal. PMID:21883384

  6. Population pharmacokinetics of ifosfamide and its 2-and 3-dechloroethylated and 4-hydroxylated metabolites in resistant small-cell lung cancer patients

    NARCIS (Netherlands)

    Kerbusch, T; vanPutten, JWG; Groen, HJM; Huitema, ADR; Mathot, RAA; Beijnen, JH

    The aim of this study was to develop a population pharmacokinetic model that could describe the pharmacokinetics of ifosfamide, 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide, and calculate their plasma exposure and urinary excretion. A group of 14 patients with small-cell lung cancer

  7. Oxaliplatin in patients with metastatic colorectal cancer: efficacy and pharmacokinetics parameters.

    Science.gov (United States)

    Burz, C; Berindan-Neagoe, I; Balacescu, O; Todor, N; Pelau, D; Floares, C; Kacso, G; Tanaselia, C; Ursu, M; Vlase, L; Leucuta, S E; Cristea, V; Irimie, A

    2010-01-01

    The aim of this study was to investigate the efficiency of the FOLFOX-4 regimen and to evaluate the pharmacokinetics of oxaliplatin in untreated patients with metastatic colorectal cancer. 43 patients were enrolled in the study. Patients received oxaliplatin 85 mg/m(2) as 2-h i.v. infusion, on day 1, and bolus 5-fluorouracil (5FU) 400 mg/m(2) plus leucovorin (LV) 200 mg/m(2) followed by 5FU 600 mg/m(2) as 22-h infusion on day 1 and 2, every 2 weeks. The pharmacokinetics of oxaliplatin evaluated in 4 patients was performed in blood, plasma and ultrafiltered plasma (UFT) by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The overall response rate and the median time to progression (TTP) were 53.49% and 7.1 months, respectively. Grade 3-4 toxic effects were observed in 11 (25.5%) patients. Grade 3 neuropathy was observed in 13.95% of the cases. In univariate analysis only Eastern Cooperative Oncology Group (ECOG) performance status (PS) was correlated with response. No correlation was found between grade 3-4 adverse events and the patient characteristics. The area under the time-concentration curve (AUC) in UFT was 4.8 + or - 0.72 standard deviation (SD) microg h/ml and the total clearance 30.17 + or - 7.75 l/min. The values for volume of distribution and the maximum concentration were 567 + or - 20 liters and 0.38 + or - 0.17 ug/ml, respectively. FOLFOX-4 was an effective regimen with good tolerability in previously untreated metastatic colorectal cancer patients. The pharmacokinetics of oxaliplatin was triphasic with a short initial distribution phase and a long terminal elimination phase.

  8. Pharmacokinetics of Antibiotics in Sub-Saharan African Patient Populations: A Systematic Review.

    Science.gov (United States)

    Bos, Jeannet C; van Hest, Reinier M; Prins, Jan M

    2017-08-01

    In sub-Saharan Africa (SSA), severe febrile illness accounts for a large majority of medical admissions. SSA patients may also suffer from cachexia and organ dysfunction resulting from tuberculosis, hepatitis B, and hypertension. It is hard to tell how these conditions influence the pharmacokinetics (PK) of antibiotics in this population. The aim of this systematic review was to summarize antibiotic PK data of SSA adult patient populations to clarify whether inappropriate drug concentrations that may also lead to antimicrobial resistance are likely to occur. An electronic search was conducted in Ovid MEDLINE, Embase, and the African Index Medicus collecting studies from 1946 to May 2016. Reviewers independently selected studies reporting outcome data on volume of distribution (V), clearance, and half-life. Relevant information was abstracted and quality assessed. Twelve studies were selected, addressing 6 antibiotic classes. There were 6 studies on fluoroquinolones and 1 on β-lactam antibiotics. Nine out of 12 originated from South Africa and 6 of those dealt with intensive care unit (ICU) populations. The quality of most studies was low. Studies on amikacin, teicoplanin, and ertapenem (n = 4) displayed a pattern of a large V with low drug concentrations. Fluoroquinolone PK changes were less prominent and more diverse whereas the probability of pharmacodynamic target attainment was low for the treatment of tuberculosis in South Africa. Interindividual variability of V was high for 10/12 studies. Antibiotic PK data of SSA adult patient populations are scarce, but disease-induced inappropriate drug concentrations do occur. Data from non-ICU, severely ill patients, and β-lactam data are particularly lacking, whereas β-lactam antibiotics are commonly used, and typically vulnerable to disease-induced PK changes. Studies investigating the PK and pharmacodynamics of β-lactam antibiotics in severely ill, adult SSA patient populations are needed to improve local

  9. Population pharmacokinetics of cytarabine, etoposide and daunorubicin in the treatment of acute myeloid leukaemia

    DEFF Research Database (Denmark)

    Krogh-Madsen, Mikkel; Bender, B.; Jensen, M. K.

    2012-01-01

    PURPOSE: Interpatient variability in the pharmacokinetics (PK) of cytarabine, etoposide, and daunorubicin following body surface area-adjusted doses calls for studies that point to other covariates to explain this variability. The purpose of this study was to investigate such relationships and gi...... and the relationship between kidney function and etoposide clearance to clinical end points would support dose individualization. Patients with above-normal creatinine clearances and high bWBC may receive sub-optimal treatment due to elevated etoposide clearances....... insights into the PK of this combination treatment. METHODS: A prospective population PK study of twenty-three patients with acute myeloid leukemia was undertaken. Plasma concentrations of patients were determined by high-pressure liquid chromatography. PK models were developed with NONMEM...... in creatinine clearance of 60 mL/min resulted in a decrease in etoposide clearance of 32%. CONCLUSIONS: Population-based models characterized the PK for all three drugs. bWBC was a significant covariate for etoposide and cytarabine and showed a trend for daunorubicin. Linking the significant bWBC relationships...

  10. Pharmacokinetic/pharmacodynamic evaluation of marbofloxacin as a single injection for Pasteurellaceae respiratory infections in cattle using population pharmacokinetics and Monte Carlo simulations.

    Science.gov (United States)

    Paulin, A; Schneider, M; Dron, F; Woehrle, F

    2018-02-01

    Population pharmacokinetic of marbofloxacin was investigated with 52 plasma concentration-time profiles obtained after intramuscular administration of Forcyl® in cattle. Animal's status, pre-ruminant, ruminant, or dairy cow, was retained as a relevant covariate for clearance. Monte Carlo simulations were performed using a stratification by status, and 1000 virtual disposition curves were generated in each bovine subpopulation for the recommended dosage regimen of 10 mg/kg as a single injection. The probability of target attainment (PTA) of pharmacokinetic/pharmacodynamic (PK/PD) ratios associated with clinical efficacy and prevention of resistance was determined in each simulated subpopulation. The cumulative fraction of response (CFR) of animals achieving a PK/PD ratio predictive of positive clinical outcome was then calculated for the simulated dosage regimen, taking into account the minimum inhibitory concentration (MIC) distribution of Pasteurella multocida, Mannheimia haemolytica, and Histophilus somni. When considering a ratio of AUC 0-24 hr /MIC (area under the curve/minimum inhibitory concentration) greater than 125 hr, CFRs ranging from 85% to 100% against the three Pasteurellaceae in each bovine subpopulation were achieved. The PTA of the PK/PD threshold reflecting the prevention of resistances was greater than 90% up to MPC (mutant prevention concentration) values of 1 μg/ml in pre-ruminants and ruminants and 0.5 μg/ml in dairy cows. © 2017 The Authors. Journal of Veterinary Pharmacology and Therapeutics Published by John Wiley & Sons Ltd.

  11. Population Pharmacokinetic Model for Vancomycin Used in Open Heart Surgery: Model-Based Evaluation of Standard Dosing Regimens.

    Science.gov (United States)

    Alqahtani, Saeed A; Alsultan, Abdullah S; Alqattan, Hussain M; Eldemerdash, Ahmed; Albacker, Turki B

    2018-04-23

    The purpose of this study was to investigate the population pharmacokinetics of vancomycin in patients undergoing open heart surgery. In this observational pharmacokinetic study, multiple blood samples were drawn over a 48-h period of intravenous vancomycin in patients who were undergoing open heart surgery. Blood samples were analysed using the Architect i4000SR Immunoassay Analyzer. Population pharmacokinetic models were developed using Monolix 4.4 software. Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. One-hundred and sixty-eight blood samples were analysed from 28 patients. The pharmacokinetics of vancomycin was best described by a two-compartment model with between-subject variability in CL, V of the central compartment, and V of the peripheral compartment. CL and central compartment V of vancomycin were related to CL CR , body weight, and albumin concentration. Dosing simulations showed that standard dosing regimens of 1 and 1.5 g failed to achieve the PK-PD target of AUC 0--24 /MIC > 400 for an MIC of 1 mg/L, while high weight-based dosing regimens were able to achieve the PK-PD target. In summary, administration of standard doses of 1 and 1.5 g of vancomycin two times daily provided inadequate antibiotic prophylaxis in patients undergoing open heart surgery. The same findings were obtained when 15 mg/kg and 20 mg/kg doses of vancomycin were administered. Achieving the PK-PD target required higher doses (25 mg/kg and 30 mg/kg) of vancomycin. Copyright © 2018 American Society for Microbiology.

  12. Prediction of pharmacokinetic and toxicological parameters of a 4-phenylcoumarin isolated from geopropolis: In silico and in vitro approaches.

    Science.gov (United States)

    da Cunha, Marcos Guilherme; Franco, Gilson César Nobre; Franchin, Marcelo; Beutler, John A; de Alencar, Severino Matias; Ikegaki, Masaharu; Rosalen, Pedro Luiz

    2016-11-30

    In silico and in vitro methodologies have been used as important tools in the drug discovery process, including from natural sources. The aim of this study was to predict pharmacokinetic and toxicity (ADME/Tox) properties of a coumarin isolated from geopropolis using in silico and in vitro approaches. Cinnamoyloxy-mammeisin (CNM) isolated from Brazilian M. scutellaris geopropolis was evaluated for its pharmacokinetic parameters by in silico models (ACD/Percepta™ and MetaDrug™ software). Genotoxicity was assessed by in vitro DNA damage signaling PCR array. CNM did not pass all parameters of Lipinski's rule of five, with a predicted low oral bioavailability and high plasma protein binding, but with good predicted blood brain barrier penetration. CNM was predicted to show low affinity to cytochrome P450 family members. Furthermore, the predicted Ames test indicated potential mutagenicity of CNM. Also, the probability of toxicity for organs and tissues was classified as moderate and high for liver and kidney, and moderate and low for skin and eye irritation, respectively. The PCR array analysis showed that CNM significantly upregulated about 7% of all DNA damage-related genes. By exploring the biological function of these genes, it was found that the predicted CNM genotoxicity is likely to be mediated by apoptosis. The predicted ADME/Tox profile suggests that external use of CNM may be preferable to systemic exposure, while its genotoxicity was characterized by the upregulation of apoptosis-related genes after treatment. The combined use of in silico and in vitro approaches to evaluate these parameters generated useful hypotheses to guide further preclinical studies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. Possible impact of the CYP2D6*10 polymorphism on the nonlinear pharmacokinetic parameter estimates of paroxetine in Japanese patients with major depressive disorders

    Directory of Open Access Journals (Sweden)

    Saruwatari J

    2014-04-01

    Full Text Available Junji Saruwatari,1 Hiroo Nakashima,1 Shoko Tsuchimine,2 Miki Nishimura,1 Naoki Ogusu,1 Norio Yasui-Furukori21Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; 2Department of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki, JapanAbstract: It has been suggested that the reduced function allele with reduced cytochrome P450 (CYP 2D6 activity, CYP2D6*10, is associated with the interindividual differences in the plasma paroxetine concentrations, but there is no data presently available regarding the influence of the CYP2D6*10 polymorphism on the pharmacokinetic parameters, eg, Michaelis–Menten constant (Km and maximum velocity (Vmax, in Asian populations. The present study investigated the effects of the CYP2D6 polymorphisms, including CYP2D6*10, on the pharmacokinetic parameters of paroxetine in Japanese patients with major depressive disorders. This retrospective study included 15 Japanese patients with major depressive disorders (four males and eleven females who were treated with paroxetine. The CYP2D6*2, CYP2D6*4, CYP2D6*5, CYP2D6*10, CYP2D6*18, CYP2D6*39, and CYP2D6*41 polymorphisms were evaluated. A total of 56 blood samples were collected from the patients. The Km and Vmax values of paroxetine were estimated for each patient. The allele frequencies of CYP2D6*2, CYP2D6*4, CYP2D6*5, CYP2D6*10, CYP2D6*18, CYP2D6*39, and CYP2D6*41 were 6.7%, 0%, 10.0%, 56.7%, 0%, 26.7%, and 0%, respectively. The mean values of Km and Vmax were 50.5±68.4 ng/mL and 50.6±18.8 mg/day, respectively. Both the Km and Vmax values were significantly smaller in CYP2D6*10 allele carriers than in the noncarriers (24.2±18.3 ng/mL versus 122.5±106.3 ng/mL, P=0.008; 44.2±16.1 mg/day versus 68.3±15.0 mg/day, P=0.022, respectively. This is the first study to demonstrate that the CYP2D6*10 polymorphism could affect the nonlinear pharmacokinetic parameter estimates of

  14. Pooled population pharmacokinetic model of imipenem in plasma and the lung epithelial lining fluid.

    Science.gov (United States)

    van Hasselt, J G Coen; Rizk, Matthew L; Lala, Mallika; Chavez-Eng, Cynthia; Visser, Sandra A G; Kerbusch, Thomas; Danhof, Meindert; Rao, Gauri; van der Graaf, Piet H

    2016-06-01

    Several clinical trials have confirmed the therapeutic benefit of imipenem for treatment of lung infections. There is however no knowledge of the penetration of imipenem into the lung epithelial lining fluid (ELF), the site of action relevant for lung infections. Furthermore, although the plasma pharmacokinetics (PK) of imipenem has been widely studied, most studies have been based on selected patient groups. The aim of this analysis was to characterize imipenem plasma PK across populations and to quantify imipenem ELF penetration. A population model for imipenem plasma PK was developed using data obtained from healthy volunteers, elderly subjects and subjects with renal impairment, in order to identify predictors for inter-individual variability (IIV) of imipenem PK. Subsequently, a clinical study which measured plasma and ELF concentrations of imipenem was included in order to quantify lung penetration. A two compartmental model best described the plasma PK of imipenem. Creatinine clearance and body weight were included as subject characteristics predictive for IIV on clearance. Typical estimates for clearance, central and peripheral volume, and inter-compartmental clearance were 11.5 l h(-1) , 9.37 l, 6.41 l, 13.7 l h(-1) , respectively (relative standard error (RSE) imipenem into ELF was described using a time-independent penetration coefficient of 0.44 (RSE 14%). The identified lung penetration coefficient confirms the clinical relevance of imipenem for treatment of lung infections, while the population PK model provided insights into predictors of IIV for imipenem PK and may be of relevance to support dose optimization in various subject groups. © 2016 The British Pharmacological Society.

  15. Population pharmacokinetics and dosing simulations of imipenem in serious bacteraemia in immunocompromised patients with febrile neutropenia.

    Science.gov (United States)

    Jaruratanasirikul, Sutep; Wongpoowarak, Wibul; Jullangkoon, Monchana; Samaeng, Maseetoh

    2015-02-01

    The aims of this study were to i) reveal the population pharmacokinetics; and ii) assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) (defined as the expected population PTA for a specific drug dose and a specific population of microorganisms) of imipenem in febrile neutropenic patients with bacteraemia. Ten patients were randomised into two groups: Group I received a 0.5-h infusion of 0.5 g of imipenem every 6 h (q6h) for 8 doses; and Group II received a 4-h infusion of 0.5 g q6h for 8 doses. A Monte Carlo simulation was performed to determine the PTA. The volume of distribution and total clearance of imipenem were 20.78 ± 1.35 l and 23.19 ± 1.34 l/h, respectively. Only a 4-h infusion of 1 g q6h regimen achieved a PTA >93% for 80% T>MIC for a MIC of 2 μg/ml. A 4-h infusion of all simulated regimens and a 0.5-h infusion of 0.5 g q6h and 1 g q6h achieved targets (CFR ≥ 90%) against Escherichia coli and Klebsiella spp. However, against Pseudomonas aeruginosa and Acinetobacter spp., no regimens achieved their targets. In conclusion, the results indicate that a higher than manufacturer's dosage recommendation is required to maximize the activity of imipenem. Copyright © 2014 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

  16. [Post-marketing re-evaluation about usage and dosage of Chinese medicine based on human population pharmacokinetics].

    Science.gov (United States)

    Jiang, Junjie; Xie, Yanming

    2011-10-01

    The usage and dosage of Chinese patent medicine are determined by rigorous evaluation which include four clinical trail stages: I, II, III. But the usage and dosage of Chinese patent medicine are lacked re-evaluation after marketing. And this lead to unchanging or fixed of the usage and dosage of Chinese patent medicine instead of different quantity based on different situations in individual patients. The situation of Chinese patent medicine used in clinical application is far away from the idea of the "Treatment based on syndrome differentiation" in traditional Chinese medicine and personalized therapy. Human population pharmacokinetics provides data support to the personalized therapy in clinical application, and achieved the postmarking reevaluating of the usage and dosage of Chinese patent medicine. This paper briefly introduced the present situation, significance and the application of human population pharmacokinetics about re-evaluation of the usage and dosage of Chinese patent medicine after marketing.

  17. Association of pharmacokinetic and metabolic parameters derived using simultaneous PET/MRI: Initial findings and impact on response evaluation in breast cancer.

    Science.gov (United States)

    Jena, Amarnath; Taneja, Sangeeta; Singh, Aru; Negi, Pradeep; Mehta, Shashi Bhushan; Ahuja, Aashim; Singhal, Manish; Sarin, Ramesh

    2017-07-01

    To study relationships among pharmacokinetic and 18 F-fluorodeoxyglucose ( 18 F-FDG) PET parameters obtained through simultaneous PET/MRI in breast cancer patients and evaluate their combined potential for response evaluation. The study included 41 breast cancer patients for correlation study and 9 patients (pre and post therapy) for response evaluation. All patients underwent simultaneous PET/MRI with dedicated breast imaging. Pharmacokinetic parameters and PET parameters for tumor were derived using an in- house developed and vendor provided softwares respectively. Relationships between SUV and pharmacokinetic parameters and clinical as well as histopathologic parameters were evaluated using Spearman correlation analysis. Response to chemotherapy was derived as percentage reduction in size and in parameters post therapy. Significant correlations were observed between SUVmean, max, peak, TLG with K trans (ρ=0.446, 0.417, 0.491, 0.430; p≤0.01); with Kep(ρ=0.303, ρ=0.315, ρ=0.319; p≤0.05); and with iAUC(ρ=0.401, ρ=0.410, ρ=0.379; p≤0.05, p≤0.01). The ratio of ve/iAUC showed significant negative correlation to SUVmean, max, peak and TLG (ρ=0.420, 0.446, 0.443, 0.426; p≤0.01). Ability of SUV as well as pharmacokinetic parameters to predict response to therapy matched the RECIST criteria in 9 out of 11 lesions in 9 patients. Maximum post therapy quantitative reduction was observed in SUVpeak, TLG and K trans . Simultaneous PET/MRI enables illustration of close interactions between glucose metabolism and pharmacokinetic parameters in breast cancer patients and potential of their simultaneity in response assessment to therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Population pharmacokinetic/ pharmacodynamic modelling of eltrombopag in healthy volunteers and subjects with chronic liver disease

    Science.gov (United States)

    Farrell, Colm; Hayes, Siobhan C; Wire, Mary; Zhang, Jianping

    2014-01-01

    Aims To characterize the pharmacokinetics (PK)/pharmacodynamics (PD) of eltrombopag in chronic liver disease (CLD). Methods The PK/PD model was developed using data from 79 CLD patients using nonlinear mixed-effects modelling. Results The PK of eltrombopag were described by a two-compartment model with dual sequential first-order absorption. Gender, race and severity of CLD were predictors of the apparent clearance of eltrombopag. The PD of eltrombopag in CLD were adequately described by a four-compartment lifespan model, in which eltrombopag stimulated platelet precursor production rate. East Asian CLD patients were less sensitive to the stimulatory effect of eltrombopag. Following a daily dose regimen of 50 mg eltrombopag, the time to achieve peak platelet counts was longer for the CLD population compared with patients who had immune thrombocytopenic purpura, but was comparable to patients with hepatitis C. Likewise, it took a longer time for platelet counts to rebound back to baseline once eltrombopag treatment was discontinued. Conclusions The time course of the platelet response in CLD was different from that in immune thrombocytopenic purpura but comparable to that in hepatitis C. PMID:24117976

  19. Pharmacokinetics and pharmacodynamics of insulin analogs in special populations with type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Morello CM

    2011-12-01

    Full Text Available Candis M Morello1,21Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 2School of Pharmacy, University of California San Francisco, Veterans Affairs San Diego Healthcare System, San Diego, CA, USAIntroduction: The goal of insulin therapy in patients with either type 1 diabetes mellitus (T1DM or type 2 diabetes mellitus (T2DM is to match as closely as possible normal physiologic insulin secretion to control fasting and postprandial plasma glucose. Modifications of the insulin molecule have resulted in two long-acting insulin analogs (glargine and detemir and three rapid-acting insulins (aspart, lispro, and glulisine with improved pharmacokinetic/pharmacodynamic (PK/PD profiles. These agents can be used together in basal-bolus therapy to more closely mimic physiologic insulin secretion patterns.Methods: This study reviews effects of the multiple demographic and clinical parameters in the insulin analogs glargine, detemir, lispro, aspart, and glulisine in patients with T2DM. A search was conducted on PubMed for each major topic considered (effects of injection site, age, race/ethnicity, obesity, renal or hepatic dysfunction, pregnancy, exercise, drug interactions using the topic words and name of each type of insulin analog. Information was also obtained from the prescribing information for each insulin analog.Results: The PK/PD profiles for insulin analogs may be influenced by many variables including age, weight, and hepatic and renal function. However, these variables do not have equivalent effects on all long-acting or rapid-acting insulin analogs.Conclusion: Rapid-acting and long-acting insulin analogs represent major advances in treatment for patients with T2DM who require insulin therapy. However, there are potentially important PK and PD differences between the two long-acting agents and among the three rapid-acting insulin analogs, which should be considered when designing treatment regimens for

  20. Influence of scan duration on the estimation of pharmacokinetic parameters for breast lesions: a study based on CAIPIRINHA-Dixon-TWIST-VIBE technique

    Energy Technology Data Exchange (ETDEWEB)

    Hao, Wen; Zhao, Bin; Wang, Guangbin; Wang, Cuiyan [Shandong University, Department of MR Imaging, Shandong Medical Imaging Research Institute, Jinan, Shandong (China); Liu, Hui [Siemens Healthcare, MR Collaborations NE Asia, Shanghai (China)

    2015-04-01

    To evaluate the influence of scan duration on pharmacokinetic parameters and their performance in differentiating benign from malignant breast lesions. Dynamic breast imaging was performed on a 3.0-T MR system using a prototype CAIPIRINHA-Dixon-TWISTVIBE (CDT-VIBE) sequence with a temporal resolution of 11.9 s. Enrolled in the study were 53 women with 55 lesions (26 benign and 29 malignant). Pharmacokinetic parameters (Ktrans, ve, kep and iAUC) were calculated for various scan durations from 1 to 7 min after injection of contrast medium using the Tofts model. Ktrans, kep and ve calculated from the 1-min dataset were significantly different from those calculated from the other datasets. In benign lesions, Ktrans, kep and ve were significantly different only between 1 min and 2 min (corrected P > 0.05), but in malignant lesions there were significant differences for any of the comparisons up to 6 min vs. 7 min (corrected P > 0.05). There were no significant differences in AUCs for any of the parameters (P > 0.05). In breast dynamic contrast-enhanced MRI the scan duration has a significant impact on pharmacokinetic parameters, but the diagnostic ability may not be significantly affected. A scan duration of 5 min after injection of contrast medium may be sufficient for calculation of Tofts model pharmacokinetic parameters. (orig.)

  1. Influence of scan duration on the estimation of pharmacokinetic parameters for breast lesions: a study based on CAIPIRINHA-Dixon-TWIST-VIBE technique

    International Nuclear Information System (INIS)

    Hao, Wen; Zhao, Bin; Wang, Guangbin; Wang, Cuiyan; Liu, Hui

    2015-01-01

    To evaluate the influence of scan duration on pharmacokinetic parameters and their performance in differentiating benign from malignant breast lesions. Dynamic breast imaging was performed on a 3.0-T MR system using a prototype CAIPIRINHA-Dixon-TWISTVIBE (CDT-VIBE) sequence with a temporal resolution of 11.9 s. Enrolled in the study were 53 women with 55 lesions (26 benign and 29 malignant). Pharmacokinetic parameters (Ktrans, ve, kep and iAUC) were calculated for various scan durations from 1 to 7 min after injection of contrast medium using the Tofts model. Ktrans, kep and ve calculated from the 1-min dataset were significantly different from those calculated from the other datasets. In benign lesions, Ktrans, kep and ve were significantly different only between 1 min and 2 min (corrected P > 0.05), but in malignant lesions there were significant differences for any of the comparisons up to 6 min vs. 7 min (corrected P > 0.05). There were no significant differences in AUCs for any of the parameters (P > 0.05). In breast dynamic contrast-enhanced MRI the scan duration has a significant impact on pharmacokinetic parameters, but the diagnostic ability may not be significantly affected. A scan duration of 5 min after injection of contrast medium may be sufficient for calculation of Tofts model pharmacokinetic parameters. (orig.)

  2. Population pharmacokinetics of piperacillin in the early phase of septic shock: does standard dosing result in therapeutic plasma concentrations?

    Science.gov (United States)

    Öbrink-Hansen, Kristina; Juul, Rasmus Vestergaard; Storgaard, Merete; Thomsen, Marianne Kragh; Hardlei, Tore Forsingdal; Brock, Birgitte; Kreilgaard, Mads; Gjedsted, Jakob

    2015-11-01

    Antibiotic dosing in septic shock patients poses a challenge for clinicians due to the pharmacokinetic (PK) variability seen in this patient population. Piperacillin-tazobactam is often used for empirical treatment, and initial appropriate dosing is crucial for reducing mortality. Accordingly, we determined the pharmacokinetic profile of piperacillin (4 g) every 8 h, during the third consecutive dosing interval, in 15 patients treated empirically for septic shock. We developed a population pharmacokinetic model to assess empirical dosing and to simulate alternative dosing regimens and modes of administration. Time above the MIC (T>MIC) predicted for each patient was evaluated against clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/liter). Pharmacokinetic-pharmacodynamic (PK/PD) targets evaluated were 50% fT>4×MIC and 100% fT>MIC. A population PK model was developed using NONMEM, and data were best described by a two-compartment model. Central and intercompartmental clearances were 3.6 liters/h (relative standard error [RSE], 15.7%) and 6.58 liters/h (RSE, 16.4%), respectively, and central and peripheral volumes were 7.3 liters (RSE, 11.8%) and 3.9 liters (RSE, 9.7%), respectively. Piperacillin plasma concentrations varied considerably between patients and were associated with levels of plasma creatinine. Patients with impaired renal function were more likely to achieve predefined PK/PD targets than were patients with preserved or augmented renal function. Simulations of alternative dosing regimens showed that frequent intermittent bolus dosing as well as dosing by extended and continuous infusion increases the probability of attaining therapeutic plasma concentrations. For septic shock patients with preserved or augmented renal function, dose increment or prolonged infusion of the drug needs to be considered. (This study has been registered at ClinicalTrials.gov under registration no. NCT02306928.). Copyright © 2015, American Society for Microbiology

  3. Population pharmacokinetics of methylphenidate hydrochloride extended-release multiple-layer beads in pediatric subjects with attention deficit hyperactivity disorder

    Directory of Open Access Journals (Sweden)

    Teuscher NS

    2015-05-01

    Full Text Available Nathan S Teuscher,1 Akwete Adjei,2 Robert L Findling,3,4 Laurence L Greenhill,5 Robert J Kupper,2 Sharon Wigal6 1PK/PD Associates, Trophy Club, TX, 2Rhodes Pharmaceuticals L.P., Coventry, RI, 3Department of Psychiatric Services and Research, Kennedy Krieger Institute, Baltimore, MD, 4Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, 5Department of Psychiatry, Division of Child and Adolescent Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY, 6AVIDA Inc., Newport Beach, CA, USA Abstract: A new multilayer-bead formulation of extended-release methylphenidate hydrochloride (MPH-MLR has been evaluated in pharmacokinetic studies in healthy adults and in Phase III efficacy/safety studies in children and adolescents with attention deficit hyperactivity disorder (ADHD. Using available data in healthy adults, a two-input, one-compartment, first-order elimination population pharmacokinetic model was developed using nonlinear mixed-effect modeling. The model was then extended to pediatric subjects, and was found to adequately describe plasma concentration–time data for this population. A pharmacokinetic/pharmacodynamic model was also developed using change from baseline in the ADHD Rating Scale (ADHD-RS-IV total scores from a pediatric Phase III trial and simulated plasma concentration–time data. During simulations for each MPH-MLR dose level (10–80 mg, increased body weight resulted in decreased maximum concentration. Additionally, as maximum concentration increased, ADHD-RS-IV total score improved (decreased. Knowledge of the relationship between dose, body weight, and clinical response following the administration of MPH-MLR in children and adolescents may be useful for clinicians selecting initial dosing of MPH-MLR. Additional study is needed to confirm these results. Keywords: population pharmacokinetics, Aptensio XR™, MPH-MLR, methylphenidate

  4. Investigation of pharmacokinetic parameters of tiamulin after intramuscular and subcutaneous administration in normal dogs.

    Science.gov (United States)

    Laber, G

    1988-03-01

    Kinetic variables for tiamulin in the normal dog have been determined. Serum concentrations of tiamulin were compared after intramuscular (i.m.) and subcutaneous (s.c.) administration of a single dose of tiamulin. Following a single i.m. dose of 10 mg/kg body weight, the compound was calculated to have a Cmax = 0.61 +/- 0.15 micrograms/ml, a Tmax = 6 h and a t1/2 = 4.7 +/- 1.4 h. Tiamulin showed dose-dependent pharmacokinetics when given as a single s.c. dose of either 10 mg or 25 mg/kg body weight. For the lower dose, the values Cmax = 1.55 +/- 0.11 micrograms/ml, Tmax = 8 h and t1/2 = 4.28 +/- 0.18 h were obtained. For the higher dose Cmax = 3.14 +/- 0.04 micrograms/ml, Tmax = 8 h and t1/2 = 12.4 +/- 3.4 h were calculated. When tiamulin was administered subcutaneously at a dose rate of 10 mg/kg body weight, higher and better maintained serum levels were achieved than those following i.m. administration. After repeated s.c. doses no significant accumulation of tiamulin occurred. Assuming that a continuous effective serum concentration is necessary throughout the course of therapy, these data would indicate that tiamulin should be given every 24 h.

  5. Population Parameters of Blainvilles and Cuviers Beaked Whales

    Science.gov (United States)

    2015-09-30

    cetacean populations. Long-term monitoring of beaked whale populations in El Hierro , a nearly pristine habitat far from areas of sonar testing or...marine industry, enables valuable studies of demographic trends and life history dictated mainly by natural parameters. El Hierro is in process of...functioning (expected in 2018-2019), it is essential to continue monitoring the populations in El Hierro to obtain an uninterrupted long-term dataset of

  6. Evaluation of enrofloxacin use in koalas (Phascolarctos cinereus) via population pharmacokinetics and Monte Carlo simulation.

    Science.gov (United States)

    Black, L A; Landersdorfer, C B; Bulitta, J B; Griffith, J E; Govendir, M

    2014-06-01

    Clinically normal koalas (n = 6) received a single dose of intravenous enrofloxacin (10 mg/kg). Serial plasma samples were collected over 24 h, and enrofloxacin concentrations were determined via high-performance liquid chromatography. Population pharmacokinetic modeling was performed in S-ADAPT. The probability of target attainment (PTA) was predicted via Monte Carlo simulations (MCS) using relevant target values (30-300) based on the unbound area under the curve over 24 h divided by the minimum inhibitory concentration (MIC) (fAUC0-24 /MIC), and published subcutaneous data were incorporated (Griffith et al., 2010). A two-compartment disposition model with allometrically scaled clearances (exponent: 0.75) and volumes of distribution (exponent: 1.0) adequately described the disposition of enrofloxacin. For 5.4 kg koalas (average weight), point estimates for total clearance (SE%) were 2.58 L/h (15%), central volume of distribution 0.249 L (14%), and peripheral volume 2.77 L (20%). MCS using a target fAUC0-24 /MIC of 40 predicted highest treatable MICs of 0.0625 mg/L for intravenous dosing and 0.0313 mg/L for subcutaneous dosing of 10 mg/kg enrofloxacin every 24 h. Thus, the frequently used dosage of 10 mg/kg enrofloxacin every 24 h subcutaneously may be appropriate against gram-positive bacteria with MICs ≤ 0.03 mg/L (PTA > 90%), but appears inadequate against gram-negative bacteria and Chlamydiae in koalas. © 2013 John Wiley & Sons Ltd.

  7. Population pharmacokinetic analysis of clopidogrel in healthy Jordanian subjects with emphasis optimal sampling strategy.

    Science.gov (United States)

    Yousef, A M; Melhem, M; Xue, B; Arafat, T; Reynolds, D K; Van Wart, S A

    2013-05-01

    Clopidogrel is metabolized primarily into an inactive carboxyl metabolite (clopidogrel-IM) or to a lesser extent an active thiol metabolite. A population pharmacokinetic (PK) model was developed using NONMEM(®) to describe the time course of clopidogrel-IM in plasma and to design a sparse-sampling strategy to predict clopidogrel-IM exposures for use in characterizing anti-platelet activity. Serial blood samples from 76 healthy Jordanian subjects administered a single 75 mg oral dose of clopidogrel were collected and assayed for clopidogrel-IM using reverse phase high performance liquid chromatography. A two-compartment (2-CMT) PK model with first-order absorption and elimination plus an absorption lag-time was evaluated, as well as a variation of this model designed to mimic enterohepatic recycling (EHC). Optimal PK sampling strategies (OSS) were determined using WinPOPT based upon collection of 3-12 post-dose samples. A two-compartment model with EHC provided the best fit and reduced bias in C(max) (median prediction error (PE%) of 9.58% versus 12.2%) relative to the basic two-compartment model, AUC(0-24) was similar for both models (median PE% = 1.39%). The OSS for fitting the two-compartment model with EHC required the collection of seven samples (0.25, 1, 2, 4, 5, 6 and 12 h). Reasonably unbiased and precise exposures were obtained when re-fitting this model to a reduced dataset considering only these sampling times. A two-compartment model considering EHC best characterized the time course of clopidogrel-IM in plasma. Use of the suggested OSS will allow for the collection of fewer PK samples when assessing clopidogrel-IM exposures. Copyright © 2013 John Wiley & Sons, Ltd.

  8. Population pharmacokinetics of telapristone (CDB-4124) and its active monodemethylated metabolite CDB-4453, with a mixture model for total clearance.

    Science.gov (United States)

    Morris, Denise; Podolski, Joseph; Kirsch, Alan; Wiehle, Ronald; Fleckenstein, Lawrence

    2011-12-01

    Telapristone is a selective progesterone antagonist that is being developed for the long-term treatment of symptoms associated with endometriosis and uterine fibroids. The population pharmacokinetics of telapristone (CDB-4124) and CDB-4453 was investigated using nonlinear mixed-effects modeling. Data from two clinical studies (n = 32) were included in the analysis. A two-compartment (parent) one compartment (metabolite) mixture model (with two populations for apparent clearance) with first-order absorption and elimination adequately described the pharmacokinetics of telapristone and CDB-4453. Telapristone was rapidly absorbed with an absorption rate constant (Ka) of 1.26 h(-1). Moderate renal impairment resulted in a 74% decrease in Ka. The population estimates for oral clearance (CL/F) for the two populations were 11.6 and 3.34 L/h, respectively, with 25% of the subjects being allocated to the high-clearance group. Apparent volume of distribution for the central compartment (V2/F) was 37.4 L, apparent inter-compartmental clearance (Q/F) was 21.9 L/h, and apparent peripheral volume of distribution for the parent (V4/F) was 120 L. The ratio of the fraction of telapristone converted to CDB-4453 to the distribution volume of CDB-4453 (Fmet(est)) was 0.20/L. Apparent volume of distribution of the metabolite compartment (V3/F) was fixed to 1 L and apparent clearance of the metabolite (CLM/F) was 2.43 L/h. A two-compartment parent-metabolite model adequately described the pharmacokinetics of telapristone and CDB-4453. The clearance of telapristone was separated into two populations and could be the result of metabolism via polymorphic CYP3A5.

  9. The effects of yohimbine on the pharmacokinetic parameters of detomidine in the horse.

    Science.gov (United States)

    Knych, Heather K; Steffey, Eugene P; Stanley, Scott D

    2012-05-01

    To describe the pharmacokinetics of detomidine and yohimbine when administered in combination. Randomized crossover design. Nine healthy adult horses aged 9 ± 4 years and weighing of 561 ± 56 kg. Three dose regimens were employed in the current study. 1) 0.03 mg kg(-1) detomidine IV (D), 2) 0.2 mg kg(-1) yohimbine IV (Y) and 3) 0.03 mg kg(-1) detomidine IV followed 15 minutes later by 0.2 mg kg(-1) yohimbine IV (DY). Each horse received all three dose regimens with a minimum of 1 week in between subsequent regimens. Blood samples were obtained and plasma analyzed for detomidine and yohimbine concentrations by liquid chromatography-mass spectrometry. Data were analyzed using both non-compartmental and compartmental analysis. The maximum measured detomidine concentrations were 76.0 and 129.9 ng mL(-1) for the D and DY treatments, respectively. Systemic clearance and volume of distribution of detomidine were not significantly different for either treatment. There was a significant increase in the maximum measured yohimbine plasma concentrations from Y (173.9 ng mL(-1)) to DY (289.8 ng mL(-1)). Both the Cl and V(d) for yohimbine were significantly less (6.8 mL minute(-1) kg(-1) (Cl) and 1.7 L kg(-1) (V(d) )) for the DY as compared to the Y treatments (13.9 mL minute(-1) kg(-1) (Cl) and 2.7 L kg(-1) (V(d))). Plasma concentrations were below the limit of quantitation (0.05 and 0.5 ng mL(-1)) by 18 hours for both detomidine and yohimbine. The Cl and V(d) of yohimbine were affected by prior administration of detomidine. The elimination half life of yohimbine remained unaffected when administered subsequent to detomidine. However, the increased plasma concentrations in the presence of detomidine has the potential to cause untoward effects and therefore further studies to assess the physiologic effects of this combination of drugs are warranted. © 2012 The Authors. Veterinary Anaesthesia and Analgesia. © 2012 Association of Veterinary Anaesthetists and the American

  10. Mechanistic Population Pharmacokinetics of Morphine in Neonates With Abstinence Syndrome After Oral Administration of Diluted Tincture of Opium.

    Science.gov (United States)

    Liu, Tao; Lewis, Tamorah; Gauda, Estelle; Gobburu, Jogarao; Ivaturi, Vijay

    2016-08-01

    Conducting and analyzing clinical trials in vulnerable neonates are extremely challenging. The aim of this analysis is to develop a morphine population pharmacokinetics (PK) model using data collected during a randomized control trial in neonates with abstinence syndrome (NAS). A 3-compartment morphine structural PK model after intravenous (IV) administration from previously published work was utilized as prior, whereas an allometric scaling method with physiological consideration was used to extrapolate a PK profile from adults to pediatrics. The absorption rate constant and bioavailability were estimated in NAS after oral administration of diluted tincture of opium (DTO). Goodness-of-fit plots along with normalized prediction distribution error and bootstrap method were performed for model evaluation. We successfully extrapolated the PK profile from adults to pediatrics after IV administration. The estimated first-order absorption rate constant and bioavailability were 0.751 hour(-1) and 48.5%, respectively. Model evaluations showed that the model can accurately and precisely describe the observed data. The population pharmacokinetic model we derived for morphine after oral administration of DTO is reasonable and acceptable; therefore, it can be used to describe the PK and guide future studies. The integration of the previous population PK knowledge as prior information successfully overcomes the logistic and practical issue in vulnerable neonate population. © 2016, The American College of Clinical Pharmacology.

  11. Treatment with subcutaneous and transdermal fentanyl: results from a population pharmacokinetic study in cancer patients

    NARCIS (Netherlands)

    Oosten, A.W.; Abrantes, J.A.; Jonsson, S.; Bruijn, P. de; Kuip, E.J.M.; Falcao, A.; Rijt, C.C. van der; Mathijssen, R.H.

    2016-01-01

    PURPOSE: Transdermal fentanyl is effective for the treatment of moderate to severe cancer-related pain but is unsuitable for fast titration. In this setting, continuous subcutaneous fentanyl may be used. As data on the pharmacokinetics of continuous subcutaneous fentanyl are lacking, we studied the

  12. Treatment with subcutaneous and transdermal fentanyl: Results from a population pharmacokinetic study in cancer patients

    NARCIS (Netherlands)

    A.W. Oosten (Astrid); J.A. Abrantes (João A.); S. Jönsson (Siv); P. de Bruijn (Peter); E.J.M. Kuip (Evelien); A. Falcão (Amílcar); C.C.D. van der Rijt (Carin); A.H.J. Mathijssen (Ron)

    2016-01-01

    textabstractPurpose: Transdermal fentanyl is effective for the treatment of moderate to severe cancer-related pain but is unsuitable for fast titration. In this setting, continuous subcutaneous fentanyl may be used. As data on the pharmacokinetics of continuous subcutaneous fentanyl are lacking, we

  13. Similar Results in Children with Asthma for Steady State Pharmacokinetic Parameters of Ciclesonide Inhaled with or without Spacer

    Directory of Open Access Journals (Sweden)

    H. Boss

    2010-01-01

    Full Text Available Background Ciclesonide is an inhaled corticosteroid administered by a metered dose inhaler (MDI to treat bronchial asthma. After inhalation, the inactive ciclesonide is converted by esterases in the airways to active metabolite desisobutyryl-ciclesonide (des-CIC. Aim To compare the pharmacokinetic (PK parameters of des-CIC in children after administration of therapeutic dose of ciclesonide with and without spacer (AeroChamber Plus™. Methods Open-label, 3 period, cross over, repeated dose, PK study in 37 children with mild to moderate stable asthma (age: 6–11 y; body weight: 20–53 kg. During each 7-day treatment period, ciclesonide was inhaled once in the morning: A 160 μg MDI with spacer, B 80 μg MDI with spacer, and C 160 μg MDI without spacer. Serum PK parameters of ciclesonide and des-CIC were determined on Day 7 of each period. The primary PK parameters were the AUC τ and C max for des-CIC. Results Inhaling ciclesonide with spacer led to a dose proportional systemic exposure (AUC τ of des-CIC (0.316 μg*h/L for 80 μg and 0.663 μg*h/L for 160 μg. The dose-normalized systemic exposure for des-CIC (based on AUC τ was 27% higher after inhalation of ciclesonide 80 μg or 160 μg with spacer than without spacer; the corresponding C max values for des-CIC were, respectively, 63% and 55% higher with spacer. No clinically relevant abnormalities or adverse drug reactions were observed. Conclusions Inhalation of therapeutic ciclesonide dose with spacer led to a slight increase in the systemic exposure of des-CIC, which does not warrant dose adjustment.

  14. Population Pharmacokinetic Modelling of FE 999049, a Recombinant Human Follicle-Stimulating Hormone, in Healthy Women After Single Ascending Doses

    DEFF Research Database (Denmark)

    Rose, Trine Høyer; Röshammar, Daniel; Erichsen, Lars

    2016-01-01

    reproductive technologies. Methods: Serum FSH levels were measured following a single subcutaneous FE 999049 injection of 37.5, 75, 150, 225 or 450 IU in 27 pituitary-suppressed healthy female subjects participating in this first-in-human single ascending dose trial. Data was analysed by nonlinear mixed...... volume of distribution (V/F) estimates were found to increase with body weight. Body weight was included as an allometrically scaled covariate with a power exponent of 0.75 for CL/F and 1 for V/F. Conclusions: The single-dose pharmacokinetics of FE 999049 were adequately described by a population...

  15. Population pharmacokinetics and pharmacodynamics of teicoplanin in neonates: making better use of C-reactive protein to deliver individualized therapy.

    Science.gov (United States)

    Ramos-Martín, V; Neely, M N; McGowan, P; Siner, S; Padmore, K; Peak, M; Beresford, M W; Turner, M A; Paulus, S; Hope, W W

    2016-11-01

    There is uncertainty about the optimal teicoplanin regimens for neonates. The study aim was to determine the population pharmacokinetics (PK) of teicoplanin in neonates, evaluate currently recommended regimens and explore the exposure-effect relationships. An open-label PK study was conducted. Neonates from 26 to 44 weeks post-menstrual age were recruited (n = 18). The teicoplanin regimen was a 16 mg/kg loading dose, followed by 8 mg/kg once daily. Therapeutic drug monitoring and dose adjustment were not conducted. A standard two-compartment PK model was developed, followed by models that incorporated weight. A PK/pharmacodynamic (PD) model with C-reactive protein serial measurements as the PD input was fitted to the data. Monte Carlo simulations (n = 5000) were performed using Pmetrics. The AUCs at steady state and the proportion of patients achieving the recommended drug exposures (i.e. C min >15 mg/L) were determined. The study was registered in the European Clinical Trials Database Registry (EudraCT: 2012-005738-12). The PK allometric model best accounted for the observed data. The PK parameters medians were: clearance = 0.435 × (weight/70) 0.75 (L/h); volume = 0.765 (L); K cp  = 1.3 (h -1 ); and K pc  = 0.629 (h -1 ). The individual time-course of C-reactive protein was well described using the Bayesian posterior estimates for each patient. The simulated median AUC 96-120 was 302.3 mg·h/L and the median C min at 120 h was 12.9 mg/L; 38.8% of patients attained a C min >15 mg/L by 120 h. Teicoplanin population PK is highly variable in neonates, weight being the best descriptor of PK variability. A low percentage of neonates were able to achieve C min >15 mg/L. The routine use of therapeutic drug monitoring and improved knowledge on the PD of teicoplanin is required. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e

  16. Population pharmacokinetics of imipenem in critically ill patients with suspected ventilator-associated pneumonia and evaluation of dosage regimens.

    Science.gov (United States)

    Couffignal, Camille; Pajot, Olivier; Laouénan, Cédric; Burdet, Charles; Foucrier, Arnaud; Wolff, Michel; Armand-Lefevre, Laurence; Mentré, France; Massias, Laurent

    2014-11-01

    Significant alterations in the pharmacokinetics (PK) of antimicrobials have been reported in critically ill patients. We describe PK parameters of imipenem in intensive care unit (ICU) patients with suspected ventilator-associated pneumonia and evaluate several dosage regimens. This French multicentre, prospective, open-label study was conducted in ICU patients with a presumptive diagnosis of ventilator-associated pneumonia caused by Gram-negative bacilli, who empirically received imipenem intravenously every 8 h. Plasma imipenem concentrations were measured during the fourth imipenem infusion using six samples (trough, 0.5, 1, 2, 5 and 8 h). Data were analysed with a population approach using the stochastic approximation expectation maximization algorithm in Monolix 4.2. A Monte Carlo simulation was performed to evaluate the following six dosage regimens: 500, 750 or 1000 mg with administration every 6 or 8 h. The pharmacodynamic target was defined as the probability of achieving a fractional time above the minimal inhibitory concentration (MIC) of >40%. Fifty-one patients were included in the PK analysis. Imipenem concentration data were best described by a two-compartment model with three covariates (creatinine clearance, total bodyweight and serum albumin). Estimated clearance (between-subject variability) was 13.2 l h(-1) (38%) and estimated central volume 20.4 l (31%). At an MIC of 4 μg ml(-1) , the probability of achieving 40% fractional time > MIC was 91.8% for 0.5 h infusions of 750 mg every 6 h, 86.0% for 1000 mg every 8 h and 96.9% for 1000 mg every 6 h. This population PK model accurately estimated imipenem concentrations in ICU patients. The simulation showed that for these patients, the best dosage regimen of imipenem is 750 mg every 6 h and not 1000 mg every 8 h. © 2014 The British Pharmacological Society.

  17. Neural network modelling of antifungal activity of a series of oxazole derivatives based on in silico pharmacokinetic parameters

    Directory of Open Access Journals (Sweden)

    Kovačević Strahinja Z.

    2013-01-01

    Full Text Available In the present paper, the antifungal activity of a series of benzoxazole and oxazolo[ 4,5-b]pyridine derivatives was evaluated against Candida albicans by using quantitative structure-activity relationships chemometric methodology with artificial neural network (ANN regression approach. In vitro antifungal activity of the tested compounds was presented by minimum inhibitory concentration expressed as log(1/cMIC. In silico pharmacokinetic parameters related to absorption, distribution, metabolism and excretion (ADME were calculated for all studied compounds by using PreADMET software. A feedforward back-propagation ANN with gradient descent learning algorithm was applied for modelling of the relationship between ADME descriptors (blood-brain barrier penetration, plasma protein binding, Madin-Darby cell permeability and Caco-2 cell permeability and experimental log(1/cMIC values. A 4-6-1 ANN was developed with the optimum momentum and learning rates of 0.3 and 0.05, respectively. An excellent correlation between experimental antifungal activity and values predicted by the ANN was obtained with a correlation coefficient of 0.9536. [Projekat Ministarstva nauke Republike Srbije, br. 172012 i br. 172014

  18. Pharmacokinetic MRI of the prostate. Parameters for differentiating low-grade and high-grade prostate cancer

    International Nuclear Information System (INIS)

    Franiel, T.; Taupitz, M.; Asbach, P.; Beyersdorff, D.; Luedemann, L.; Rost, J.

    2009-01-01

    Purpose: to investigate whether pharmacokinetic MRI parameters ''perfusion, blood volume, mean transit time (MTT), interstitial volume, permeability, extraction coefficient, delay, and dispersion'' allow the differentiation of low-grade (Gleason score ≤ 6) and high-grade (Gleason score ≥ 7) prostate cancer. Materials and method: forty-two patients with prostate cancer verified by biopsy (PSA 2.7 to 31.4ng/ml) and scheduled for prostatectomy underwent MRI at 1.5 Tesla using the dynamic contrast-enhanced inversion-prepared dual-contrast gradient echo sequence (temporal resolution, 1.65 s) and a combined endorectal body phased array coil. Parametric maps were computed using a sequential 3-compartment model and the corresponding post-processing algorithms. A total of 41 areas of prostate cancer (15 low-grade, 26 high-grade cancers) in 32 patients were able to be correlated with the prostatectomy specimens and were included in the analysis. Results: low-grade prostate cancers had a higher mean blood volume (1.76% vs. 1.64%, p = 0.039), longer MTT (6.39 s vs. 3.25 s, p -1 vs. 3.86 min -1 , p = 0.011) than high-grade cancers. No statistically significant difference was found for perfusion (p = 0.069), interstitial volume (p = 0.849), extraction coefficient (p = 0.615), delay (p = 0.489), and dispersion (p = 0.306). (orig.)

  19. Predictive performance of the 'Minto' remifentanil pharmacokinetic parameter set in morbidly obese patients ensuing from a new method for calculating lean body mass.

    Science.gov (United States)

    La Colla, Luca; Albertin, Andrea; La Colla, Giorgio; Porta, Andrea; Aldegheri, Giorgio; Di Candia, Domenico; Gigli, Fausto

    2010-01-01

    In a previous article, we showed that the pharmacokinetic set of remifentanil used for target-controlled infusion (TCI) might be biased in obese patients because it incorporates flawed equations for the calculation of lean body mass (LBM), which is a covariate of several pharmacokinetic parameters in this set. The objectives of this study were to determine the predictive performance of the original pharmacokinetic set, which incorporates the James equation for LBM calculation, and to determine the predictive performance of the pharmacokinetic set when a new method to calculate LBM was used (the Janmahasatian equations). This was an observational study with intraoperative observations and no follow-up. Fifteen morbidly obese inpatients scheduled for bariatric surgery were included in the study. The intervention included manually controlled continuous infusion of remifentanil during the surgery and analysis of arterial blood samples to determine the arterial remifentanil concentration, to be compared with concentrations predicted by either the unadjusted or the adjusted pharmacokinetic set. The statistical analysis included parametric and non-parametric tests on continuous variables and determination of the median performance error (MDPE), median absolute performance error (MDAPE), divergence and wobble. The median values (interquartile ranges) of the MDPE, MDAPE, divergence and wobble for the James equations during maintenance were -53.4% (-58.7% to -49.2%), 53.4% (49.0-58.7%), 3.3% (2.9-4.7%) and 1.4% h(-1) (1.1-2.5% h(-1)), respectively. The respective values for the Janmahasatian equations were -18.9% (-24.2% to -10.4%), 20.5% (13.3-24.8%), 2.6% (-0.7% to 4.5%) and 1.9% h(-1) (1.4-3.0% h(-1)). The performance (in terms of the MDPE and MDAPE) of the corrected pharmacokinetic set was better than that of the uncorrected one. The predictive performance of the original pharmacokinetic set is not clinically acceptable. Use of a corrected LBM value in morbidly obese

  20. Parameter Estimates in Differential Equation Models for Population Growth

    Science.gov (United States)

    Winkel, Brian J.

    2011-01-01

    We estimate the parameters present in several differential equation models of population growth, specifically logistic growth models and two-species competition models. We discuss student-evolved strategies and offer "Mathematica" code for a gradient search approach. We use historical (1930s) data from microbial studies of the Russian biologist,…

  1. Selected fishery and population parameters of eight shore-angling ...

    African Journals Online (AJOL)

    Selected fishery and population parameters of eight shore-angling species in the ... Five different estimates of natural mortality (M), and the coefficients of ... for the most abundant species, blacktail Diplodus capensis, with a mean CPUE of 0.252 ... Keywords: catch per unit effort; fisheries management; marine protected area; ...

  2. Comparison of the population structure and life-history parameters ...

    African Journals Online (AJOL)

    Blacktail seabream Diplodus capensis were sampled from proximate (10 km apart) exploited and unexploited areas in southern Angola to compare their population structures and life-history parameters. Females dominated the larger size and older age classes in the unexploited area. In the exploited area the length and ...

  3. Population pharmacokinetics of olmesartan following oral administration of its prodrug, olmesartan medoxomil: in healthy volunteers and hypertensive patients.

    Science.gov (United States)

    Yoshihara, Kazutaka; Gao, Yuying; Shiga, Hiroshi; Wada, D Russell; Hisaoka, Masafumi

    2005-01-01

    Olmesartan medoxomil (CS-866) is a new orally active angiotensin II receptor antagonist that is highly selective for the AT1 receptor subtype. To develop a population pharmacokinetic model for olmesartan (RNH-6270), the active metabolite of olmesartan medoxomil, in healthy volunteers and hypertensive patients, and to evaluate effects of covariates on the apparent oral clearance (CL/F), with particular emphasis on the effect of race. Retrospective analysis of data from 12 phase I-III trials in the US, Europe and Japan. Eighty-nine healthy volunteers and 383 hypertensive patients. Nonlinear mixed-effects modelling was used to evaluate 7911 olmesartan plasma sample concentrations. The covariates included age, bodyweight, sex, race (Westerners [including Caucasians and Hispanics] versus Japanese), patient status (hypertensive patients versus healthy volunteers), serum creatinine level as an index of renal function and serum chemistry data as indices of hepatic function. The pharmacokinetic data of olmesartan were well described by a two-compartment linear model with first-order absorption and an absorption lag-time, parameterised in terms of CL/F (6.66 L/h for a typical male Western hypertensive patient), absorption rate constant (1.46h-1), elimination rate constant (0.193h-1), rate constant from the central to peripheral compartment (0.061h-1), rate constant from the peripheral to central compartment (0.079h-1) and absorption lag-time (0.427h). Analysis of covariates showed that age, bodyweight, sex, patient status and renal function were factors influencing the clearance of olmesartan. The population pharmacokinetic analysis of olmesartan showed that: (i) severe renal impairment (serum creatinine >265 micromol/L [approximately 3 mg/dL]) could cause a clearance decrease of > or =30%; (ii) older age, lower bodyweight and being female were determinants of lower clearance but their effects on olmesartan clearance were within 20%; (iii) no statistically significant

  4. Population Pharmacokinetic Modeling of a Desmopressin Oral Lyophilisate in Growing Piglets as a Model for the Pediatric Population

    Directory of Open Access Journals (Sweden)

    Elke Gasthuys

    2018-01-01

    Full Text Available Desmopressin is used to treat primary nocturnal enuresis in children. Over the years, various formulations of desmopressin were commercialized of which the sublingual melt tablet is preferred in the pediatric population, despite the lack of full PK studies in this population. A full PK study was performed in growing conventional piglets to evaluate if this juvenile animal model can provide supplementary information to complement the information gap in the pediatric population. A desmopressin sublingual melt tablet (120 μg was administered to 32 male piglets aged 8 days, 4 weeks, 7 weeks, and 6 months (each group n = 8. Population PK (pop-PK analysis was performed to derive the PK parameters, the between- and within-subject variabilities and the effects of covariates. Desmopressin demonstrated two-compartmental PK, with a dual, sequential absorption process, and linear elimination. Body weight was the only significant covariate on clearance and on apparent volume of distribution of the central compartment. In human pediatric trials, no double peak in the absorption phase was observed in the plasma concentration-time curves, possibly due to the sparse sampling strategy applied in those pediatric studies. Therefore, it is recommended to perform additional studies, based on the sampling protocol applied in the current study.

  5. Population Pharmacokinetics of an Indian F(ab'2 Snake Antivenom in Patients with Russell's Viper (Daboia russelii Bites.

    Directory of Open Access Journals (Sweden)

    Geoffrey K Isbister

    Full Text Available There is limited information on antivenom pharmacokinetics. This study aimed to investigate the pharmacokinetics of an Indian snake antivenom in humans with Russell's viper bites.Patient data and serial blood samples were collected from patients with Russell's viper (Daboia russelii envenoming in Sri Lanka. All patients received Indian F(ab'2 snake antivenom manufactured by VINS Bioproducts Ltd. Antivenom concentrations were measured with sandwich enzyme immunoassays. Timed antivenom concentrations were analysed using MONOLIXvs4.2. One, two and three compartment models with zero order input and first order elimination kinetics were assessed. Models were parameterized with clearance (CL, intercompartmental clearance (Q, central compartment volume (V and peripheral compartment volume (VP. Between-subject-variability (BSV on relative bioavailability (F was included to account for dose variations. Covariates effects (age, sex, weight, antivenom batch, pre-antivenom concentrations were explored by visual inspection and in model building. There were 75 patients, median age 57 years (40-70 y and 64 (85% were male. 411 antivenom concentration data points were analysed. A two compartment model with zero order input, linear elimination kinetics and a combined error model best described the data. Inclusion of BSV on F and weight as a covariate on V improved the model. Inclusion of pre-antivenom concentrations or different batches on BSV of F did not. Final model parameter estimates were CL,0.078 L h(-1, V,2.2L, Q,0.178 L h(-1 and VP,8.33L. The median half-life of distribution was 4.6 h (10-90%iles:2.6-7.1 h and half-life of elimination, 140 h (10th-90th percentilesx:95-223h.Indian F(ab'2 snake antivenom displayed biexponential disposition pharmacokinetics, with a rapid distribution half-life and more prolonged elimination half-life.

  6. POPULATION SYNTHESIS OF HOT SUBDWARFS: A PARAMETER STUDY

    International Nuclear Information System (INIS)

    Clausen, Drew; Wade, Richard A.; Kopparapu, Ravi Kumar; O'Shaughnessy, Richard

    2012-01-01

    Binaries that contain a hot subdwarf (sdB) star and a main-sequence companion may have interacted in the past. This binary population has historically helped determine our understanding of binary stellar evolution. We have computed a grid of binary population synthesis models using different assumptions about the minimum core mass for helium ignition, the envelope binding energy, the common-envelope ejection efficiency, the amount of mass and angular momentum lost during stable mass transfer, and the criteria for stable mass transfer on the red giant branch and in the Hertzsprung gap. These parameters separately and together can significantly change the entire predicted population of sdBs. Nonetheless, several different parameter sets can reproduce the observed subpopulation of sdB + white dwarf and sdB + M dwarf binaries, which has been used to constrain these parameters in previous studies. The period distribution of sdB + early F dwarf binaries offers a better test of different mass transfer scenarios for stars that fill their Roche lobes on the red giant branch.

  7. Dataset for Phase I randomized clinical trial for safety and tolerability of GET 73 in single and repeated ascending doses including preliminary pharmacokinetic parameters

    Directory of Open Access Journals (Sweden)

    Carolina L. Haass-Koffler

    2017-12-01

    Full Text Available The data in this article outline the methods used for the administration of GET 73 in the first time-in-human manuscript entitled “Phase I randomized clinical trial for the safety, tolerability and preliminary pharmacokinetics of the mGluR5 negative allosteric modulator GET 73 following single and repeated doses in healthy male volunteers” (Haass-Koffler et al., 2017 [1]. Data sets are provided in two different manners. The first series of tables provided includes procedural information about the experiments conducted. The next series of tables provided includes Pharmacokinetic (PK parameters for GET 73 and its main metabolite MET 2. This set of data is comprised by two experiments: Experiment 1 references a single ascending dose administration of GET 73 and Experiment 2 references a repeated ascending dose administration of GET 73. Keywords: Glutamate receptor subtype 5 (mGlu5, Allosteric modulator, GET 73, Safety, Tolerability

  8. Dataset for Phase I randomized clinical trial for safety and tolerability of GET 73 in single and repeated ascending doses including preliminary pharmacokinetic parameters.

    Science.gov (United States)

    Haass-Koffler, Carolina L; Goodyear, Kimberly; Long, Victoria M; Tran, Harrison H; Loche, Antonella; Cacciaglia, Roberto; Swift, Robert M; Leggio, Lorenzo

    2017-12-01

    The data in this article outline the methods used for the administration of GET 73 in the first time-in-human manuscript entitled "Phase I randomized clinical trial for the safety, tolerability and preliminary pharmacokinetics of the mGluR5 negative allosteric modulator GET 73 following single and repeated doses in healthy male volunteers" (Haass-Koffler et al., 2017) [1]. Data sets are provided in two different manners. The first series of tables provided includes procedural information about the experiments conducted. The next series of tables provided includes Pharmacokinetic (PK) parameters for GET 73 and its main metabolite MET 2. This set of data is comprised by two experiments: Experiment 1 references a single ascending dose administration of GET 73 and Experiment 2 references a repeated ascending dose administration of GET 73.

  9. Role of pharmacokinetic parameters derived with high temporal resolution DCE MRI using simultaneous PET/MRI system in breast cancer: A feasibility study

    Energy Technology Data Exchange (ETDEWEB)

    Jena, Amarnath, E-mail: drjena2002@gmail.com [Department of Molecular Imaging and Nuclear Medicine, Indraprastha Apollo Hospitals, Sarita Vihar, Delhi–Mathura Road, New Delhi 110076 (India); Taneja, Sangeeta; Singh, Aru; Negi, Pradeep; Mehta, Shashi Bhushan [Department of Molecular Imaging and Nuclear Medicine, Indraprastha Apollo Hospitals, Sarita Vihar, Delhi–Mathura Road, New Delhi 110076 (India); Sarin, Ramesh [Department of Surgical Oncology, Indraprastha Apollo Hospitals, Sarita Vihar, Delhi–Mathura Road, New Delhi 110076 (India)

    2017-01-15

    Highlights: • Simultaneous PET/MRI (with 3T MRI in the core) for quantitative pharmacokinetics. • Diagnostic accuracy of pharmacokinetic parameters like K{sup trans}, K{sub ep} and v{sub e} acquired through this system. • Incorporating high temporal resolution sequence with short acquisition time of 60 s within the routine DCE MRI in a simultaneous PET/MRI system. - Abstract: Purpose: To evaluate the reliability of pharmacokinetic parameters like K{sup trans}, Kep and v{sub e} derived through DCE MRI breast protocol using 3 T Simultaneous PET/MRI (3 Tesla Positron Emission Tomography/Magnetic Resonance Imaging) system in distinguishing benign and malignant lesions. Materials and methods: High temporal resolution DCE (Dynamic Contrast Enhancement) MRI performed as routine breast MRI for diagnosis or as a part of PET/MRI for cancer staging using a 3 T simultaneous PET/MRI system in 98 women having 109 breast lesions were analyzed for calculation of pharmacokinetic parameters (K{sup trans}, v{sub e}, and Kep) at 60 s time point using an in-house developed computation scheme. Results: Receiver operating characteristic (ROC) curve analysis revealed a cut off value for K{sup trans}, Kep, v{sub e} as 0.50, 2.59, 0.15 respectively which reliably distinguished benign and malignant breast lesions. Data analysis revealed an overall accuracy of 94.50%, 79.82% and 87.16% for K{sup trans}, Kep, v{sub e} respectively. Introduction of native T1 normalization with an externally placed phantom showed a higher accuracy (94.50%) than without native T1 normalization (93.50%) with an increase in specificity of 87% vs 84%. Conclusion: Overall the results indicate that reliable measurement of pharmacokinetic parameters with reduced acquisition time is feasible in a 3TMRI embedded PET/MRI system with reasonable accuracy and application may be extended to exploit the potential of simultaneous PET/MRI in further work on breast cancer.

  10. Population pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator.

    Science.gov (United States)

    Krause, Andreas; Brossard, Patrick; D'Ambrosio, Daniele; Dingemanse, Jasper

    2014-06-01

    Ponesimod (ACT-128800), a reversible, orally active, selective S1P1 receptor modulator, prevents the egress of lymphocytes from the lymph node into the systemic circulation. It is currently in clinical development for the treatment of relapsing multiple sclerosis. Modulation of circulating lymphocytes serves as biomarker of efficacy and safety, such that the quantitative characterization of the pharmacokinetic/pharmacodynamic (PK/PD) relationship guides the clinical development of the compound. The availability of a variety of doses, dosing regimens, and treatment durations permitted estimation of the pharmacokinetics characterized by an absorption lag time followed by a sequential zero/first-order absorption and two compartments with first-order elimination. The PD are modeled as an indirect-effect model with rates of appearance and disappearance of lymphocytes in blood with a circadian rhythm and a drug effect on the rate of appearance. The model suggests a circadian variation of 9% and a maximum inhibition of 86% of total lymphocyte count with high doses at steady state. It was instrumental for the selection of doses for subsequent studies that confirmed the effect plateau in total lymphocyte count at approximately 0.5 × 10(9) counts/L.

  11. Population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children with tuberculosis: in silico evaluation of currently recommended doses.

    Science.gov (United States)

    Zvada, Simbarashe P; Denti, Paolo; Donald, Peter R; Schaaf, H Simon; Thee, Stephanie; Seddon, James A; Seifart, Heiner I; Smith, Peter J; McIlleron, Helen M; Simonsson, Ulrika S H

    2014-05-01

    To describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children and evaluate the adequacy of steady-state exposures. We used previously published data for 76 South African children with tuberculosis to describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid. Monte Carlo simulations were used to predict steady-state exposures in children following doses in fixed-dose combination tablets in accordance with the revised guidelines. Reference exposures were derived from an ethnically similar adult population with tuberculosis taking currently recommended doses. The final models included allometric scaling of clearance and volume of distribution using body weight. Maturation was included for clearance of isoniazid and clearance and absorption transit time of rifampicin. For a 2-year-old child weighing 12.5 kg, the estimated typical oral clearances of rifampicin and pyrazinamide were 8.15 and 1.08 L/h, respectively. Isoniazid typical oral clearance (adjusted for bioavailability) was predicted to be 4.44, 11.6 and 14.6 L/h for slow, intermediate and fast acetylators, respectively. Higher oral clearance values in intermediate and fast acetylators also resulted from 23% lower bioavailability compared with slow acetylators. Simulations based on our models suggest that with the new WHO dosing guidelines and utilizing available paediatric fixed-dose combinations, children will receive adequate rifampicin exposures when compared with adults, but with a larger degree of variability. However, pyrazinamide and isoniazid exposures in many children will be lower than in adults. Further studies are needed to confirm these findings in children administered the revised dosages and to optimize pragmatic approaches to dosing.

  12. Incorporation of FcRn-mediated disposition model to describe the population pharmacokinetics of therapeutic monoclonal IgG antibody in clinical patients.

    Science.gov (United States)

    Ng, Chee M

    2016-03-01

    The two-compartment linear model used to describe the population pharmacokinetics (PK) of many therapeutic monoclonal antibodies (TMAbs) offered little biological insight to antibody disposition in humans. The purpose of this study is to develop a semi-mechanistic FcRn-mediated IgG disposition model to describe the population PK of TMAbs in clinical patients. A standard two-compartment linear PK model from a previously published population PK model of pertuzumab was used to simulate intensive PK data of 100 subjects for model development. Two different semi-mechanistic FcRn-mediated IgG disposition models were developed and First Order Conditional Estimation (FOCE) with the interaction method in NONMEM was used to obtain the final model estimates. The performances of these models were then compared with the two-compartment linear PK model used to simulate the data for model development. A semi-mechanistic FcRn-mediated IgG disposition model consisting of a peripheral tissue compartment and FcRn-containing endosomes in the central compartment best describes the simulated pertuzumab population PK data. This developed semi-mechanistic population PK model had the same number of model parameters, produced very similar concentration-time profiles but provided additional biological insight to the FcRn-mediated IgG disposition in human subjects compared with the standard linear two-compartment linear PK model. This first reported semi-mechanistic model may serve as an important model framework for developing future population PK models of TMAbs in clinical patients. Copyright © 2015 John Wiley & Sons, Ltd.

  13. Population pharmacokinetics of pomalidomide in patients with relapsed or refractory multiple myeloma with various degrees of impaired renal function

    Directory of Open Access Journals (Sweden)

    Li Y

    2017-11-01

    Full Text Available Yan Li,1 Xiaomin Wang,2 Edward O’Mara,1 Meletios A Dimopoulos,3 Pieter Sonneveld,4 Katja C Weisel,5 Jeffrey Matous,6 David S Siegel,7 Jatin J Shah,8 Elisabeth Kueenburg,9 Lars Sternas,9 Chloe Cavanaugh,9 Mohamed Zaki,9 Maria Palmisano,1 Simon Zhou1 1Translational Development and Clinical Pharmacology, Celgene Corporation, Summit, NJ, USA; 2Non-Clinical Development and Drug Metabolism and Pharmacokinetics, Celgene Corporation, Summit, NJ, USA; 3Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece; 4Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; 5Department of Hematology, University Hospital Tübingen, Tübingen, Germany; 6Department of Hematology/Oncology, Colorado Blood Cancer Institute, Denver, CO, USA; 7Myeloma Division, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA; 8Department of Lymphoma/Myeloma, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, USA; 9Global Clinical R&D, Celgene Corporation, Summit, NJ, USA Abstract: Pomalidomide is an immunomodulatory drug for treatment of relapsed or refractory multiple myeloma (rrMM in patients who often have comorbid renal conditions. To assess the impact of renal impairment on pomalidomide exposure, a population pharmacokinetics (PPK model of pomalidomide in rrMM patients with various degrees of impaired renal function was developed. Intensive and sparse pomalidomide concentration data collected from two clinical studies in rrMM patients with normal renal function, moderately impaired renal function, severely impaired renal function not requiring dialysis, and with severely impaired renal function requiring dialysis were pooled over the dose range of 2 to 4 mg, to assess specifically the influence of the impaired renal function as a categorical variable and a continuous variable on pomalidomide clearance and plasma exposure. In addition, pomalidomide

  14. Population Physiologically-Based Pharmacokinetic Modeling for the Human Lactational Transfer of PCB 153 with Consideration of Worldwide Human Biomonitoring Results

    Energy Technology Data Exchange (ETDEWEB)

    Redding, Laurel E.; Sohn, Michael D.; McKone, Thomas E.; Wang, Shu-Li; Hsieh, Dennis P. H.; Yang, Raymond S. H.

    2008-03-01

    We developed a physiologically based pharmacokinetic model of PCB 153 in women, and predict its transfer via lactation to infants. The model is the first human, population-scale lactational model for PCB 153. Data in the literature provided estimates for model development and for performance assessment. Physiological parameters were taken from a cohort in Taiwan and from reference values in the literature. We estimated partition coefficients based on chemical structure and the lipid content in various body tissues. Using exposure data in Japan, we predicted acquired body burden of PCB 153 at an average childbearing age of 25 years and compare predictions to measurements from studies in multiple countries. Forward-model predictions agree well with human biomonitoring measurements, as represented by summary statistics and uncertainty estimates. The model successfully describes the range of possible PCB 153 dispositions in maternal milk, suggesting a promising option for back estimating doses for various populations. One example of reverse dosimetry modeling was attempted using our PBPK model for possible exposure scenarios in Canadian Inuits who had the highest level of PCB 153 in their milk in the world.

  15. Application of whole-lesion histogram analysis of pharmacokinetic parameters in dynamic contrast-enhanced MRI of breast lesions with the CAIPIRINHA-Dixon-TWIST-VIBE technique.

    Science.gov (United States)

    Li, Zhiwei; Ai, Tao; Hu, Yiqi; Yan, Xu; Nickel, Marcel Dominik; Xu, Xiao; Xia, Liming

    2018-01-01

    To investigate the application of whole-lesion histogram analysis of pharmacokinetic parameters for differentiating malignant from benign breast lesions on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). In all, 92 women with 97 breast lesions (26 benign and 71 malignant lesions) were enrolled in this study. Patients underwent dynamic breast MRI at 3T using a prototypical CAIPIRINHA-Dixon-TWIST-VIBE (CDT-VIBE) sequence and a subsequent surgery or biopsy. Inflow rate of the agent between plasma and interstitium (K trans ), outflow rate of agent between interstitium and plasma (K ep ), extravascular space volume per unit volume of tissue (v e ) including mean value, 25th/50th/75th/90th percentiles, skewness, and kurtosis were then calculated based on the whole lesion. A single-sample Kolmogorov-Smirnov test, paired t-test, and receiver operating characteristic curve (ROC) analysis were used for statistical analysis. Malignant breast lesions had significantly higher K trans , K ep , and lower v e in mean values, 25th/50th/75th/90th percentiles, and significantly higher skewness of v e than benign breast lesions (all P 0.05). The 90th percentile of K trans , the 90th percentile of K ep , and the 50th percentile of v e showed the greatest areas under the ROC curve (AUC) for each pharmacokinetic parameter derived from DCE-MRI. The 90th percentile of K ep achieved the highest AUC value (0.927) among all histogram-derived values. The whole-lesion histogram analysis of pharmacokinetic parameters can improve the diagnostic accuracy of breast DCE-MRI with the CDT-VIBE technique. The 90th percentile of K ep may be the best indicator in differentiation between malignant and benign breast lesions. 4 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2018;47:91-96. © 2017 International Society for Magnetic Resonance in Medicine.

  16. Further Evaluation of Covariate Analysis using Empirical Bayes Estimates in Population Pharmacokinetics: the Perception of Shrinkage and Likelihood Ratio Test.

    Science.gov (United States)

    Xu, Xu Steven; Yuan, Min; Yang, Haitao; Feng, Yan; Xu, Jinfeng; Pinheiro, Jose

    2017-01-01

    Covariate analysis based on population pharmacokinetics (PPK) is used to identify clinically relevant factors. The likelihood ratio test (LRT) based on nonlinear mixed effect model fits is currently recommended for covariate identification, whereas individual empirical Bayesian estimates (EBEs) are considered unreliable due to the presence of shrinkage. The objectives of this research were to investigate the type I error for LRT and EBE approaches, to confirm the similarity of power between the LRT and EBE approaches from a previous report and to explore the influence of shrinkage on LRT and EBE inferences. Using an oral one-compartment PK model with a single covariate impacting on clearance, we conducted a wide range of simulations according to a two-way factorial design. The results revealed that the EBE-based regression not only provided almost identical power for detecting a covariate effect, but also controlled the false positive rate better than the LRT approach. Shrinkage of EBEs is likely not the root cause for decrease in power or inflated false positive rate although the size of the covariate effect tends to be underestimated at high shrinkage. In summary, contrary to the current recommendations, EBEs may be a better choice for statistical tests in PPK covariate analysis compared to LRT. We proposed a three-step covariate modeling approach for population PK analysis to utilize the advantages of EBEs while overcoming their shortcomings, which allows not only markedly reducing the run time for population PK analysis, but also providing more accurate covariate tests.

  17. Sensitivity analysis of effective population size to demographic parameters in house sparrow populations.

    Science.gov (United States)

    Stubberud, Marlene Waege; Myhre, Ane Marlene; Holand, Håkon; Kvalnes, Thomas; Ringsby, Thor Harald; Saether, Bernt-Erik; Jensen, Henrik

    2017-05-01

    The ratio between the effective and the census population size, Ne/N, is an important measure of the long-term viability and sustainability of a population. Understanding which demographic processes that affect Ne/N most will improve our understanding of how genetic drift and the probability of fixation of alleles is affected by demography. This knowledge may also be of vital importance in management of endangered populations and species. Here, we use data from 13 natural populations of house sparrow (Passer domesticus) in Norway to calculate the demographic parameters that determine Ne/N. Using the global variance-based Sobol' method for the sensitivity analyses, we found that Ne/N was most sensitive to demographic variance, especially among older individuals. Furthermore, the individual reproductive values (that determine the demographic variance) were most sensitive to variation in fecundity. Our results draw attention to the applicability of sensitivity analyses in population management and conservation. For population management aiming to reduce the loss of genetic variation, a sensitivity analysis may indicate the demographic parameters towards which resources should be focused. The result of such an analysis may depend on the life history and mating system of the population or species under consideration, because the vital rates and sex-age classes that Ne/N is most sensitive to may change accordingly. © 2017 John Wiley & Sons Ltd.

  18. Population pharmacokinetics of recombinant coagulation factor VIII-SingleChain in patients with severe hemophilia A.

    Science.gov (United States)

    Zhang, Y; Roberts, J; Tortorici, M; Veldman, A; St Ledger, K; Feussner, A; Sidhu, J

    2017-06-01

    Essentials rVIII-SingleChain is a unique recombinant factor VIII (FVIII) molecule. A population pharmacokinetic model was based on FVIII activity of severe hemophilia A patients. The model was used to simulate factor VIII activity-time profiles for various dosing scenarios. The model supports prolonged dosing of rVIII-SingleChain with intervals of up to twice per week. Background Single-chain recombinant coagulation factor VIII (rVIII-SingleChain) is a unique recombinant coagulation factor VIII molecule. Objectives To: (i) characterize the population pharmacokinetics (PK) of rVIII-SingleChain in patients with severe hemophilia A; (ii) identify correlates of variability in rVIII-SingleChain PK; and (iii) simulate various dosing scenarios of rVIII-SingleChain. Patients/Methods A population PK model was developed, based on FVIII activity levels of 130 patients with severe hemophilia A (n = 91 for ≥ 12-65 years; n = 39 for  85% and > 93% of patients were predicted to maintain FVIII activity level above 1 IU dL -1 , at all times with three-times-weekly dosing (given on days 0, 2, and 4.5) at the lowest (20 IU kg -1 ) and highest (50 IU kg -1 ) doses, respectively. For twice weekly dosing (days 0 and 3.5) of 50 IU kg -1 rVIII-SingleChain, 62-80% of patients across all ages were predicted to maintain a FVIII activity level above 1 IU dL -1 at day 7. Conclusions The population PK model adequately characterized rVIII-SingleChain PK, and the model can be utilized to simulate FVIII activity-time profiles for various dosing scenarios. © 2017 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

  19. Population parameters to compare dog breeds : differences between five Dutch purebred populations

    NARCIS (Netherlands)

    Nielen, A.L.J.; Beek, van der S.; Ubbink, G.J.; Knol, B.W.

    2001-01-01

    Differences in five purebred dog populations born in 1994 in the Netherlands were evaluated using different parameters. Numerically, the Golden Retriever was the largest breed (840 litters of 234 sires) and the Kooiker Dog (101 litters of 41 sires) the smallest. The litter per sire ratio was largest

  20. Population pharmacokinetics of oxcarbazepine and its metabolite 10-hydroxycarbazepine in healthy subjects.

    Science.gov (United States)

    Antunes, Natalicia de Jesus; van Dijkman, Sven C; Lanchote, Vera Lucia; Wichert-Ana, Lauro; Coelho, Eduardo Barbosa; Alexandre Junior, Veriano; Takayanagui, Osvaldo Massaiti; Tozatto, Eduardo; van Hasselt, J G Coen; Della Pasqua, Oscar

    2017-11-15

    Oxcarbazepine is indicated for the treatment of partial or generalised tonic-clonic seizures. Most of the absorbed oxcarbazepine is converted into its active metabolite, 10-hydroxycarbazepine (MHD), which can exist as R-(-)- and S-(+)-MHD enantiomers. Here we describe the influence of the P-glycoprotein (P-gp) inhibitor verapamil, on the disposition of oxcarbazepine and MHD enantiomers, both of which are P-gp substrates. Healthy subjects (n=12) were randomised to oxcarbazepine or oxcarbazepine combined with verapamil at doses of 300mg b.i.d. and 80mg t.i.d., respectively. Blood samples (n=185) were collected over a period of 12h post oxcarbazepine dose. An integrated PK model was developed using nonlinear mixed effects modelling using a meta-analytical approach. The pharmacokinetics of oxcarbazepine was described by a two-compartment model with absorption transit compartments and first-order elimination. The concentration-time profiles of both MHD enantiomers were characterised by a one-compartment distribution model. Clearance estimates (95% CI) were 84.9L/h (69.5-100.3) for oxcarbazepine and 2.0L/h (1.9-2.1) for both MHD enantiomers. The volume of distribution was much larger for oxcarbazepine (131L (97-165)) as compared to R-(-)- and S-(+)-MHD (23.6L (14.4-32.8) vs. 31.7L (22.5-40.9), respectively). Co-administration of verapamil resulted in a modest increase of the apparent bioavailability of oxcarbazepine by 12% (10-28), but did not affect parent or metabolite clearances. Despite the evidence of comparable systemic levels of OXC and MHD following administration of verapamil, differences in brain exposure to both moieties cannot be excluded after P-glycoprotein inhibition. Copyright © 2017. Published by Elsevier B.V.

  1. Prediction of chemotherapeutic response in bladder cancer using K-means clustering of dynamic contrast-enhanced (DCE)-MRI pharmacokinetic parameters.

    Science.gov (United States)

    Nguyen, Huyen T; Jia, Guang; Shah, Zarine K; Pohar, Kamal; Mortazavi, Amir; Zynger, Debra L; Wei, Lai; Yang, Xiangyu; Clark, Daniel; Knopp, Michael V

    2015-05-01

    To apply k-means clustering of two pharmacokinetic parameters derived from 3T dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict the chemotherapeutic response in bladder cancer at the mid-cycle timepoint. With the predetermined number of three clusters, k-means clustering was performed on nondimensionalized Amp and kep estimates of each bladder tumor. Three cluster volume fractions (VFs) were calculated for each tumor at baseline and mid-cycle. The changes of three cluster VFs from baseline to mid-cycle were correlated with the tumor's chemotherapeutic response. Receiver-operating-characteristics curve analysis was used to evaluate the performance of each cluster VF change as a biomarker of chemotherapeutic response in bladder cancer. The k-means clustering partitioned each bladder tumor into cluster 1 (low kep and low Amp), cluster 2 (low kep and high Amp), cluster 3 (high kep and low Amp). The changes of all three cluster VFs were found to be associated with bladder tumor response to chemotherapy. The VF change of cluster 2 presented with the highest area-under-the-curve value (0.96) and the highest sensitivity/specificity/accuracy (96%/100%/97%) with a selected cutoff value. The k-means clustering of the two DCE-MRI pharmacokinetic parameters can characterize the complex microcirculatory changes within a bladder tumor to enable early prediction of the tumor's chemotherapeutic response. © 2014 Wiley Periodicals, Inc.

  2. Contrast-enhanced magnetic resonance imaging of the breast: the value of pharmacokinetic parameters derived from fast dynamic imaging during initial enhancement in classifying lesions

    International Nuclear Information System (INIS)

    Veltman, J.; Stoutjesdijk, M.; Mann, R.; Huisman, H.J.; Barentsz, J.O.; Blickman, J.G.; Boetes, C.

    2008-01-01

    The value of pharmacokinetic parameters derived from fast dynamic imaging during initial enhancement in characterizing breast lesions on magnetic resonance imaging (MRI) was evaluated. Sixty-eight malignant and 34 benign lesions were included. In the scanning protocol, high temporal resolution imaging was combined with high spatial resolution imaging. The high temporal resolution images were recorded every 4.1 s during initial enhancement (fast dynamic analysis). The high spatial resolution images were recorded at a temporal resolution of 86 s (slow dynamic analysis). In the fast dynamic evaluation pharmacokinetic parameters (K trans , V e and k ep ) were evaluated. In the slow dynamic analysis, each lesion was scored according to the BI-RADS classification. Two readers evaluated all data prospectively. ROC and multivariate analysis were performed. The slow dynamic analysis resulted in an AUC of 0.85 and 0.83, respectively. The fast dynamic analysis resulted in an AUC of 0.83 in both readers. The combination of both the slow and fast dynamic analyses resulted in a significant improvement of diagnostic performance with an AUC of 0.93 and 0.90 (P = 0.02). The increased diagnostic performance found when combining both methods demonstrates the additional value of our method in further improving the diagnostic performance of breast MRI. (orig.)

  3. Prediction of the pharmacokinetic parameters of triptolide in rats based on endogenous molecules in pre-dose baseline serum.

    Directory of Open Access Journals (Sweden)

    Linsheng Liu

    Full Text Available BACKGROUND: Individual variances usually affect drug metabolism and disposition, and hence result in either ineffectiveness or toxicity of a drug. In addition to genetic polymorphism, the multiple confounding factors of lifestyles, such as dietary preferences, contribute partially to individual variances. However, the difficulty of quantifying individual diversity greatly challenges the realization of individualized drug therapy. This study aims at quantitative evaluating the association between individual variances and the pharmacokinetics. METHODOLOGY/PRINCIPAL FINDINGS: Molecules in pre-dose baseline serum were profiled using gas chromatography mass spectrometry to represent the individual variances of the model rats provided with high fat diets (HFD, routine chows and calorie restricted (CR chows. Triptolide and its metabolites were determined using high performance liquid chromatography mass spectrometry. Metabonomic and pharmacokinetic data revealed that rats treated with the varied diets had distinctly different metabolic patterns and showed differential C(max values, AUC and drug metabolism after oral administration of triptolide. Rats with fatty chows had the lowest C(max and AUC values and the highest percentage of triptolide metabolic transformation, while rats with CR chows had the highest C(max and AUC values and the least percentage of triptolide transformation. Multivariate linear regression revealed that in baseline serum, the concentrations of creatinine and glutamic acid, which is the precursor of GSH, were linearly negatively correlated to C(max and AUC values. The glutamic acid and creatinine in baseline serum were suggested as the potential markers to represent individual diversity and as predictors of the disposal and pharmacokinetics of triptolide. CONCLUSIONS/SIGNIFICANCE: These results highlight the robust potential of metabonomics in characterizing individual variances and identifying relevant markers that have the

  4. Prediction of the Pharmacokinetic Parameters of Triptolide in Rats Based on Endogenous Molecules in Pre-Dose Baseline Serum

    Science.gov (United States)

    Aa, Jiye; Zheng, Tian; Shi, Jian; Li, Mengjie; Wang, Xinwen; Zhao, Chunyan; Xiao, Wenjing; Yu, Xiaoyi; Sun, Runbin; Gu, Rongrong; Zhou, Jun; Wu, Liang; Hao, Gang; Zhu, Xuanxuan; Wang, Guangji

    2012-01-01

    Background Individual variances usually affect drug metabolism and disposition, and hence result in either ineffectiveness or toxicity of a drug. In addition to genetic polymorphism, the multiple confounding factors of lifestyles, such as dietary preferences, contribute partially to individual variances. However, the difficulty of quantifying individual diversity greatly challenges the realization of individualized drug therapy. This study aims at quantitative evaluating the association between individual variances and the pharmacokinetics. Methodology/Principal Findings Molecules in pre-dose baseline serum were profiled using gas chromatography mass spectrometry to represent the individual variances of the model rats provided with high fat diets (HFD), routine chows and calorie restricted (CR) chows. Triptolide and its metabolites were determined using high performance liquid chromatography mass spectrometry. Metabonomic and pharmacokinetic data revealed that rats treated with the varied diets had distinctly different metabolic patterns and showed differential Cmax values, AUC and drug metabolism after oral administration of triptolide. Rats with fatty chows had the lowest Cmax and AUC values and the highest percentage of triptolide metabolic transformation, while rats with CR chows had the highest Cmax and AUC values and the least percentage of triptolide transformation. Multivariate linear regression revealed that in baseline serum, the concentrations of creatinine and glutamic acid, which is the precursor of GSH, were linearly negatively correlated to Cmax and AUC values. The glutamic acid and creatinine in baseline serum were suggested as the potential markers to represent individual diversity and as predictors of the disposal and pharmacokinetics of triptolide. Conclusions/Significance These results highlight the robust potential of metabonomics in characterizing individual variances and identifying relevant markers that have the potential to facilitate

  5. Clinical pharmacokinetics of phenobarbital in neonates

    NARCIS (Netherlands)

    Touw, D J; Graafland, O; Cranendonk, A; Vermeulen, R J; van Weissenbruch, M M

    2000-01-01

    Demographic and clinical pharmacokinetic data collected from term and preterm neonates who were treated with intravenous phenobarbital have been analysed to evaluate the role of patient characteristics in pharmacokinetic parameters. Significant relationships between total body weight (TBW) or body

  6. Dynamic contrast-enhanced MR imaging pharmacokinetic parameters as predictors of treatment response of brain metastases in patients with lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kuchcinski, Gregory; Duhal, Romain; Lalisse, Maxime; Dumont, Julien; Lopes, Renaud; Pruvo, Jean-Pierre; Leclerc, Xavier; Delmaire, Christine [University of Lille, CHU Lille, Department of Neuroradiology, Lille (France); Le Rhun, Emilie [University of Lille, CHU Lille, Department of Neurosurgery, Lille (France); Oscar Lambret Center, Department of Medical Oncology, Lille (France); Inserm U1192-PRISM-Laboratoire de Proteomique, Reponse Inflammatoire, Spectrometrie de Masse, Lille (France); Cortot, Alexis B. [University of Lille, CHU Lille, Department of Thoracic Oncology, Lille (France); Drumez, Elodie [University of Lille, CHU Lille, Department of Biostatistics, Lille (France)

    2017-09-15

    To determine the diagnostic accuracy of pharmacokinetic parameters measured by dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in predicting the response of brain metastases to antineoplastic therapy in patients with lung cancer. Forty-four consecutive patients with lung cancer, harbouring 123 newly diagnosed brain metastases prospectively underwent conventional 3-T MRI at baseline (within 1 month before treatment), during the early (7-10 weeks) and midterm (5-7 months) post-treatment period. An additional DCE MRI sequence was performed during baseline and early post-treatment MRI to evaluate baseline pharmacokinetic parameters (K{sup trans}, k{sub ep}, v{sub e}, v{sub p}) and their early variation (∇K{sup trans}, ∇k{sub ep}, ∇v{sub e}, ∇v{sub p}). The objective response was judged by the volume variation of each metastasis from baseline to midterm MRI. ROC curve analysis determined the best DCE MRI parameter to predict the objective response. Baseline DCE MRI parameters were not associated with the objective response. Early ∇K{sup trans}, ∇v{sub e} and ∇v{sub p} were significantly associated with the objective response (p = 0.02, p = 0.001 and p = 0.02, respectively). The best predictor of objective response was ∇v{sub e} with an area under the curve of 0.93 [95% CI = 0.87, 0.99]. DCE MRI and early ∇v{sub e} may be a useful tool to predict the objective response of brain metastases in patients with lung cancer. (orig.)

  7. Genetic parameters on Bali cattle progeny test population

    Science.gov (United States)

    Hariansyah, A. R.; Raharjo, A.; Zainuri, A.; Parwoto, Y.; Prasetiyo, D.; Prastowo, S.; Widyas, N.

    2018-03-01

    Bali cattle (Bos javanicus) is Indonesian indigenous cattle with having superior genetics potential on fitness traits in tropical environment and low feed quality. Bali Cattle Breeding Center Pulukan Indonesia conducted progeny test per annum in order to select bulls using offspring’s phenotype. This paper aimed to estimate the genetic parameters of yearling weight in Bali cattle progeny test populations and to observe the variation between periods in the above breeding center. Data were collected from the year of 2013 to 2014. There were four bulls (3 tests, 1 AI control) in 2013 and five bulls (4 tests, 1 AI) in 2014. Thirty breeding females were allocated per paddock per bull and allowed to mate naturally. In total 80 and 104 offspring’s records were obtained from 2013 and 2014 data, respectively. We built half-sib family model to estimate the additive genetic variance due to the sire and later estimate the breeding value (EBV) of each sire. Results showed that in 2013 the heritability (h2) for yearling weight was 0.19 while in 2014 was 0.79. In both years, tested bulls had higher EBV compared to the control bulls. The remarkable difference of heritability between years was due to the variations among bull candidates which might differ every year with regards to their origins. The fact that the EBV of tested bulls were higher than the control bulls gave us insight that despite the conservation policy and the continuous departure of Bali cattle bulls outside the Island, the population could still maintain its genetic quality.

  8. Population pharmacokinetic-pharmacodynamic target attainment analysis of imipenem plasma and urine data in neonates and children.

    Science.gov (United States)

    Yoshizawa, Kenichi; Ikawa, Kazuro; Ikeda, Kayo; Ohge, Hiroki; Morikawa, Norifumi

    2013-11-01

    Population pharmacokinetic (PK)-pharmacodynamic target attainment analysis of imipenem was performed to elucidate the PK properties in neonates and children and to rationalize and optimize dosing regimens. Population PK models were separately developed in neonates and children by simultaneously fitting plasma and urine data from 60 neonates and 39 children. The newly developed models were then used to estimate the probability of attaining the pharmacodynamic target (40% of the time above the minimum inhibitory concentration) against clinical isolates of common bacteria in pediatric patients. The data were best described by a 1-compartment model in neonates and a 2-compartment model in children, respectively. Renal clearance in children (0.187 L/h/kg) was double that of neonates (0.0783 L/h/kg), whereas the volume of distribution at steady-state was approximately 1.8-fold larger in neonates (0.466 L/kg) than in children (0.260 L/kg). Age was not a statistically significant covariate in the PK of both groups. Infusions (0.5 h) of 15 mg/kg every 8 h (45 mg/kg/day) and 25 mg/kg every 12 h (50 mg/kg/day) were shown to be sufficient against common bacterial isolates in both patient populations. However, 1.5-h infusions of 25 mg/kg every 8 h (75 mg/kg/day) in neonates and 25 mg/kg every 6 h (100 mg/kg/day) in children were required to be effective against Pseudomonas aeruginosa (minimum inhibitory concentration for 90% of the isolates=16 μg/mL). These results explain the changes in imipenem PK properties during the human growth process and provide guidance for tailoring dosing regimens in each pediatric age group.

  9. Integrated pharmacokinetics/pharmacodynamics parameters-based dosing guidelines of enrofloxacin in grass carp Ctenopharyngodon idella to minimize selection of drug resistance.

    Science.gov (United States)

    Xu, Lijuan; Wang, Hao; Yang, Xianle; Lu, Liqun

    2013-06-25

    Antibiotic resistance has become a serious global problem and is steadily increasing worldwide in almost every bacterial species treated with antibiotics. In aquaculture, the therapeutic options for the treatment of A. hydrophila infection were only limited to several antibiotics, which contributed for the fast-speed emergence of drug tolerance. Accordingly, the aim of this study was to establish a medication regimen to prevent drug resistant bacteria. To determine a rational therapeutic guideline, integrated pharmacodynamics and pharmacokinetics parameters were based to predict dose and dosage interval of enrofloxacin in grass carp Ctenopharyngodon idella infected by a field-isolated A. hydrophila strain. The pathogenic A. hydrophila strain (AH10) in grass carp was identified and found to be sensitive to enrofloxacin. The mutant selection window (MSW) of enrofloxacin on isolate AH10 was determined to be 0.5-3 μg/mL based on the mutant prevention concentration (MPC) and minimum inhibitory concentration (MIC) value. By using high-performance liquid chromatography (HPLC) system, the Pharmacokinetic (PK) parameters of enrofloxacin and its metabolite ciprofloxacin in grass carp were monitored after a single oral gavage of 10, 20, 30 μg enrofloxacin per g body weight. Dosing of 30 μg/g resulted in serum maximum concentration (Cmax) of 7.151 μg/mL, and concentration in serum was above MPC till 24 h post the single dose. Once-daily dosing of 30 μg/g was determined to be the rational choice for controlling AH10 infection and preventing mutant selection in grass carp. Data of mean residue time (MRT) and body clearance (CLz) indicated that both enrofloxacin and its metabolite ciprofloxacin present similar eliminating rate and pattern in serum, muscle and liver. A withdraw time of more than 32 d was suggested based on the drug eliminating rate and pharmacokinetic model described by a polyexponential equation. Based on integrated PK/PD parameters (AUC/MIC, Cmax/MIC, and T

  10. Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent-Metabolite Population Pharmacokinetic Model.

    Science.gov (United States)

    Cook, Sarah F; Stockmann, Chris; Samiee-Zafarghandy, Samira; King, Amber D; Deutsch, Nina; Williams, Elaine F; Wilkins, Diana G; Sherwin, Catherine M T; van den Anker, John N

    2016-11-01

    This study aimed to model the population pharmacokinetics of intravenous paracetamol and its major metabolites in neonates and to identify influential patient characteristics, especially those affecting the formation clearance (CL formation ) of oxidative pathway metabolites. Neonates with a clinical indication for intravenous analgesia received five 15-mg/kg doses of paracetamol at 12-h intervals (paracetamol, paracetamol-glucuronide, paracetamol-sulfate, and the combined oxidative pathway metabolites (paracetamol-cysteine and paracetamol-N-acetylcysteine) were simultaneously modeled in NONMEM 7.2. The model incorporated 259 plasma and 350 urine samples from 35 neonates with a mean gestational age of 33.6 weeks (standard deviation 6.6). CL formation for all metabolites increased with weight; CL formation for glucuronidation and oxidation also increased with postnatal age. At the mean weight (2.3 kg) and postnatal age (7.5 days), CL formation estimates (bootstrap 95% confidence interval; between-subject variability) were 0.049 L/h (0.038-0.062; 62 %) for glucuronidation, 0.21 L/h (0.17-0.24; 33 %) for sulfation, and 0.058 L/h (0.044-0.078; 72 %) for oxidation. Expression of individual oxidation CL formation as a fraction of total individual paracetamol clearance showed that, on average, fractional oxidation CL formation increased paracetamol and its metabolites in neonates. Maturational changes in the fraction of paracetamol undergoing oxidation were small relative to between-subject variability.

  11. Pharmacokinetic and pharmacodynamic analysis comparing diverse effects of detomidine, medetomidine, and dexmedetomidine in the horse: a population analysis.

    Science.gov (United States)

    Grimsrud, K N; Ait-Oudhia, S; Durbin-Johnson, B P; Rocke, D M; Mama, K R; Rezende, M L; Stanley, S D; Jusko, W J

    2015-02-01

    The present study characterizes the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of the α2-adrenergic receptor agonists detomidine (DET), medetomidine (MED) and dexmedetomidine (DEX) in parallel groups of horses from in vivo data after single bolus doses. Head height (HH), heart rate (HR), and blood glucose concentrations were measured over 6 h. Compartmental PK and minimal physiologically based PK (mPBPK) models were applied and incorporated into basic and extended indirect response models (IRM). Population PK/PD analysis was conducted using the Monolix software implementing the stochastic approximation expectation maximization algorithm. Marked reductions in HH and HR were found. The drug concentrations required to obtain inhibition at half-maximal effect (IC50 ) were approximately four times larger for DET than MED and DEX for both HH and HR. These effects were not gender dependent. Medetomidine had a greater influence on the increase in glucose concentration than DEX. The developed models demonstrate the use of mechanistic and mPBPK/PD models for the analysis of clinically obtainable in vivo data. © 2014 John Wiley & Sons Ltd.

  12. Population Pharmacokinetic Modeling and Dosing Simulations of Nitrogen-Scavenging Compounds: Disposition of Glycerol Phenylbutyrate and Sodium Phenylbutyrate in Adult and Pediatric Patients with Urea Cycle Disorders

    OpenAIRE

    Monteleone, Jon P. R.; Mokhtarani, M.; Diaz, G. A.; Rhead, W.; Lichter-Konecki, U.; Berry, S. A.; LeMons, C.; Dickinson, K.; Coakley, D.; Lee, B.; Scharschmidt, B. F.

    2013-01-01

    Sodium phenylbutyrate and glycerol phenylbutyrate mediate waste nitrogen excretion in the form of urinary phenylacetylglutamine (PAGN) in patients with urea cycle disorders (UCDs); rare genetic disorders characterized by impaired urea synthesis and hyperammonemia. Sodium phenylbutyrate is approved for UCD treatment; the development of glycerol phenylbutyrate afforded the opportunity to characterize the pharmacokinetics (PK) of both compounds. A population PK model was developed using data fro...

  13. Evaluation of Approaches to Deal with Low-Frequency Nuisance Covariates in Population Pharmacokinetic Analyses.

    Science.gov (United States)

    Lagishetty, Chakradhar V; Duffull, Stephen B

    2015-11-01

    Clinical studies include occurrences of rare variables, like genotypes, which due to their frequency and strength render their effects difficult to estimate from a dataset. Variables that influence the estimated value of a model-based parameter are termed covariates. It is often difficult to determine if such an effect is significant, since type I error can be inflated when the covariate is rare. Their presence may have either an insubstantial effect on the parameters of interest, hence are ignorable, or conversely they may be influential and therefore non-ignorable. In the case that these covariate effects cannot be estimated due to power and are non-ignorable, then these are considered nuisance, in that they have to be considered but due to type 1 error are of limited interest. This study assesses methods of handling nuisance covariate effects. The specific objectives include (1) calibrating the frequency of a covariate that is associated with type 1 error inflation, (2) calibrating its strength that renders it non-ignorable and (3) evaluating methods for handling these non-ignorable covariates in a nonlinear mixed effects model setting. Type 1 error was determined for the Wald test. Methods considered for handling the nuisance covariate effects were case deletion, Box-Cox transformation and inclusion of a specific fixed effects parameter. Non-ignorable nuisance covariates were found to be effectively handled through addition of a fixed effect parameter.

  14. Population pharmacokinetics and limited sampling strategy for first-line tuberculosis drugs and moxifloxacin

    NARCIS (Netherlands)

    Magis-Escurra, C.; Later-Nijland, H. M. J.; Alffenaar, J. W. C.; Broeders, J.; Burger, D. M.; van Crevel, R.; Boeree, M. J.; Donders, A. R. T.; van Altena, R.; van der Werf, T. S.; Aarnoutse, R. E.

    Therapeutic drug monitoring (TDM) of tuberculosis (TB) drugs currently focuses on peak plasma concentrations, yet total exposure [area under the 24-h concentration-time curve (AUC(0-24))] is probably most relevant to the efficacy of these drugs. We therefore assessed population AUC(0-24) data for

  15. Population Pharmacokinetics of an Indian F(ab')2 Snake Antivenom in Patients with Russell's Viper (Daboia russelii) Bites

    OpenAIRE

    Isbister, Geoffrey K.; Maduwage, Kalana; Saiao, Ana; Buckley, Nicholas A.; Jayamanne, Shaluka F.; Seyed, Shahmy; Mohamed, Fahim; Chathuranga, Umesh; Alexandre, Mendes; Abeysinghe, Chandana; Karunathilake, Harinda; Gawarammana, Indika; Lalloo, David; Janaka de Silva, H.

    2015-01-01

    Background\\ud \\ud There is limited information on antivenom pharmacokinetics. This study aimed to investigate the pharmacokinetics of an Indian snake antivenom in humans with Russell’s viper bites.\\ud \\ud Methods/Principal Findings\\ud \\ud Patient data and serial blood samples were collected from patients with Russell’s viper (Daboia russelii) envenoming in Sri Lanka. All patients received Indian F(ab’)2 snake antivenom manufactured by VINS Bioproducts Ltd. Antivenom concentrations were measur...

  16. Therapeutic dosage assessment based on population pharmacokinetics of a novel single-dose transdermal donepezil patch in healthy volunteers.

    Science.gov (United States)

    Choi, Hee Youn; Kim, Yo Han; Hong, Donghyun; Kim, Seong Su; Bae, Kyun-Seop; Lim, Hyeong-Seok

    2015-08-01

    We performed population pharmacokinetic (PK) analysis of a novel transdermal donepezil patch in healthy subjects who participated in a phase I trial. We also studied the optimal dosage regimen with repeated patch application for achieving a therapeutic range using a PK simulation model. This study used data from a randomized, single-dose escalation phase I clinical trial conducted in Korea. The population PK analysis was performed using NONMEM software, version 7.3. From the final PK model, we simulated repeat patch application results assuming various transdermal absorption rates. Based on the clinical trial data, novel donepezil patches with doses of 43.75 mg/12.5 cm(2), 87.5 mg/25 cm(2), and 175 mg/50 cm(2) were placed on each subject. A linear one-compartment, first-order elimination with sequential zero- and first-order absorption model best described the donepezil plasma concentrations after patch application. Simulated results on the basis of the PK model showed that repeat application of the patches of 87.5 mg/25 cm(2) and 175 mg/50 cm(2) every 72 h would cover the therapeutic range of donepezil and reach steady-state faster with fewer fluctuations in concentration compared to typical oral administrations. A linear one-compartment with sequential zero- and first-order absorption model was effective for describing the PKs of donepezil after application of patch. Based on this analysis, 87.5 mg/25 cm(2) or 175 mg/50 cm(2) patch application every 72 h is expected to achieve the desired plasma concentration of donepezil.

  17. Computational opioid prescribing: a novel application of clinical pharmacokinetics.

    Science.gov (United States)

    Linares, Oscar A; Linares, Annemarie L

    2011-01-01

    We implemented a pharmacokinetics-based mathematical modeling technique using algebra to assist prescribers with point-of-care opioid dosing. We call this technique computational opioid prescribing (COP). Because population pharmacokinetic parameter values are needed to estimate drug dosing regimen designs for individual patients using COP, and those values are not readily available to prescribers because they exist scattered in the vast pharmacology literature, we estimated the population pharmacokinetic parameter values for 12 commonly prescribed opioids from various sources using the bootstrap resampling technique. Our results show that opioid dosing regimen design, evaluation, and modification is feasible using COP. We conclude that COP is a new technique for the quantitative assessment of opioid dosing regimen design evaluation and adjustment, which may help prescribers to manage acute and chronic pain at the point-of-care. Potential benefits include opioid dose optimization and minimization of adverse opioid drug events, leading to potential improvement in patient treatment outcomes and safety.

  18. Population pharmacokinetic/pharmacodynamic modelling of the hypothalamic-pituitary-gonadal axis

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel

    2005-01-01

    model mis-specification feasible by quantifying the model uncertainty, which subsequently provides the basis for systematic population PK/PD model development. To support the model building process, the SDE approach was applied to clinical PK/PD data and used as a tool for tracking unexplained...... was stimulated and inhibited by the plasma triptorelin and degarelix concentrations, respec-tively. Circulating LH stimulated the testosterone secretion while the delayed testosterone feedback on the non-basal LH synthesis and release was modelled through a receptor compartment where testosterone stimulates...

  19. Impact of imipenem and amikacin pharmacokinetic/pharmacodynamic parameters on microbiological outcome of Gram-negative bacilli ventilator-associated pneumonia.

    Science.gov (United States)

    Pajot, O; Burdet, C; Couffignal, C; Massias, L; Armand-Lefevre, L; Foucrier, A; Da Silva, D; Lasocki, S; Laouénan, C; Mentec, H; Mentré, F; Wolff, M

    2015-05-01

    Despite recent advances, antibiotic therapy of ventilator-associated pneumonia (VAP) in ICU patients is still challenging. We assessed the impact of imipenem and amikacin pharmacokinetic and pharmacodynamic parameters on microbiological outcome in these patients. Patients with Gram-negative bacilli (GNB) VAP were prospectively included. Blood samples for pharmacokinetic analysis were collected after empirical administration of a combination of imipenem three times daily and one single dose of amikacin. MICs were estimated for each GNB obtained from respiratory samples. Microbiological success was defined as a ≥10(3) cfu/mL decrease in bacterial count in quantitative cultures between baseline and the third day of treatment. Thirty-nine patients [median (min-max) age = 60 years (28-84) and median SAPS2 at inclusion = 40 (19-73)] were included. Median MICs of imipenem and amikacin were 0.25 mg/L (0.094-16) and 2 mg/L (1-32), respectively. Median times over MIC and over 5× MIC for imipenem were 100% (8-100) and 74% (3-100), respectively. The median C1/MIC ratio for amikacin was 23 (1-76); 34 patients (87%) achieved a C1/MIC ≥10. Microbiological success occurred in 29 patients (74%). No imipenem pharmacodynamic parameter was significantly associated with the microbiological success. For amikacin, C1/MIC was significantly higher in the microbiological success group: 26 (1-76) versus 11 (3-26) (P = 0.004). In ICU patients with VAP, classic imipenem pharmacodynamic targets are easily reached with usual dosing regimens. In this context, for amikacin, a higher C1/MIC ratio than previously described might be necessary. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  20. Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen

    Directory of Open Access Journals (Sweden)

    Galactéros Frédéric

    2011-05-01

    Full Text Available Abstract Background Hydroxyurea (HU is the first approved pharmacological treatment of sickle cell anemia (SCA. The objectives of this study were to develop population pharmacokinetic(PK-pharmacodynamic(PD models for HU in order to characterize the exposure-efficacy relationships and their variability, compare two dosing regimens by simulations and develop some recommendations for monitoring the treatment. Methods The models were built using population modelling software NONMEM VII based on data from two clinical studies of SCA adult patients receiving 500-2000 mg of HU once daily. Fetal hemoglobin percentage (HbF% and mean corpuscular volume (MCV were used as biomarkers for response. A sequential modelling approach was applied. Models were evaluated using simulation-based techniques. Comparisons of two dosing regimens were performed by simulating 10000 patients in each arm during 12 months. Results The PK profiles were described by a bicompartmental model. The median (and interindividual coefficient of variation (CV of clearance was 11.6 L/h (30%, the central volume was 45.3 L (35%. PK steady-state was reached in about 35 days. For a given dosing regimen, HU exposure varied approximately fivefold among patients. The dynamics of HbF% and MCV were described by turnover models with inhibition of elimination of response. In the studied range of drug exposures, the effect of HU on HbF% was at its maximum (median Imax was 0.57, CV was 27%; the effect on MCV was close to its maximum, with median value of 0.14 and CV of 49%. Simulations showed that 95% of the steady-state levels of HbF% and MCV need 26 months and 3 months to be reached, respectively. The CV of the steady-state value of HbF% was about 7 times larger than that of MCV. Simulations with two different dosing regimens showed that continuous dosing led to a stronger HbF% increase in some patients. Conclusions The high variability of response to HU was related in part to pharmacokinetics and

  1. Population Pharmacokinetics and Optimal Sampling Strategy for Model-Based Precision Dosing of Melphalan in Patients Undergoing Hematopoietic Stem Cell Transplantation.

    Science.gov (United States)

    Mizuno, Kana; Dong, Min; Fukuda, Tsuyoshi; Chandra, Sharat; Mehta, Parinda A; McConnell, Scott; Anaissie, Elias J; Vinks, Alexander A

    2018-05-01

    High-dose melphalan is an important component of conditioning regimens for patients undergoing hematopoietic stem cell transplantation. The current dosing strategy based on body surface area results in a high incidence of oral mucositis and gastrointestinal and liver toxicity. Pharmacokinetically guided dosing will individualize exposure and help minimize overexposure-related toxicity. The purpose of this study was to develop a population pharmacokinetic model and optimal sampling strategy. A population pharmacokinetic model was developed with NONMEM using 98 observations collected from 15 adult patients given the standard dose of 140 or 200 mg/m 2 by intravenous infusion. The determinant-optimal sampling strategy was explored with PopED software. Individual area under the curve estimates were generated by Bayesian estimation using full and the proposed sparse sampling data. The predictive performance of the optimal sampling strategy was evaluated based on bias and precision estimates. The feasibility of the optimal sampling strategy was tested using pharmacokinetic data from five pediatric patients. A two-compartment model best described the data. The final model included body weight and creatinine clearance as predictors of clearance. The determinant-optimal sampling strategies (and windows) were identified at 0.08 (0.08-0.19), 0.61 (0.33-0.90), 2.0 (1.3-2.7), and 4.0 (3.6-4.0) h post-infusion. An excellent correlation was observed between area under the curve estimates obtained with the full and the proposed four-sample strategy (R 2  = 0.98; p strategy promises to achieve the target area under the curve as part of precision dosing.

  2. Population pharmacokinetics of pomalidomide in patients with relapsed or refractory multiple myeloma with various degrees of impaired renal function.

    Science.gov (United States)

    Li, Yan; Wang, Xiaomin; O'Mara, Edward; Dimopoulos, Meletios A; Sonneveld, Pieter; Weisel, Katja C; Matous, Jeffrey; Siegel, David S; Shah, Jatin J; Kueenburg, Elisabeth; Sternas, Lars; Cavanaugh, Chloe; Zaki, Mohamed; Palmisano, Maria; Zhou, Simon

    2017-01-01

    Pomalidomide is an immunomodulatory drug for treatment of relapsed or refractory multiple myeloma (rrMM) in patients who often have comorbid renal conditions. To assess the impact of renal impairment on pomalidomide exposure, a population pharmacokinetics (PPK) model of pomalidomide in rrMM patients with various degrees of impaired renal function was developed. Intensive and sparse pomalidomide concentration data collected from two clinical studies in rrMM patients with normal renal function, moderately impaired renal function, severely impaired renal function not requiring dialysis, and with severely impaired renal function requiring dialysis were pooled over the dose range of 2 to 4 mg, to assess specifically the influence of the impaired renal function as a categorical variable and a continuous variable on pomalidomide clearance and plasma exposure. In addition, pomalidomide concentration data collected on dialysis days from both the withdrawal (arterial) side and from the returning (venous) side of the dialyzer, from rrMM patients with severely impaired renal function requiring dialysis, were used to assess the extent to which dialysis contributes to the removal of pomalidomide from blood circulation. PPK analyses demonstrated that moderate to severe renal impairment not requiring dialysis has no influence on pomalidomide clearance or plasma exposure, as compared to those patients with normal renal function, while pomalidomide exposure increased approximately 35% in patients with severe renal impairment requiring dialysis on nondialysis days. In addition, dialysis increased total body pomalidomide clearance from 5 L/h to 12 L/h, indicating that dialysis will significantly remove pomalidomide from the blood circulation. Thus, pomalidomide should be administered post-dialysis on the days of dialysis.

  3. Evaluation of the Microbiological Efficacy of a Single 2-Gram Dose of Extended-Release Azithromycin by Population Pharmacokinetics and Simulation in Japanese Patients with Gonococcal Urethritis.

    Science.gov (United States)

    Soda, Midori; Ito, Shin; Matsumaru, Naoki; Nakamura, Sakiko; Nagase, Izumi; Takahashi, Hikari; Ohno, Yuta; Yasuda, Mitsuru; Yamamoto, Miho; Tsukamoto, Katsura; Itoh, Yoshinori; Deguchi, Takashi; Kitaichi, Kiyoyuki

    2018-01-01

    The objective of this study was to analyze the relationship between the pharmacokinetic (PK)/pharmacodynamic (PD) parameters of a single 2-g dose of extended-release formulation of azithromycin (AZM-SR) and its microbiological efficacy against gonococcal urethritis. Fifty male patients with gonococcal urethritis were enrolled in this study. In 36 patients, the plasma AZM concentrations were measured using liquid chromatography-tandem mass spectrometry, the AZM MIC values for the Neisseria gonorrhoeae isolates were determined, and the microbiological outcomes were assessed. AZM-SR monotherapy eradicated N. gonorrhoeae in 30 (83%) of the 36 patients. AZM MICs ranged from 0.03 to 2 mg/liter. The mean value of the area under the concentration-time curve (AUC), estimated by population PK analysis using a two-compartment model, was 20.8 mg · h/liter. Logistic regression analysis showed that the PK/PD target value required to predict an N. gonorrhoeae eradication rate of ≥95% was a calculated AUC/MIC of ≥59.5. The AUC/MIC value was significantly higher in patients who achieved microbiological cure than in patients who achieved microbiological failure. Monte Carlo simulation using this MIC distribution revealed that the probability that AZM-SR monotherapy would produce an AUC/MIC exceeding the AUC/MIC target of 59.5 was 47%. Furthermore, the MIC distribution for strains isolated in this study was mostly consistent with that for strains currently circulating in Japan. In conclusion, in Japan, AZM-SR monotherapy may not be effective against gonococcal urethritis. Therefore, use of a single 2-g dose of AZM-SR either with or without other antibiotics could be an option to treat gonococcal urethritis if patients are allergic to ceftriaxone and spectinomycin or are diagnosed to be infected with an AZM-sensitive strain. Copyright © 2017 American Society for Microbiology.

  4. In vitro enantioselective human liver microsomal metabolism and prediction of in vivo pharmacokinetic parameters of tetrabenazine by DLLME-CE.

    Science.gov (United States)

    Bocato, Mariana Zuccherato; de Lima Moreira, Fernanda; de Albuquerque, Nayara Cristina Perez; de Gaitani, Cristiane Masetto; de Oliveira, Anderson Rodrigo Moraes

    2016-09-05

    A new capillary electrophoresis method for the enantioselective analysis of cis- and trans- dihydrotetrabenazine (diHTBZ) after in vitro metabolism by human liver microsomes (HLMs) was developed. The chiral electrophoretic separations were performed by using tris-phosphate buffer (pH 2.5) containing 1% (w/v) carboxymethyl-β-CD as background electrolyte with an applied voltage of +15kV and capillary temperature kept at 15°C. Dispersive liquid-liquid microextraction was employed to extract the analytes from HLMs. Dichloromethane was used as extraction solvent (75μL) and acetone as disperser solvent (150μL). The method was validated according to official guidelines and showed to be linear over the concentration range of 0.29-19.57μmolL(-1) (r=0.9955) for each metabolite enantiomer. Within- and between-day precision and accuracy evaluated by relative standard deviation and relative error were lower than 15% for all enantiomers. The stability assay showed that the analytes kept stable under handling, storage and in metabolism conditions. After method validation, an enantioselective in vitro metabolism and in vivo pharmacokinetic prediction was carried out. This study showed a stereoselective metabolism and the observed kinetic profile indicated a substrate inhibition behavior. DiHTBZ enantiomers were catalyzed mainly by CYP2C19 and the predicted clearance suggests that liver metabolism is the main route for TBZ elimination which supports the literature data. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. A cancer research UK pharmacokinetic study of BPA-mannitol in patients with high grade glioma to optimise uptake parameters for clinical trials of BNCT

    International Nuclear Information System (INIS)

    Green, S.; James, N.D.; Cruickshank, G.S.

    2006-01-01

    This presentation will describe a human pharmacokinetic study which is scheduled to begin recruitment in Summer 2006. The study has been ongoing for approximately 4 years to develop the necessary protocols, validate boron assays and to develop a new formulation of BPA. The study population will be patients with glioblastoma multiforme and the study focuses on the route of infusion (intra venous or intra carotid artery) and in each will assess the effect of administration of mannitol (as a blood-brain barrier disrupter). Mannitol will be administered as a bolus at the beginning of a two hour infusion of BPA. The BPA formulation (BPA - mannitol) is also new and avoids some of the problems of low solubility associated with BPA-fructose as well as the potential risk of fructose intolerance. The approach will include stereotactic biopsy which is necessary to confirm diagnosis. Tissue samples collected will include needle biopsy samples of tumour and brain around tumour for estimation of BPA transporter expression, together with microdialysis catheter collection of extra-cellular fluid and routine collection of blood and urine for BPA levels. Where possible, according to surgical plan and the route of entry, samples of cerebro-spinal will also be collected. These data will be used to develop a pharmacokinetic model following the general approach already established by others in the field. This paper presents initial pre-clinical studies on the BPA-mannitol formulation and some assay validation work together with suggestions for approaches to normalisation of the macroscopic boron assays using simultaneous measurement of Mg levels in tissue. (author)

  6. Clinical Determinants of Target Non-Attainment of Linezolid in Plasma and Interstitial Space Fluid: A Pooled Population Pharmacokinetic Analysis with Focus on Critically Ill Patients.

    Science.gov (United States)

    Minichmayr, Iris K; Schaeftlein, André; Kuti, Joseph L; Zeitlinger, Markus; Kloft, Charlotte

    2017-06-01

    We aimed to assess linezolid pharmacokinetics in the plasma and interstitial space fluid (ISF) of patients with sepsis, diabetic foot infections or cystic fibrosis and healthy volunteers. The impacts of joint characteristics and disease on plasma and target-site exposure were to be identified together with the benefit of dose intensification in critically ill patients. Rich plasma (n = 1598) and ISF concentrations in subcutaneous adipose (n = 1430) and muscle tissue (n = 1089) measured by microdialysis were pooled from three clinical trials with 51 individuals receiving 600 mg of intravenous and oral linezolid. All data were analysed simultaneously by a population approach also considering methodological aspects of microdialysis. The impact of covariates on the attainment of the pharmacokinetic/pharmacodynamic targets, AUC/MIC = 100 (area under the concentration-time curve/minimum inhibitory concentration) and fT >MIC  = 99 % (time that unbound concentrations exceed the MIC), was assessed by deterministic and Monte Carlo simulations. A two-compartment pharmacokinetic model with nonlinear elimination and tissue distribution factors accounting for differences between plasma and ISF concentrations adequately predicted all measurements. Clearance (CL) was highest in septic patients (11.2 L/h vs. CL Healthy /CL Cystic fibrosis /CL Diabetic  = 7.67/6.87/6.35 L/h). Penetration into subcutaneous adipose ISF was lowest in diabetic patients (-34.9 % compared with healthy volunteers). Creatinine clearance and total body weight further impacted linezolid exposure. To achieve timely efficacious therapy, front-loaded dosing and continuous infusion seemed beneficial in septic patients. Our analysis suggests that after standard linezolid doses, particularly patients with sepsis and conserved renal function are at risk of not attaining pharmacokinetic/pharmacodynamic targets and would benefit from initial dose intensification.

  7. Prediction of human pharmacokinetics of activated recombinant factor VII and B-domain truncated factor VIII from animal population pharmacokinetic models of haemophilia

    DEFF Research Database (Denmark)

    Larsen, Malte Selch; Juul, Rasmus Vestergaard; Groth, Andreas Velsing

    2018-01-01

    activated factor VII (rFVIIa) and recombinant factor VIII (rFVIII) in several experimental animal models using population PK modelling, and apply a simulation-based approach to evaluate how well the developed animal population PK models predict human PK. PK models were developed for rFVIIa and r...

  8. Effects of body size and gender on the population pharmacokinetics of artesunate and its active metabolite dihydroartemisinin in pediatric malaria patients.

    Science.gov (United States)

    Morris, Carrie A; Tan, Beesan; Duparc, Stephan; Borghini-Fuhrer, Isabelle; Jung, Donald; Shin, Chang-Sik; Fleckenstein, Lawrence

    2013-12-01

    Despite the important role of the antimalarial artesunate and its active metabolite dihydroartemisinin (DHA) in malaria treatment efforts, there are limited data on the pharmacokinetics of these agents in pediatric patients. This study evaluated the effects of body size and gender on the pharmacokinetics of artesunate-DHA using data from pediatric and adult malaria patients. Nonlinear mixed-effects modeling was used to obtain a base model consisting of first-order artesunate absorption and one-compartment models for artesunate and for DHA. Various methods of incorporating effects of body size descriptors on clearance and volume parameters were tested. An allometric scaling model for weight and a linear body surface area (BSA) model were deemed optimal. The apparent clearance and volume of distribution of DHA obtained with the allometric scaling model, normalized to a 38-kg patient, were 63.5 liters/h and 65.1 liters, respectively. Estimates for the linear BSA model were similar. The 95% confidence intervals for the estimated gender effects on clearance and volume parameters for artesunate fell outside the predefined no-relevant-clinical-effect interval of 0.75 to 1.25. However, the effect of gender on apparent DHA clearance was almost entirely contained within this interval, suggesting a lack of an influence of gender on this parameter. Overall, the pharmacokinetics of artesunate and DHA following oral artesunate administration can be described for pediatric patients using either an allometric scaling or linear BSA model. Both models predict that, for a given artesunate dose in mg/kg of body weight, younger children are expected to have lower DHA exposure than older children or adults.

  9. A Semi-Physiological Population Model to Quantify the Effect of Hematocrit on Everolimus Pharmacokinetics and Pharmacodynamics in Cancer Patients

    NARCIS (Netherlands)

    Erp, N.P. van; Herpen, C.M. van; Wit, D. de; Willemsen, A.; Burger, D.M.; Huitema, A.D.; Kapiteijn, E.; Heine, R. ter

    2016-01-01

    INTRODUCTION AND OBJECTIVE: Everolimus (a drug from the class of mammalian target of rapamycin [mTOR] inhibitors) is associated with frequent toxicity-related dose reductions. Everolimus accumulates in erythrocytes, but the extent to which hematocrit affects everolimus plasma pharmacokinetics and

  10. Population Pharmacokinetic-Pharmacodynamic Modeling of Haloperidol in Patients With Schizophrenia Using Positive and Negative Syndrome Rating Scale

    NARCIS (Netherlands)

    Reddy, Venkatesh Pilla; Kozielska, Magdalena; Johnson, Martin; Mafirakureva, Nyashadzaishe; Vermeulen, An; Liu, Jing; de Greef, Rik; Rujescu, Dan; Groothuis, Geny M. M.; Danhof, Meindert; Proost, Johannes H.

    2013-01-01

    The aim of this study was to develop a pharmacokinetic-pharmacodynamic (PKPD) model that quantifies the efficacy of haloperidol, accounting for the placebo effect, the variability in exposure-response, and the dropouts. Subsequently, the developed model was utilized to characterize an effective

  11. Population pharmacokinetics of caffeine and its metabolites theobromine, paraxanthine and theophylline after inhalation in combination with diacetylmorphine

    NARCIS (Netherlands)

    Zandvliet, Anthe S.; Huitema, Alwin D. R.; de Jonge, Milly E.; den Hoed, Rob; Sparidans, Rolf W.; Hendriks, Vincent M.; van den Brink, Wim; van Ree, Jan M.; Beijnen, Jos H.

    2005-01-01

    The stimulant effect of caffeine, as an additive in diacetylmorphine preparations for study purposes, may interfere with the pharmacodynamic effects of diacetylmorphine. In order to obtain insight into the pharmacology of caffeine after inhalation in heroin users, the pharmacokinetics of caffeine

  12. Determination of quantitative retention-activity relationships between pharmacokinetic parameters and biological effectiveness fingerprints of Salvia miltiorrhiza constituents using biopartitioning and microemulsion high-performance liquid chromatography.

    Science.gov (United States)

    Gao, Haoshi; Huang, Hongzhang; Zheng, Aini; Yu, Nuojun; Li, Ning

    2017-11-01

    In this study, we analyzed danshen (Salvia miltiorrhiza) constituents using biopartitioning and microemulsion high-performance liquid chromatography (MELC). The quantitative retention-activity relationships (QRARs) of the constituents were established to model their pharmacokinetic (PK) parameters and chromatographic retention data, and generate their biological effectiveness fingerprints. A high-performance liquid chromatography (HPLC) method was established to determine the abundance of the extracted danshen constituents, such as sodium danshensu, rosmarinic acid, salvianolic acid B, protocatechuic aldehyde, cryptotanshinone, and tanshinone IIA. And another HPLC protocol was established to determine the abundance of those constituents in rat plasma samples. An experimental model was built in Sprague Dawley (SD) rats, and calculated the corresponding PK parameterst with 3P97 software package. Thirty-five model drugs were selected to test the PK parameter prediction capacities of the various MELC systems and to optimize the chromatographic protocols. QRARs and generated PK fingerprints were established. The test included water/oil-soluble danshen constituents and the prediction capacity of the regression model was validated. The results showed that the model had good predictability. Copyright © 2017. Published by Elsevier B.V.

  13. Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients.

    Science.gov (United States)

    Karaiskos, Ilias; Friberg, Lena E; Pontikis, Konstantinos; Ioannidis, Konstantinos; Tsagkari, Vasiliki; Galani, Lamprini; Kostakou, Eirini; Baziaka, Fotini; Paskalis, Charalambos; Koutsoukou, Antonia; Giamarellou, Helen

    2015-12-01

    Colistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430-3436, 2009, http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241- 4249, 2012, http://dx.doi.org/10.1128/AAC.06426-11; S. M. Garonzik, J. Li, V. Thamlikitkul, D. L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284-3294, 2011, http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (∼ 270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while

  14. Validated TLC-densitometric analysis for determination of carotenoids in fancy carp (Cyprinus carpio serum and the application for pharmacokinetic parameter assessment

    Directory of Open Access Journals (Sweden)

    Bundit Yuangsoi

    2008-09-01

    Full Text Available A densitometric Thin-layer Chromatographic (TLC method of carotenoids such as astaxanthin, lutein, and B-carotene have been established and validated for quantitative determination of carotenoids in fancy carp serum. This study can be used in the evaluation of pharmacokinetic parameters of carotenoids in fancy carp serum. Analyses of carotenoids were performed on TLC glass plates pre-coated with silica gel 60 as the stationary phase. Linear ascending development was carried out in a twin trough glass chamber saturated with mobile phase consisting of petroleum ether-diethyl ether-acetone(75:15:10, v/v/v at a temperature of 25±2oC. TLC scanner was used for spectrodensitometric scanning and analysis inabsorbance mode at 450 nm. The system was found to give compact spots for astaxanthin, lutein, and b-carotene (Rf values of 0.21, 0.17 and 0.97, respectively. The method was validated for linearity, precision, accuracy, LOD, LOQ and HORRAT value. The linear regression analysis data of astaxanthin, lutein, and b-carotene for the calibration plots showed a good linear relationship with r2 = 0.999, 0.998 and 0.998, respectively, in a concentration range of 0.01-6.50 ug/spot with respect to the peak area. Precision (% RSDr of astaxanthin, lutein, and b-carotene was 2.93, 3.34, and 2.61, respectively. The limit of detection (LOD was 0.011, 0.023 and 0.026 μg/spot, respectively. The additionally limit of quantization (LOQ was 0.036, 0.075 and 0.085 μg/spot, respectively. The percent recoveries of astaxanthin, lutein, and b-carotene spiked to sample blank showed an average of percent recoveries for astaxanthin (0.3-2.0 mg/ml of 91.70%, for lutein(0.2-3.0 mg/ul of 90.47%, and for b-carotene (0.1-1.0 mg/ul of 102.25%. In all carotenoids, the HORRAT values were below the critical value. Therefore, this method enables simple, rapid, economical and precise quantitative determination of carotenoids in fancy carp serum for evaluated pharmacokinetic parameters

  15. [Impact of ECMO on drugs pharmacokinetics].

    Science.gov (United States)

    Hasni, Nesrine; Lemaitre, Florian; Fernandez, Christine; Combes, Alain; Farinotti, Robert

    2011-01-01

    Extracorporeal membrane oxygenation (ECMO) is a life support system used in the treatment of patients of all ages with severe respiratory or cardiorespiratory failure. Despite the intensive use of drugs in the treatment of patients on ECMO, few studies have been conducted to determine the impact of this device on the pharmacokinetics of drugs. Publications in this field have shown pharmacokinetics changes resulting in an increase in volume of distribution of drugs and/or decreased clearance with consequent increase of their half-life. Reduced plasma concentrations of some drugs due to their adsorption on the different components of the circuit further complicates the determination of pharmacokinetic parameters of patients treated by ECMO. The literature published up to now on the pharmacokinetic changes associated with ECMO provide preliminary support for dosage adjustment. However, more research is needed to identify dosage strategies for this patient population. © 2011 Société Française de Pharmacologie et de Thérapeutique.

  16. Population pharmacokinetics of modafinil acid and estimation of the metabolic conversion of modafinil into modafinil acid in 5 major ethnic groups of China.

    Science.gov (United States)

    Wu, Ke-hua; Guo, Tao; Deng, Chen-hui; Guan, Zheng; Li, Liang; Zhou, Tian-yan; Lu, Wei

    2012-11-01

    To describe the population pharmacokinetic profile of modafinil acid and to compare the extent of metabolism of modafinil into modafinil acid in 5 major ethnic groups (Han, Mongolian, Korean, Uygur, and Hui) of China. In a multi-center, open-label, single dose clinical trial, 49 healthy volunteers from the 5 ethnic groups received 200 mg of modafinil orally. Blood samples for pharmacokinetic evaluation of modafinil and modafinil acid were drawn before and at different time after the administration. Systematic population pharmacokinetic (PopPK) modeling for modafinil acid was conducted, integrating with our previous PopPK model for modafinil. The influence of ethnicity, gender, height, body weight and body mass index (BMI) was estimated. The extent of metabolism of modafinil into modafinil acid, expressed as the relative conversion fraction, was estimated and compared among the 5 ethnic groups. When combined with the PopPK model of modafinil, the concentration of modafinil acid versus time profile was best described with a one-compartment model. The typical clearance and volume of distribution for modafinil acid were 4.94 (l/h) and 2.73 (l), respectively. The Korean group had 25% higher clearance, and the Uygur and Hui groups had 12% higher clearance than the Han group. The median for the relative conversion fraction was 0.53 for Koreans, and 0.24 for the other 4 ethnicities. Ethnicity has significant influence on the clearance of modafinil acid. When patients in the 5 ethnic groups are administered drugs or prodrugs catalyzed by esterases and/or amidases, the variability in the extent of drug metabolism should be considered.

  17. No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects.

    Science.gov (United States)

    Salem, Ahmed Hamed; Jones, Aksana Kaefer; Santini-Oliveira, Marilia; Taylor, Graham P; Patterson, Kristine B; Nilius, Angela M; Klein, Cheri Enders

    2016-01-01

    Lopinavir-ritonavir is frequently prescribed to HIV-1-infected women during pregnancy. Decreased lopinavir exposure has been reported during pregnancy, but the clinical significance of this reduction is uncertain. This analysis aimed to evaluate the need for lopinavir dose adjustment during pregnancy. We conducted a population pharmacokinetic analysis of lopinavir and ritonavir concentrations collected from 84 pregnant and 595 nonpregnant treatment-naive and -experienced HIV-1-infected subjects enrolled in six clinical studies. Lopinavir-ritonavir doses in the studies ranged between 400/100 and 600/150 mg twice daily. In addition, linear mixed-effect analysis was used to compare the area under the concentration-time curve from 0 to 12 h (AUC0-12) and concentration prior to dosing (Cpredose) in pregnant women and nonpregnant subjects. The relationship between lopinavir exposure and virologic suppression in pregnant women and nonpregnant subjects was evaluated. Population pharmacokinetic analysis estimated 17% higher lopinavir clearance in pregnant women than in nonpregnant subjects. Lopinavir clearance values postpartum were 26.4% and 37.1% lower than in nonpregnant subjects and pregnant women, respectively. As the tablet formulation was estimated to be 20% more bioavailable than the capsule formulation, no statistically significant differences between lopinavir exposure in pregnant women receiving the tablet formulation and nonpregnant subjects receiving the capsule formulation were identified. In the range of lopinavir AUC0-12 or Cpredose values observed in the third trimester, there was no correlation between lopinavir exposure and viral load or proportion of subjects with virologic suppression. Similar efficacy was observed between pregnant women and nonpregnant subjects receiving lopinavir-ritonavir at 400/100 mg twice daily. The pharmacokinetic and pharmacodynamic results support the use of a lopinavir-ritonavir 400/100-mg twice-daily dose during pregnancy

  18. Bridging the gaps between non-invasive genetic sampling and population parameter estimation

    Science.gov (United States)

    Francesca Marucco; Luigi Boitani; Daniel H. Pletscher; Michael K. Schwartz

    2011-01-01

    Reliable estimates of population parameters are necessary for effective management and conservation actions. The use of genetic data for capture­recapture (CR) analyses has become an important tool to estimate population parameters for elusive species. Strong emphasis has been placed on the genetic analysis of non-invasive samples, or on the CR analysis; however,...

  19. Development of a Pharmacokinetic Model to Describe the Complex Pharmacokinetics of Pazopanib in Cancer Patients

    NARCIS (Netherlands)

    Yu, Huixin; van Erp, Nielka; Bins, Sander; Mathijssen, Ron H J; Schellens, Jan H M; Beijnen, Jos H.; Steeghs, Neeltje; Huitema, Alwin D R

    Background and Objective: Pazopanib is a multi-targeted anticancer tyrosine kinase inhibitor. This study was conducted to develop a population pharmacokinetic (popPK) model describing the complex pharmacokinetics of pazopanib in cancer patients. Methods: Pharmacokinetic data were available from 96

  20. Development of a Pharmacokinetic Model to Describe the Complex Pharmacokinetics of Pazopanib in Cancer Patients

    NARCIS (Netherlands)

    Yu, H.; Erp, N. van; Bins, S.; Mathijssen, R.H.; Schellens, J.H.; Beijnen, J.H.; Steeghs, N.; Huitema, A.D.

    2017-01-01

    BACKGROUND AND OBJECTIVE: Pazopanib is a multi-targeted anticancer tyrosine kinase inhibitor. This study was conducted to develop a population pharmacokinetic (popPK) model describing the complex pharmacokinetics of pazopanib in cancer patients. METHODS: Pharmacokinetic data were available from 96

  1. Evaluation of Tumor Angiogenesis Using Dynamic Enhanced Magnetic Resonance Imaging: Comparison of Plasma Vascular Endothelial Growth Factor, Hemodynamic, and Pharmacokinetic Parameters

    International Nuclear Information System (INIS)

    Ikeda, O.; Nishimura, R.; Miyayama, H.; Yasunaga, T.; Ozaki, Y.; Tuji, A.; Yamashita, Y.

    2004-01-01

    Purpose: To assess whether tumor angiogenesis of breast cancers can be predicted on the basis of dynamic magnetic resonance imaging (MRI). Material and Methods: Seventy-one patients with 71 breast cancers underwent Gd-DTPA enhanced dynamic MRI. Two regions of interest measurements were obtained in the periphery and in the center of the breast cancers. Hemodynamic parameters obtained by dynamic MRI included peak time, contrast enhancement ratio (CE ratio), and washout ratio. The triexponential concentration curve of Gd-DTPA was fitted to a theoretical model based on compartmental analysis. The transfer constant (or permeability surface product per unit volume of compartment 'k') was obtained using this method. Tumor angiogenesis was assessed by plasma vascular endothelial growth factor (P-VEGF). Results: The P-VEGF was positive in 28 of 71 tumors (39%). The CE ratio, washout ratio, and k in the periphery in P-VEGF positive breast cancers (mean 178%, 18%, and 1.5x10 -2 (s-1)) were significantly greater (P -2 (s-1)). The peak time in the periphery in P-VEGF positive breast cancers was more marked than for P-VEGF negative breast cancers, but this difference was not significant. Conclusion: The hemodynamic and pharmacokinetic analysis of MRI provides valuable information about angiogenesis of breast cancers

  2. Limited-sampling strategy models for estimating the pharmacokinetic parameters of 4-methylaminoantipyrine, an active metabolite of dipyrone

    Directory of Open Access Journals (Sweden)

    Suarez-Kurtz G.

    2001-01-01

    Full Text Available Bioanalytical data from a bioequivalence study were used to develop limited-sampling strategy (LSS models for estimating the area under the plasma concentration versus time curve (AUC and the peak plasma concentration (Cmax of 4-methylaminoantipyrine (MAA, an active metabolite of dipyrone. Twelve healthy adult male volunteers received single 600 mg oral doses of dipyrone in two formulations at a 7-day interval in a randomized, crossover protocol. Plasma concentrations of MAA (N = 336, measured by HPLC, were used to develop LSS models. Linear regression analysis and a "jack-knife" validation procedure revealed that the AUC0-¥ and the Cmax of MAA can be accurately predicted (R²>0.95, bias 0.85 of the AUC0-¥ or Cmax for the other formulation. LSS models based on three sampling points (1.5, 4 and 24 h, but using different coefficients for AUC0-¥ and Cmax, predicted the individual values of both parameters for the enrolled volunteers (R²>0.88, bias = -0.65 and -0.37%, precision = 4.3 and 7.4% as well as for plasma concentration data sets generated by simulation (R²>0.88, bias = -1.9 and 8.5%, precision = 5.2 and 8.7%. Bioequivalence assessment of the dipyrone formulations based on the 90% confidence interval of log-transformed AUC0-¥ and Cmax provided similar results when either the best-estimated or the LSS-derived metrics were used.

  3. PHARMACOKINETIC RESEARCHES AND PRACTICAL MEDICINE

    Directory of Open Access Journals (Sweden)

    V. G. Belolipetskaya

    2015-12-01

    Full Text Available An article gives in a comprehensive manner the main idea of pharmacokinetics, as the science about rules of substances behavior in the internal environment of the organism, as well as of main parameters of pharmacokinetic researches. The article provides vivid and very  persuasive examples of high practical importance of this science both for creating new medical forms of drugs and for choosing the optimal of therapy regime.

  4. PHARMACOKINETIC RESEARCHES AND PRACTICAL MEDICINE

    Directory of Open Access Journals (Sweden)

    V. G. Belolipetskaya

    2005-01-01

    Full Text Available An article gives in a comprehensive manner the main idea of pharmacokinetics, as the science about rules of substances behavior in the internal environment of the organism, as well as of main parameters of pharmacokinetic researches. The article provides vivid and very  persuasive examples of high practical importance of this science both for creating new medical forms of drugs and for choosing the optimal of therapy regime.

  5. Characterisation of Population Pharmacokinetics and Endogenous Follicle Stimulating Hormone (FSH) Levels after Multiple Dosing of a Recombinant Human FSH, FE 999049, in Healthy Women

    DEFF Research Database (Denmark)

    Rose, Trine Høyer; Röshammer, Daniel; Erichsen, Lars

    2016-01-01

    : Longitudinal measurements of FSH, luteinising hormone, progesterone, estradiol, and inhibin B levels were collected after repeated subcutaneous dosing with 225 IU of FE 999049 in 24 gonadotropin downregulated healthy women. The FSH data were described using nonlinear mixed-effects modelling. Results...... increased with body weight in accordance with an allometrically scaled power exponent of 0.75 and 1, respectively. Endogenous FSH levels were lower in individuals with higher progesterone levels at baseline and were further suppressed over time with increasing inhibin B levels. Conclusions......: This characterisation of FE 999049 population pharmacokinetics after repeated dosing is in line with previous findings after single-dose administration. The results provide a basis for study design and data evaluation in the future development of recombinant FSH products, and show it can be of importance to account...

  6. Improved physiologically based pharmacokinetic model for oral exposures to chromium in mice, rats, and humans to address temporal variation and sensitive populations.

    Science.gov (United States)

    Kirman, C R; Suh, M; Proctor, D M; Hays, S M

    2017-06-15

    A physiologically based pharmacokinetic (PBPK) model for hexavalent chromium [Cr(VI)] in mice, rats, and humans developed previously (Kirman et al., 2012, 2013), was updated to reflect an improved understanding of the toxicokinetics of the gastrointestinal tract following oral exposures. Improvements were made to: (1) the reduction model, which describes the pH-dependent reduction of Cr(VI) to Cr(III) in the gastrointestinal tract under both fasted and fed states; (2) drinking water pattern simulations, to better describe dosimetry in rodents under the conditions of the NTP cancer bioassay; and (3) parameterize the model to characterize potentially sensitive human populations. Important species differences, sources of non-linear toxicokinetics, and human variation are identified and discussed within the context of human health risk assessment. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Population pharmacokinetics and pharmacodynamics of fosfomycin in non-critically ill patients with bacteremic urinary infection caused by multidrug-resistant Escherichia coli.

    Science.gov (United States)

    Merino-Bohórquez, V; Docobo-Pérez, F; Sojo, J; Morales, I; Lupión, C; Martín, D; Cameán, M; Hope, W; Pascual, Á; Rodríguez-Baño, J

    2018-04-10

    To describe the population pharmacokinetics of fosfomycin for patients with bacteraemic urinary tract infection (BUTI). The analysis identified optimal regimens on the basis of pharmacodynamic targets and assessed the adequacy of Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) susceptibility breakpoints for Escherichia coli. Data of 16 patients with BUTI caused by multidrug-resistant E. coli (FOREST clinical trial) received intravenous fosfomycin (4 g every 6 hours) were analysed. A population pharmacokinetic analysis was performed, and Monte Carlo simulations were undertaken using 4 g every 6 hours and 8 g every 8 hours. The probability of pharmacodynamic target attainment was assessed using pharmacodynamic targets for E. coli for static effect, 1-log drop in bacterial burden and resistance suppression. Sixty-four plasma samples were collected over a single dosing interval (day 2 or 3 after starting fosfomycin treatment). Fosfomycin concentrations were highly variable. Pharmacodynamic target attainment analysis showed mild improvement by increasing fosfomycin dosing (4 g every 6 hours vs. every 8 hours). These dosages showed success for decreasing 1-log bacterial burden in 89% to 96% (EUCAST breakpoints) and 33% to 54% (CLSI breakpoints) of patients, but they were unable to reach bacterial resistance suppression targets. Fosfomycin concentrations are highly variable-a fact partially explained by renal impairment. The present work supports the use of 4 g every 6 hours as an effective regimen for the treatment of non-critically ill patients with BUTI caused by multidrug-resistant E. coli, as higher dosages might increase toxicity but may not significantly increase efficacy. The current information may suggest that fosfomycin susceptibility breakpoints need to be reappraised. Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by

  8. Estimating demographic parameters from large-scale population genomic data using Approximate Bayesian Computation

    Directory of Open Access Journals (Sweden)

    Li Sen

    2012-03-01

    Full Text Available Abstract Background The Approximate Bayesian Computation (ABC approach has been used to infer demographic parameters for numerous species, including humans. However, most applications of ABC still use limited amounts of data, from a small number of loci, compared to the large amount of genome-wide population-genetic data which have become available in the last few years. Results We evaluated the performance of the ABC approach for three 'population divergence' models - similar to the 'isolation with migration' model - when the data consists of several hundred thousand SNPs typed for multiple individuals by simulating data from known demographic models. The ABC approach was used to infer demographic parameters of interest and we compared the inferred values to the true parameter values that was used to generate hypothetical "observed" data. For all three case models, the ABC approach inferred most demographic parameters quite well with narrow credible intervals, for example, population divergence times and past population sizes, but some parameters were more difficult to infer, such as population sizes at present and migration rates. We compared the ability of different summary statistics to infer demographic parameters, including haplotype and LD based statistics, and found that the accuracy of the parameter estimates can be improved by combining summary statistics that capture different parts of information in the data. Furthermore, our results suggest that poor choices of prior distributions can in some circumstances be detected using ABC. Finally, increasing the amount of data beyond some hundred loci will substantially improve the accuracy of many parameter estimates using ABC. Conclusions We conclude that the ABC approach can accommodate realistic genome-wide population genetic data, which may be difficult to analyze with full likelihood approaches, and that the ABC can provide accurate and precise inference of demographic parameters from

  9. Population based reference intervals for common blood haematological and biochemical parameters in the akuapem north district.

    Science.gov (United States)

    Koram, Ka; Addae, Mm; Ocran, Jc; Adu-Amankwah, S; Rogers, Wo; Nkrumah, Fk

    2007-12-01

    To estimate the reference intervals for commonly used blood haematology and biochemical parameters in an adult (18-55yrs) population of residents of Mampong Akuapem. This was a population based cross sectional study of a randomly selected sample of the adult population of Mampong. The sample was selected from an updated census list of the Mampong area. Median values (95% range) for measured parameters were established as follows: Haemoglobin, (males) 14.2 g/dl (females) 12.0 g/dl Alanine aminotransferase (ALT), (female) 19.6 U/L (males) 26.1 U/L and Creatinine, (males) 108 mmol/L (females) 93 mmol/L. In comparison to reference values that are commonly used in Ghana, the haemoglobulin levels from this study were lower, and liver function parameters higher. This could be a result of genetic or environmental differences and calls for the need to establish site specific reference values applicable to our population.

  10. Effect of feeding on the pharmacokinetics of oral minocycline in healthy research dogs.

    Science.gov (United States)

    Hnot, Melanie L; Cole, Lynette K; Lorch, Gwendolen; Rajala-Schultz, Paivi J; Papich, Mark G

    2015-12-01

    The effect of food on minocycline oral absorption in dogs is unknown. The objective was to determine the pharmacokinetics of minocycline after administration of a single oral dose in fed and fasted dogs. Ten research hounds were administered oral minocycline (approximately 5 mg/kg) with and without food, in a crossover study, with a one-week wash-out between treatments. Blood samples were collected immediately prior to minocycline administration and over 24 h. Minocycline plasma drug concentrations were measured using high-performance liquid chromatography using ultraviolet detection and were analysed with compartmental modelling to determine primary pharmacokinetic parameters. Each dog was analysed independently, followed by calculation of means and variation of the dogs. The Wilcoxon signed-rank test [analysing secondary pharmacokinetic parameters - peak concentration (CMAX ), area under the concentration versus time curve (AUC)] was used to compare the two groups. A population pharmacokinetic modelling approach was performed using nonlinear mixed effects modelling of primary parameters for the population as fixed effects and the difference between subjects as a random effect. Covariate analysis was used to identify the source of variability in the population. No significant difference was found between treatments for AUC (P = 0.0645), although AUC was higher in fasted dogs. A significant difference was found for CMAX (P = 0.0059), with fasted dogs attaining a higher CMAX . The covariate of fed versus fasted accounted for a significant variation in the pharmacokinetics. Because feeding was a significant source of variation for the population's primary pharmacokinetic parameters and fasted dogs had higher minocycline concentrations, we recommend administering minocycline without food. © 2015 ESVD and ACVD.

  11. An audit of the statistics and the comparison with the parameter in the population

    Science.gov (United States)

    Bujang, Mohamad Adam; Sa'at, Nadiah; Joys, A. Reena; Ali, Mariana Mohamad

    2015-10-01

    The sufficient sample size that is needed to closely estimate the statistics for particular parameters are use to be an issue. Although sample size might had been calculated referring to objective of the study, however, it is difficult to confirm whether the statistics are closed with the parameter for a particular population. All these while, guideline that uses a p-value less than 0.05 is widely used as inferential evidence. Therefore, this study had audited results that were analyzed from various sub sample and statistical analyses and had compared the results with the parameters in three different populations. Eight types of statistical analysis and eight sub samples for each statistical analysis were analyzed. Results found that the statistics were consistent and were closed to the parameters when the sample study covered at least 15% to 35% of population. Larger sample size is needed to estimate parameter that involve with categorical variables compared with numerical variables. Sample sizes with 300 to 500 are sufficient to estimate the parameters for medium size of population.

  12. A Preclinical Population Pharmacokinetic Model for Anti-CD20/CD3 T-Cell-Dependent Bispecific Antibodies.

    Science.gov (United States)

    Ferl, Gregory Z; Reyes, Arthur; Sun, Liping L; Cheu, Melissa; Oldendorp, Amy; Ramanujan, Saroja; Stefanich, Eric G

    2018-05-01

    CD20 is a cell-surface receptor expressed by healthy and neoplastic B cells and is a well-established target for biologics used to treat B-cell malignancies. Pharmacokinetic (PK) and pharmacodynamic (PD) data for the anti-CD20/CD3 T-cell-dependent bispecific antibody BTCT4465A were collected in transgenic mouse and nonhuman primate (NHP) studies. Pronounced nonlinearity in drug elimination was observed in the murine studies, and time-varying, nonlinear PK was observed in NHPs, where three empirical drug elimination terms were identified using a mixed-effects modeling approach: i) a constant nonsaturable linear clearance term (7 mL/day/kg); ii) a rapidly decaying time-varying, linear clearance term (t ½  = 1.6 h); and iii) a slowly decaying time-varying, nonlinear clearance term (t ½  = 4.8 days). The two time-varying drug elimination terms approximately track with time scales of B-cell depletion and T-cell migration/expansion within the central blood compartment. The mixed-effects NHP model was scaled to human and prospective clinical simulations were generated. © 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  13. Genetic algorithm with small population size for search feasible control parameters for parallel hybrid electric vehicles

    Directory of Open Access Journals (Sweden)

    Yu-Huei Cheng

    2017-11-01

    Full Text Available The control strategy is a major unit in hybrid electric vehicles (HEVs. In order to provide suitable control parameters for reducing fuel consumptions and engine emissions while maintaining vehicle performance requirements, the genetic algorithm (GA with small population size is applied to search for feasible control parameters in parallel HEVs. The electric assist control strategy (EACS is used as the fundamental control strategy of parallel HEVs. The dynamic performance requirements stipulated in the Partnership for a New Generation of Vehicles (PNGV is considered to maintain the vehicle performance. The known ADvanced VehIcle SimulatOR (ADVISOR is used to simulate a specific parallel HEV with urban dynamometer driving schedule (UDDS. Five population sets with size 5, 10, 15, 20, and 25 are used in the GA. The experimental results show that the GA with population size of 25 is the best for selecting feasible control parameters in parallel HEVs.

  14. Heritability of audiometric shape parameters and familial aggregation of presbycusis in an elderly Flemish population.

    Science.gov (United States)

    Demeester, Kelly; van Wieringen, Astrid; Hendrickx, Jan-jaap; Topsakal, Vedat; Huyghe, Jeroen; Fransen, Erik; Van Laer, Lut; Van Camp, Guy; Van de Heyning, Paul

    2010-06-14

    This study describes the heritability of audiometric shape parameters and the familial aggregation of different types of presbycusis in a healthy, otologically screened population between 50 and 75 years old. About 342 siblings of 64 families (average family-size: 5.3) were recruited through population registries. Audiometric shape was mathematically quantified by objective parameters developed to measure size, slope, concavity, percentage of frequency-dependent and frequency-independent hearing loss and Bulge Depth. The heritability of each parameter was calculated using a variance components model. Logistic regression models were used to estimate the odds ratios (ORs). Estimates of sibling recurrence risk ratios (lambda(s)) are also provided. Heritability estimates were generally higher compared to previous studies. ORs and lambda(s) for the parameters Total Hearing Loss (size), Uniform Hearing Loss (percentage of frequency-dependent hearing loss) and Bulge Depth suggest a higher heredity for severe types of presbycusis compared to moderate or mild types. Our results suggest that the separation of the parameter 'Total Hearing Loss' into the two parameters 'Uniform Hearing Loss' and 'Non-uniform Hearing Loss' could lead to the discovery of different genetic subtypes of presbycusis. The parameter 'Bulge Depth', instead of 'Concavity', seemed to be an important parameter for classifying subjects into 'susceptible' or 'resistant' to societal or intensive environmental exposure. 2010 Elsevier B.V. All rights reserved.

  15. [The gene pool of the Belgorod oblast population: Malecot's isolation-by-distance parameters].

    Science.gov (United States)

    Sorokina, I N; Balanovskaia, E V; Churnoson, M I

    2009-03-01

    The mean distance between birthplaces of spouses (sigma, sigma'), the proportion of medium migrations (k), and the effective migration pressure (M(e)) have considerably increased, and the linear systematic pressure coefficient (b) has decreased in the human population of the Central Chernozem region during the past 50 years. However, the local inbreeding level (a), which is determined by both an increase in the migration intensity and a decrease in the effective population size (N(e)), has remained practically unchanged. A change in the regional administrative structure has affected the genetic structure of populations. In the 1950s, raions (administrative districts) of Kursk and Voronezh oblasts (regions) were similar with respect differentiation parameters, whereas the oblasts considerably differed from each other. At present, some Malecot's isolation-by-distance parameters for the populations of the districts that were included to Belgorod oblast in 1954 are lower and similar to those for the districts that remain in Kursk and Voronezh oblasts.

  16. Population pharmacokinetic modeling and dosing simulations of nitrogen-scavenging compounds: disposition of glycerol phenylbutyrate and sodium phenylbutyrate in adult and pediatric patients with urea cycle disorders.

    Science.gov (United States)

    Monteleone, Jon P R; Mokhtarani, M; Diaz, G A; Rhead, W; Lichter-Konecki, U; Berry, S A; Lemons, C; Dickinson, K; Coakley, D; Lee, B; Scharschmidt, B F

    2013-07-01

    Sodium phenylbutyrate and glycerol phenylbutyrate mediate waste nitrogen excretion in the form of urinary phenylacetylglutamine (PAGN) in patients with urea cycle disorders (UCDs); rare genetic disorders characterized by impaired urea synthesis and hyperammonemia. Sodium phenylbutyrate is approved for UCD treatment; the development of glycerol phenylbutyrate afforded the opportunity to characterize the pharmacokinetics (PK) of both compounds. A population PK model was developed using data from four Phase II/III trials that collectively enrolled patients ages 2 months to 72 years. Dose simulations were performed with particular attention to phenylacetic acid (PAA), which has been associated with adverse events in non-UCD populations. The final model described metabolite levels in plasma and urine for both drugs and was characterized by (a) partial presystemic metabolism of phenylbutyric acid (PBA) to PAA and/or PAGN, (b) slower PBA absorption and greater presystemic conversion with glycerol phenylbutyrate, (c) similar systemic disposition with saturable conversion of PAA to PAGN for both drugs, and (d) body surface area (BSA) as a significant covariate accounting for age-related PK differences. Dose simulations demonstrated similar PAA exposure following mole-equivalent PBA dosing of both drugs and greater PAA exposure in younger patients based on BSA. © The Author(s) 2013.

  17. Semi-Mechanistic Population Pharmacokinetic Modeling of L-Histidine Disposition and Brain Uptake in Wildtype and Pht1 Null Mice.

    Science.gov (United States)

    Wang, Xiao-Xing; Li, Yang-Bing; Feng, Meihua R; Smith, David E

    2018-01-05

    To develop a semi-mechanistic population pharmacokinetic (PK) model to quantitate the disposition kinetics of L-histidine, a peptide-histidine transporter 1 (PHT1) substrate, in the plasma, cerebrospinal fluid and brain parenchyma of wildtype (WT) and Pht1 knockout (KO) mice. L-[ 14 C]Hisidine (L-His) was administrated to WT and KO mice via tail vein injection, after which plasma, cerebrospinal fluid (CSF) and brain parenchyma samples were collected. A PK model was developed using non-linear mixed effects modeling (NONMEM). The disposition of L-His between the plasma, brain, and CSF was described by a combination of PHT1-mediated uptake, CSF bulk flow and first-order micro-rate constants. The PK profile of L-His was best described by a four-compartment model. A more rapid uptake of L-His in brain parenchyma was observed in WT mice due to PHT1-mediated uptake, a process characterized by a Michaelis-Menten component (V max  = 0.051 nmoL/min and K m  = 34.94 μM). A semi-mechanistic population PK model was successfully developed, for the first time, to quantitatively characterize the disposition kinetics of L-His in brain under in vivo conditions. This model may prove a useful tool in predicting the uptake of L-His, and possibly other PHT1 peptide/mimetic substrates, for drug delivery to the brain.

  18. Improved sampling for airborne surveys to estimate wildlife population parameters in the African Savannah

    NARCIS (Netherlands)

    Khaemba, W.; Stein, A.

    2002-01-01

    Parameter estimates, obtained from airborne surveys of wildlife populations, often have large bias and large standard errors. Sampling error is one of the major causes of this imprecision and the occurrence of many animals in herds violates the common assumptions in traditional sampling designs like

  19. Computer-assisted semen analysis parameters as predictors for fertility of men from the general population

    DEFF Research Database (Denmark)

    Larsen, L; Scheike, Thomas Harder; Jensen, Tina Kold

    2000-01-01

    The predictive value of sperm motility parameters obtained by computer-assisted semen analysis (CASA) was evaluated for the fertility of men from general population. In a prospective study with couples stopping use of contraception in order to try to conceive, CASA was performed on semen samples...

  20. Population pharmacokinetics/pharmacodynamics of erlotinib and pharmacogenomic analysis of plasma and cerebrospinal fluid drug concentrations in Japanese patients with non-small cell lung cancer.

    Science.gov (United States)

    Fukudo, Masahide; Ikemi, Yasuaki; Togashi, Yosuke; Masago, Katsuhiro; Kim, Young Hak; Mio, Tadashi; Terada, Tomohiro; Teramukai, Satoshi; Mishima, Michiaki; Inui, Ken-Ichi; Katsura, Toshiya

    2013-07-01

    Erlotinib shows large inter-patient pharmacokinetic variability, but the impact of early drug exposure and genetic variations on the clinical outcomes of erlotinib remains fully investigated. The primary objective of this study was to clarify the population pharmacokinetics/pharmacodynamics of erlotinib in Japanese patients with non-small cell lung cancer (NSCLC). The secondary objective was to identify genetic determinant(s) for the cerebrospinal fluid (CSF) permeability of erlotinib and its active metabolite OSI-420. A total of 88 patients treated with erlotinib (150 mg/day) were enrolled, and CSF samples were available from 23 of these patients with leptomeningeal metastases. Plasma and CSF concentrations of erlotinib and OSI-420 were measured by high-performance liquid chromatography with UV detection. Population pharmacokinetic analysis was performed with the nonlinear mixed-effects modelling program NONMEM. Germline mutations including ABCB1 (1236C>T, 2677G>T/A, 3435C>T), ABCG2 (421C>A), and CYP3A5 (6986A>G) polymorphisms, as well as somatic EGFR activating mutations if available, were examined. Early exposure to erlotinib and its safety/efficacy relationship were evaluated. The apparent clearance of erlotinib and OSI-420 were significantly decreased by 24 and 35 % in patients with the ABCG2 421A allele, respectively (p OSI-420 (p model showed that erlotinib trough (C0) levels on day 8 were an independent risk factor for the development of grade ≥2 diarrhea (p = 0.037) and skin rash (p = 0.031). Interstitial lung disease (ILD)-like events occurred in 3 patients (3.4 %), and the median value of erlotinib C0 levels adjacent to these events was approximately 3 times higher than that in patients who did not develop ILD (3253 versus 1107 ng/mL; p = 0.014). The objective response rate in the EGFR wild-type group was marginally higher in patients achieving higher erlotinib C0 levels (≥1711 ng/mL) than that in patients having lower erlotinib C0

  1. Population pharmacokinetics analysis of olanzapine for Chinese psychotic patients based on clinical therapeutic drug monitoring data with assistance of meta-analysis.

    Science.gov (United States)

    Yin, Anyue; Shang, Dewei; Wen, Yuguan; Li, Liang; Zhou, Tianyan; Lu, Wei

    2016-08-01

    The aim of this study was to build an eligible population pharmacokinetic (PK) model for olanzapine in Chinese psychotic patients based on therapeutic drug monitoring (TDM) data, with assistance of meta-analysis, to facilitate individualized therapy. Population PK analysis for olanzapine was performed using NONMEM software (version 7.3.0). TDM data were collected from Guangzhou Brain Hospital (China). Because of the limitations of TDM data, model-based meta-analysis was performed to construct a structural model to assist the modeling of TDM data as prior estimates. After analyzing related covariates, a simulation was performed to predict concentrations for different types of patients under common dose regimens. A two-compartment model with first-order absorption and elimination was developed for olanzapine oral tablets, based on 23 articles with 390 data points. The model was then applied to the TDM data. Gender and smoking habits were found to be significant covariates that influence the clearance of olanzapine. To achieve a blood concentration of 20 ng/mL (the lower boundary of the recommended therapeutic range), simulation results indicated that the dose regimen of olanzapine should be 5 mg BID (twice a day), ≥ 5 mg QD (every day) plus 10 mg QN (every night), or >10 mg BID for female nonsmokers, male nonsmokers and male smokers, respectively. The population PK model, built using meta-analysis, could facilitate the modeling of TDM data collected from Chinese psychotic patients. The factors that significantly influence olanzapine disposition were determined and the final model could be used for individualized treatment.

  2. Estimating population parameters of longsnout seahorses, Hippocampus reidi (Teleostei: Syngnathidae through mark-recapture

    Directory of Open Access Journals (Sweden)

    Alexandre C. Siqueira

    2017-12-01

    Full Text Available ABSTRACT Estimating population parameters is essential for understanding the ecology of species, which ultimately helps to assess their conservation status. The seahorse Hippocampus reidi is directly exposed to anthropogenic threats along the Brazilian coast, but the species still figures as Data Deficient (DD at IUCN’s Red List. To provide better information on the ecology of this species, we studied how population parameters vary over time in a natural subtropical environment. By combing mark-recapture models for open and closed populations, we estimated abundance, survival rate, emigration probability, and capture probability. We marked 111 individuals, which showed a 1:1 sex ratio, and an average size of 10.5 cm. The population showed high survival rate, low temporary emigration probability and variable capture probability and abundance. Our models considering relevant biological criteria illuminate the relatively poorly known population ecology and life history of seahorses. It is our hope that this study inspires the use of mark-recapture methods in other populations of H. reidi in a collective effort to properly assess their conservation status.

  3. Population pharmacokinetic analysis for 10-monohydroxy derivative of oxcarbazepine in pediatric epileptic patients shows no difference between Japanese and other ethnicities.

    Science.gov (United States)

    Sugiyama, Ikuo; Bouillon, Thomas; Yamaguchi, Masayuki; Suzuki, Hikoe; Hirota, Takashi; Fink, Martin

    2015-04-01

    Oxcarbazepine is an anti-epileptic drug, which is almost completely metabolized by cytosolic enzymes in the liver to the active 10-monohyroxy metabolite (MHD) following oral administration. The pharmacokinetic (PK) profiles of MHD were evaluated in pediatric epileptic patients and a possible ethnic difference in PK of MHD between Japanese and non-Japanese pediatric patients was assessed. A non-linear mixed effect modeling approach was used to determine the PK of MHD. A one-compartment population model with first-order absorption appropriately described the PK of MHD. No clinically relevant differences were found for using body surface area or weight to explain between-patient variability, therefore the final model included the effects of body weight on apparent clearance (CL/F) and apparent volume of distribution (V/F) of MHD, and in addition, the effect of 3 concomitant anti-epileptic drugs (carbamazepine, phenobarbital and phenytoin) on CL/F of MHD. Inclusion of ethnicity as a covariate in the final model, concluded no ethnic difference with respect to CL/F of MHD between Japanese and non-Japanese patients. Hence, oxcarbazepine can be generally applied using the same dosage and administration for the treatment of partial onset seizures in pediatric patients, regardless of ethnicity. Copyright © 2014 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  4. Improved physiologically based pharmacokinetic model for oral exposures to chromium in mice, rats, and humans to address temporal variation and sensitive populations

    Energy Technology Data Exchange (ETDEWEB)

    Kirman, C.R., E-mail: ckirman@summittoxicology.com [Summit Toxicology, PO Box 3209, Bozeman, MT 59715 (United States); Suh, M.; Proctor, D.M. [ToxStrategies, Mission Viejo, CA (United States); Hays, S.M. [Summit Toxicology, PO Box 3209, Bozeman, MT 59715 (United States)

    2017-06-15

    A physiologically based pharmacokinetic (PBPK) model for hexavalent chromium [Cr(VI)] in mice, rats, and humans developed previously (Kirman et al., 2012, 2013), was updated to reflect an improved understanding of the toxicokinetics of the gastrointestinal tract following oral exposures. Improvements were made to: (1) the reduction model, which describes the pH-dependent reduction of Cr(VI) to Cr(III) in the gastrointestinal tract under both fasted and fed states; (2) drinking water pattern simulations, to better describe dosimetry in rodents under the conditions of the NTP cancer bioassay; and (3) parameterize the model to characterize potentially sensitive human populations. Important species differences, sources of non-linear toxicokinetics, and human variation are identified and discussed within the context of human health risk assessment. - Highlights: • An improved version of the PBPK model for Cr(VI) toxicokinetics was developed. • The model incorporates data collected to fill important data gaps. • Model predictions for specific age groups and sensitive subpopulations are provided. • Implications to human health risk assessment are discussed.

  5. A comparative evaluation of semen parameters in pre- and post-Hurricane Katrina human population

    Directory of Open Access Journals (Sweden)

    Caner Baran

    2015-01-01

    Full Text Available A natural disaster leading to accumulation of environmental contaminants may have substantial effects on the male reproductive system. Our aim was to compare and assess semen parameters in a normospermic population residing in the Southern Louisiana, USA area pre- and post-Hurricane Katrina. We retrospectively evaluated semen analyses data (n = 3452 of 1855 patients who attended the Tulane University Andrology/Fertility Clinic between 1999 and 2013. The study inclusion criteria were men whose semen analyses showed ≥ 1.5 ml volume; ≥15 million ml -1 sperm concentration; ≥39 million total sperm count; ≥40% motility; >30% morphology, with an abstinence interval of 2-7 days. After the inclusion criteria applied to the population, 367 normospermic patients were included in the study. Descriptive statistics and group-based analyses were performed to interpret the differences between the pre-Katrina (Group 1, 1999-2005 and the post-Katrina (Group 2, 2006-2013 populations. There were significant differences in motility, morphology, number of white blood cell, immature germ cell count, pH and presence of sperm agglutination, but surprisingly there were no significant differences in sperm count between the two populations. This long-term comparative analysis further documents that a major natural disaster with its accompanied environmental issues can influence certain semen parameters (e.g., motility and morphology and, by extension, fertility potential of the population of such areas.

  6. Effects of Body Size and Gender on the Population Pharmacokinetics of Artesunate and Its Active Metabolite Dihydroartemisinin in Pediatric Malaria Patients

    OpenAIRE

    Morris, Carrie A.; Tan, Beesan; Duparc, Stephan; Borghini-Fuhrer, Isabelle; Jung, Donald; Shin, Chang-Sik; Fleckenstein, Lawrence

    2013-01-01

    Despite the important role of the antimalarial artesunate and its active metabolite dihydroartemisinin (DHA) in malaria treatment efforts, there are limited data on the pharmacokinetics of these agents in pediatric patients. This study evaluated the effects of body size and gender on the pharmacokinetics of artesunate-DHA using data from pediatric and adult malaria patients. Nonlinear mixed-effects modeling was used to obtain a base model consisting of first-order artesunate absorption and on...

  7. Determinants of the over-anticoagulation response during warfarin initiation therapy in Asian patients based on population pharmacokinetic-pharmacodynamic analyses.

    Science.gov (United States)

    Ohara, Minami; Takahashi, Harumi; Lee, Ming Ta Michael; Wen, Ming-Shien; Lee, Tsong-Hai; Chuang, Hui-Ping; Luo, Chen-Hui; Arima, Aki; Onozuka, Akiko; Nagai, Rui; Shiomi, Mari; Mihara, Kiyoshi; Morita, Takashi; Chen, Yuan-Tsong

    2014-01-01

    To clarify pharmacokinetic-pharmacodynamic (PK-PD) factors associated with the over-anticoagulation response in Asians during warfarin induction therapy, population PK-PD analyses were conducted in an attempt to predict the time-courses of the plasma S-warfarin concentration, Cp(S), and coagulation and anti-coagulation (INR) responses. In 99 Chinese patients we analyzed the relationships between dose and Cp(S) to estimate the clearance of S-warfarin, CL(S), and that between Cp(S) and the normal prothrombin concentration (NPT) as a coagulation marker for estimation of IC50. We also analyzed the non-linear relationship between NPT inhibition and the increase in INR to derive the non-linear index λ. Population analyses accurately predicted the time-courses of Cp(S), NPT and INR. Multivariate analysis showed that CYP2C9*3 mutation and body surface area were predictors of CL(S), that VKORC1 and CYP4F2 polymorphisms were predictors of IC50, and that baseline NPT was a predictor of λ. CL(S) and λ were significantly lower in patients with INR≥4 than in those with INR<4 (190 mL/h vs 265 mL/h, P<0.01 and 3.2 vs 3.7, P<0.01, respectively). Finally, logistic regression analysis revealed that CL(S), ALT and hypertension contributed significantly to INR≥4. All these results indicate that factors associated with the reduced metabolic activity of warfarin represented by CL(S), might be critical determinants of the over-anticoagulation response during warfarin initiation in Asians. ClinicalTrials.gov NCT02065388.

  8. Determinants of the over-anticoagulation response during warfarin initiation therapy in Asian patients based on population pharmacokinetic-pharmacodynamic analyses.

    Directory of Open Access Journals (Sweden)

    Minami Ohara

    Full Text Available To clarify pharmacokinetic-pharmacodynamic (PK-PD factors associated with the over-anticoagulation response in Asians during warfarin induction therapy, population PK-PD analyses were conducted in an attempt to predict the time-courses of the plasma S-warfarin concentration, Cp(S, and coagulation and anti-coagulation (INR responses. In 99 Chinese patients we analyzed the relationships between dose and Cp(S to estimate the clearance of S-warfarin, CL(S, and that between Cp(S and the normal prothrombin concentration (NPT as a coagulation marker for estimation of IC50. We also analyzed the non-linear relationship between NPT inhibition and the increase in INR to derive the non-linear index λ. Population analyses accurately predicted the time-courses of Cp(S, NPT and INR. Multivariate analysis showed that CYP2C9*3 mutation and body surface area were predictors of CL(S, that VKORC1 and CYP4F2 polymorphisms were predictors of IC50, and that baseline NPT was a predictor of λ. CL(S and λ were significantly lower in patients with INR≥4 than in those with INR<4 (190 mL/h vs 265 mL/h, P<0.01 and 3.2 vs 3.7, P<0.01, respectively. Finally, logistic regression analysis revealed that CL(S, ALT and hypertension contributed significantly to INR≥4. All these results indicate that factors associated with the reduced metabolic activity of warfarin represented by CL(S, might be critical determinants of the over-anticoagulation response during warfarin initiation in Asians.ClinicalTrials.gov NCT02065388.

  9. Ofloxacin pharmacokinetics in renal failure.

    OpenAIRE

    Fillastre, J P; Leroy, A; Humbert, G

    1987-01-01

    The pharmacokinetics of ofloxacin were investigated in 12 normal subjects and 21 uremic patients after the administration of a single oral 200-mg dose. An open three-compartment body model was used to calculate ofloxacin pharmacokinetic parameters. In healthy subjects, the peak plasma level averaged 2.24 +/- 0.90 micrograms/ml and was obtained at 0.83 +/- 0.31 h. The absorption rate constant was 4.22 +/- 1.64 h-1. The terminal half-life was 7.86 +/- 1.81 h. The apparent volume of distribution...

  10. Urinary phthalate metabolites and male reproductive function parameters in Chongqing general population, China.

    Science.gov (United States)

    Han, Xue; Cui, Zhihong; Zhou, Niya; Ma, Mingfu; Li, Lianbing; Li, Yafei; Lin, Hui; Ao, Lin; Shu, Weiqun; Liu, Jinyi; Cao, Jia

    2014-03-01

    This study was designed to investigate the phthalates exposure levels in general population in Chongqing City of China, and to determine the possible associations between phthalate exposure and male reproductive function parameters. We recruited 232 general men through Chongqing Family Planning Research Institute and Reproductive Center of Chongqing. In a single spot urine sample from each man, phthalate metabolites, including mono-butyl phthalate (MBP), mono-ethyl phthalate (MEP), mono-(2-ethylhexyl) phthalate (MEHP), mono-benzyl phthalate (MBzP), phthalic acid (PA), and total PA were analyzed using solid phase extraction and coupled with high-performance liquid chromatography and detection by tandem mass spectrometry. Semen parameters were dichotomized based on World Health Organization reference values. Sperm DNA damage were analyzed using the alkaline single-cell gel electrophoresis assay. Reproductive hormones were determined in serum by the radioimmunoassay kit. We observed a weak association between urinary MBP concentration and sperm concentration in Chongqing general population. MBP levels above the median were 1.97 times (95% confidence interval [CI] 0.97-4.04) more likely to have sperm concentration below the reference value. There were no other associations between phthalate metabolites and reproductive function parameters after adjusted for potential risk factors. Our study suggested that general population in Chongqing area of China exposure to the environmental level of phthalate have weak or without adverse effects on the reproduction. Copyright © 2013 Elsevier GmbH. All rights reserved.

  11. Influence of covariate distribution on the predictive performance of pharmacokinetic models in paediatric research

    Science.gov (United States)

    Piana, Chiara; Danhof, Meindert; Della Pasqua, Oscar

    2014-01-01

    Aims The accuracy of model-based predictions often reported in paediatric research has not been thoroughly characterized. The aim of this exercise is therefore to evaluate the role of covariate distributions when a pharmacokinetic model is used for simulation purposes. Methods Plasma concentrations of a hypothetical drug were simulated in a paediatric population using a pharmacokinetic model in which body weight was correlated with clearance and volume of distribution. Two subgroups of children were then selected from the overall population according to a typical study design, in which pre-specified body weight ranges (10–15 kg and 30–40 kg) were used as inclusion criteria. The simulated data sets were then analyzed using non-linear mixed effects modelling. Model performance was assessed by comparing the accuracy of AUC predictions obtained for each subgroup, based on the model derived from the overall population and by extrapolation of the model parameters across subgroups. Results Our findings show that systemic exposure as well as pharmacokinetic parameters cannot be accurately predicted from the pharmacokinetic model obtained from a population with a different covariate range from the one explored during model building. Predictions were accurate only when a model was used for prediction in a subgroup of the initial population. Conclusions In contrast to current practice, the use of pharmacokinetic modelling in children should be limited to interpolations within the range of values observed during model building. Furthermore, the covariate point estimate must be kept in the model even when predictions refer to a subset different from the original population. PMID:24433411

  12. Mixed-effects modelling of the interspecies pharmacokinetic scaling of pegylated human erythropoietin.

    Science.gov (United States)

    Jolling, Koen; Perez Ruixo, Juan Jose; Hemeryck, Alex; Vermeulen, An; Greway, Tony

    2005-04-01

    The aim of this study was to develop a population pharmacokinetic model for interspecies allometric scaling of pegylated r-HuEPO (PEG-EPO) pharmacokinetics to man. A total of 927 serum concentrations from 193 rats, 6 rabbits, 34 monkeys, and 9 dogs obtained after a single dose of PEG-EPO, administered by the i.v. (dose range: 12.5-550 microg/kg) and s.c. (dose range: 12.5-500 microg/kg) routes, were pooled in this analysis. An open two-compartment model with first-order absorption and lag time (Tlag) and linear elimination from the central compartment was fitted to the data using the NONMEM V software. Body weight (WT) was used as a scaling factor and the effect of brain weight (BW), sex, and pregnancy status on the pharmacokinetic parameters was investigated. The final model was evaluated by means of a non-parametric bootstrap analysis and used to predict the PEG-EPO pharmacokinetic parameters in healthy male subjects. The systemic clearance (CL) in males was estimated to be 4.08WT1.030xBW-0.345 ml/h. In females, the CL was 90.7% of the CL in males. The volumes of the central (Vc) and the peripheral (Vp) compartment were characterized as 57.8WT0.959 ml, and 48.1WT1.150 ml, respectively. Intercompartmental flow was estimated at 2.32WT0.930 ml/h. Absorption rate constant (Ka) was estimated at 0.0538WT-0.149. The absolute s.c. bioavailability F was calculated at 52.5, 80.2, and 49.4% in rat, monkey, and dog, respectively. The interindividual variability in the population pharmacokinetic parameters was fairly low (parametric bootstrap confirmed the accuracy of the NONMEM estimates. The mean model predicted pharmacokinetic parameters in healthy male subjects of 70 kg were estimated at: CL: 26.2 ml/h; Vc: 3.6l; Q: 286 l/h; Vp: 6.9l, and Ka: 0.031 h-1. The population pharmacokinetic model developed was appropriate to describe the time course of PEG-EPO serum concentrations and their variability in different species. The model predicted pharmacokinetics of PEG-EPO in

  13. Estimating mutation parameters, population history and genealogy simultaneously from temporally spaced sequence data.

    Science.gov (United States)

    Drummond, Alexei J; Nicholls, Geoff K; Rodrigo, Allen G; Solomon, Wiremu

    2002-07-01

    Molecular sequences obtained at different sampling times from populations of rapidly evolving pathogens and from ancient subfossil and fossil sources are increasingly available with modern sequencing technology. Here, we present a Bayesian statistical inference approach to the joint estimation of mutation rate and population size that incorporates the uncertainty in the genealogy of such temporally spaced sequences by using Markov chain Monte Carlo (MCMC) integration. The Kingman coalescent model is used to describe the time structure of the ancestral tree. We recover information about the unknown true ancestral coalescent tree, population size, and the overall mutation rate from temporally spaced data, that is, from nucleotide sequences gathered at different times, from different individuals, in an evolving haploid population. We briefly discuss the methodological implications and show what can be inferred, in various practically relevant states of prior knowledge. We develop extensions for exponentially growing population size and joint estimation of substitution model parameters. We illustrate some of the important features of this approach on a genealogy of HIV-1 envelope (env) partial sequences.

  14. Parameters affecting tooth loss during periodontal maintenance in a Greek population.

    Science.gov (United States)

    Tsami, Alexandra; Pepelassi, Eudoxie; Kodovazenitis, George; Komboli, Mado

    2009-09-01

    Investigators have evaluated predictive parameters of tooth loss during the maintenance phase (MP). The authors conducted a retrospective study to evaluate the rate of tooth loss and to explore the parameters that affect tooth loss during MP in a Greek population. A periodontist administered periodontal treatment and maintenance care to 280 participants with severe periodontitis for a mean period +/- standard deviation of 10.84 +/- 2.13 years. The periodontist recorded the following parameters for each participant: oral hygiene index level, simplified gingival index level, clinical attachment level, probing depth measurements, initial tooth prognosis, smoking status, tooth loss during active periodontal treatment and MP, and compliance with suggested maintenance visits. The authors found that total tooth loss during active treatment (n = 1,427) was greater than during MP (n = 918) and was associated with the initial tooth prognosis, tooth type group, participants' compliance with suggested maintenance visits, smoking status and acceptability of the quality of tooth restorations. Most of the teeth extracted during maintenance had an initial guarded prognosis (n = 612). Participants whose compliance was erratic had a greater risk of undergoing tooth extraction than did participants whose compliance was complete. Participants' initial tooth prognosis, tooth type, compliance with suggested maintenance visits and smoking status affected tooth loss during MP. Initial guarded prognosis and erratic compliance increased the risk of undergoing tooth extraction during maintenance. Determining predictive parameters for disease progression and tooth loss provides critical information to clinicians so that they can develop and implement rational treatment planning.

  15. CONNECTION BETWEEN DYNAMICALLY DERIVED INITIAL MASS FUNCTION NORMALIZATION AND STELLAR POPULATION PARAMETERS

    International Nuclear Information System (INIS)

    McDermid, Richard M.; Cappellari, Michele; Bayet, Estelle; Bureau, Martin; Davies, Roger L.; Alatalo, Katherine; Blitz, Leo; Bois, Maxime; Bournaud, Frédéric; Duc, Pierre-Alain; Crocker, Alison F.; Davis, Timothy A.; De Zeeuw, P. T.; Emsellem, Eric; Kuntschner, Harald; Khochfar, Sadegh; Krajnović, Davor; Morganti, Raffaella; Oosterloo, Tom; Naab, Thorsten

    2014-01-01

    We report on empirical trends between the dynamically determined stellar initial mass function (IMF) and stellar population properties for a complete, volume-limited sample of 260 early-type galaxies from the ATLAS 3D project. We study trends between our dynamically derived IMF normalization α dyn ≡ (M/L) stars /(M/L) Salp and absorption line strengths, and interpret these via single stellar population-equivalent ages, abundance ratios (measured as [α/Fe]), and total metallicity, [Z/H]. We find that old and alpha-enhanced galaxies tend to have on average heavier (Salpeter-like) mass normalization of the IMF, but stellar population does not appear to be a good predictor of the IMF, with a large range of α dyn at a given population parameter. As a result, we find weak α dyn -[α/Fe] and α dyn –Age correlations and no significant α dyn –[Z/H] correlation. The observed trends appear significantly weaker than those reported in studies that measure the IMF normalization via the low-mass star demographics inferred through stellar spectral analysis

  16. CONNECTION BETWEEN DYNAMICALLY DERIVED INITIAL MASS FUNCTION NORMALIZATION AND STELLAR POPULATION PARAMETERS

    Energy Technology Data Exchange (ETDEWEB)

    McDermid, Richard M. [Department of Physics and Astronomy, Macquarie University, Sydney NSW 2109 (Australia); Cappellari, Michele; Bayet, Estelle; Bureau, Martin; Davies, Roger L. [Sub-Department of Astrophysics, Department of Physics, University of Oxford, Denys Wilkinson Building, Keble Road, Oxford, OX1 3RH (United Kingdom); Alatalo, Katherine [Infrared Processing and Analysis Center, California Institute of Technology, Pasadena, CA 91125 (United States); Blitz, Leo [Department of Astronomy, Campbell Hall, University of California, Berkeley, CA 94720 (United States); Bois, Maxime [Observatoire de Paris, LERMA and CNRS, 61 Av. de l' Observatoire, F-75014 Paris (France); Bournaud, Frédéric; Duc, Pierre-Alain [Laboratoire AIM Paris-Saclay, CEA/IRFU/SAp- CNRS-Université Paris Diderot, F-91191 Gif-sur-Yvette Cedex (France); Crocker, Alison F. [Ritter Astrophysical Observatory, University of Toledo, Toledo, OH 43606 (United States); Davis, Timothy A.; De Zeeuw, P. T.; Emsellem, Eric; Kuntschner, Harald [European Southern Observatory, Karl-Schwarzschild-Str. 2, D-85748 Garching (Germany); Khochfar, Sadegh [Institute for Astronomy, University of Edinburgh, Royal Observatory, Edinburgh, EH9 3HJ (United Kingdom); Krajnović, Davor [Leibniz-Institut für Astrophysik Potsdam (AIP), An der Sternwarte 16, D-14482 Potsdam (Germany); Morganti, Raffaella; Oosterloo, Tom [Netherlands Institute for Radio Astronomy (ASTRON), Postbus 2, 7990 AA Dwingeloo (Netherlands); Naab, Thorsten, E-mail: richard.mcdermid@mq.edu.au [Max-Planck-Institut für Astrophysik, Karl-Schwarzschild-Str. 1, D-85741 Garching (Germany); and others

    2014-09-10

    We report on empirical trends between the dynamically determined stellar initial mass function (IMF) and stellar population properties for a complete, volume-limited sample of 260 early-type galaxies from the ATLAS{sup 3D} project. We study trends between our dynamically derived IMF normalization α{sub dyn} ≡ (M/L){sub stars}/(M/L){sub Salp} and absorption line strengths, and interpret these via single stellar population-equivalent ages, abundance ratios (measured as [α/Fe]), and total metallicity, [Z/H]. We find that old and alpha-enhanced galaxies tend to have on average heavier (Salpeter-like) mass normalization of the IMF, but stellar population does not appear to be a good predictor of the IMF, with a large range of α{sub dyn} at a given population parameter. As a result, we find weak α{sub dyn}-[α/Fe] and α{sub dyn} –Age correlations and no significant α{sub dyn} –[Z/H] correlation. The observed trends appear significantly weaker than those reported in studies that measure the IMF normalization via the low-mass star demographics inferred through stellar spectral analysis.

  17. Connection between Dynamically Derived Initial Mass Function Normalization and Stellar Population Parameters

    Science.gov (United States)

    McDermid, Richard M.; Cappellari, Michele; Alatalo, Katherine; Bayet, Estelle; Blitz, Leo; Bois, Maxime; Bournaud, Frédéric; Bureau, Martin; Crocker, Alison F.; Davies, Roger L.; Davis, Timothy A.; de Zeeuw, P. T.; Duc, Pierre-Alain; Emsellem, Eric; Khochfar, Sadegh; Krajnović, Davor; Kuntschner, Harald; Morganti, Raffaella; Naab, Thorsten; Oosterloo, Tom; Sarzi, Marc; Scott, Nicholas; Serra, Paolo; Weijmans, Anne-Marie; Young, Lisa M.

    2014-09-01

    We report on empirical trends between the dynamically determined stellar initial mass function (IMF) and stellar population properties for a complete, volume-limited sample of 260 early-type galaxies from the ATLAS3D project. We study trends between our dynamically derived IMF normalization αdyn ≡ (M/L)stars/(M/L)Salp and absorption line strengths, and interpret these via single stellar population-equivalent ages, abundance ratios (measured as [α/Fe]), and total metallicity, [Z/H]. We find that old and alpha-enhanced galaxies tend to have on average heavier (Salpeter-like) mass normalization of the IMF, but stellar population does not appear to be a good predictor of the IMF, with a large range of αdyn at a given population parameter. As a result, we find weak αdyn-[α/Fe] and αdyn -Age correlations and no significant αdyn -[Z/H] correlation. The observed trends appear significantly weaker than those reported in studies that measure the IMF normalization via the low-mass star demographics inferred through stellar spectral analysis.

  18. Haematological parameters in different african populations: an experience from united nations level 3 hospital

    International Nuclear Information System (INIS)

    Iftikhar, R.; Khan, N.U.; Iqbal, Z.; Anwar, M.I.

    2017-01-01

    To evaluate hematological parameters in African population to estimate normal reference intervals for these tests. Study Design: Cross sectional observational study. Place and Duration of Study: Department of Pathology, United Nations level 3 hospital, Nyala, Darfur from 1st Mar to 30th Dec 2014. Material and Methods: There were 396 healthy African male and female volunteers selected between 18-65 years of age, belonging to different countries. Fresh whole blood was used to measure haemoglobin (Hb) concentration, haematocrit (Hct), total red blood cell (TRBC) count, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), platelet count, total leucocyte count (TLC) and differential white blood cells count. Data were analysed using SPSS version 19. Results: Mean Hb of study group was 13.81 +- 1.99 g/dl. Mean TLC was 5.50 +- 1.96 x 103/ul. Mean lymphocyte count was 2.58 +- 0.95. Mean platelet count was 234 +- 92 x103 /ul. Mean values for Hb Concentration, TRBC, Hct Ratio, MCV, MCH and MCHC were all higher for African Males than Females; this difference was statistically significant (p<0.05). Conclusion: This multi-national African population based study confirms the variations in haematological parameters previously described in single nation African studies. The commonly observed variations in normal adults are low RBC indices, relative neutropenia and lymphocytosis. (author)

  19. Radiographic study of the hip joint to determine anthropometric parameters for Indian population

    International Nuclear Information System (INIS)

    Bagaria, Vaibhav; Deshpande, Shirish; Kuthe, Abhay; Rasalkar, Darshana D.; Paunipagar, Bhawan K.; Madhugiri, Tanushree Subhash

    2012-01-01

    Hip replacement surgeries are on the rise in India. However, for these surgeries, most of the implants used are imported and manufactured entirely to suit the geometrical considerations of the western population. Studies in the past have shown that there are anatomical variations in the hip joint for different ethnic backgrounds and geographical locations. There is paucity of anthropometric hip joint data related to Indian population and anthropometric variations in skeletal geometry between Asian and Western counterparts have not yet been thoroughly reviewed and considered for implant manufacturing. The purpose of this anthropometric study is to determine any anatomical variations in the normal hip joint among the Indian population and to statistically compare the mean values with the existing data on western population. 422 Hip radiographs of 211 individuals (141 males and 70 females) with normal and healthy hip joints were evaluated to obtain the horizontal offset, vertical offset and neck shaft angle. For males, mean neck shaft angle was 127.68° (SD = 3.94), horizontal offset was 34.60 mm (SD = 6.55) and vertical offset was 39.17 mm (SD = 5.86). For females, mean neck shaft angle was 125.92° (SD = 4.75), horizontal offset was 32.96 mm (SD = 7.04) and vertical offset was 36.38 mm (SD = 6.28). When these parameters were compared to the data available from western world, there were significant anatomical variations and it was evident that there is a need to evaluate existing implants in relation to this data and possibly design the implants suited and relevant to Indian population.

  20. Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV-infected infants and toddlers.

    NARCIS (Netherlands)

    Zhao, W.; Cella, M.; Pasqua, O. Della; Burger, D.M.; Jacqz-Aigrain, E.

    2012-01-01

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Abacavir is used to treat HIV infection in both adults and children. The recommended paediatric dose is 8 mg kg(-1) twice daily up to a maximum of 300 mg twice daily. Weight was identified as the central covariate influencing pharmacokinetics of abacavir in

  1. Influence of lung parameter values for the Brazilian population on inhalation dose

    International Nuclear Information System (INIS)

    Reis, Arlene A.; Lopes, Ricardo T.

    2009-01-01

    The Human Respiratory Tract Model (HRTM) proposed by the ICRP Publication 66 accounts for the morphology and physiology of the respiratory tract. The ICRP 66 presents deposition fraction in the respiratory tract regions considering reference values from Caucasian man. However, in order to obtain a more accurate assessment of intake and dose the ICRP recommends the use of specific information when they are available. The main objective of this study is to evaluate the influence in dose calculation to each region of the respiratory tract when physiological parameters from samples of Brazilian population, in different levels of exercise, are applied in the deposition model.The dosimetric model of HRTM was implemented in the software EXCEL for Windows and committed equivalent dose was determined for each respiratory tract region. First it was calculated the total number of nuclear transformations considering the fractional deposition of activity in each source tissue obtained by application of physiological and morphological Brazilian parameters in the deposition model and then it was calculated the total energy absorbed per unit mass in the target tissue.The variation in the fractional deposition in the compartments of the respiratory tract in changing the physiological parameters from Caucasian to Brazilian adult man causes variation in the number of total transformations and also in the equivalent dose in each region of the respiratory tract. The variations are not the same for all regions of the respiratory tract and depend on levels of exercise. (author)

  2. [Chromosomal instability parameters in the population affected by nuclear explosions at the Semipalatinsk nuclear test site].

    Science.gov (United States)

    Abil'dinova, G Zh; Kuleshov, N P; Sviatova, G S

    2003-08-01

    A population genetic survey of 149 persons who were born and have permanently lived in the contaminated zones of the Semipalatinsk region has been performed. A cytogenetic study has demonstrated that the frequency of aberrant cells is 1.7-3 times higher than control parameters. The total frequencies of chromosome aberrations are 3.43 +/- 0.48, 3.1 +/- 0.3, 1.8 +/- 0.2, and 1.15 +/- 0.17 aberrations per 100 cells in the populations of the extreme radiation risk (ERR), maximum radiation risk (MaxRR), minimum radiation risk (MinRR), and control zones, respectively. The high chromosome aberration rate in all three zones of radiation risk has been detected mainly due to radiation-induced chromosome markers, including paired fragments (1.2 +/- 0.2, 0.94 +/- 0.13, and 0.43 +/- 0.06 per 100 cells, respectively), dicentric and ring chromosomes (0.44 +/- 0.04, 0.45 +/- 0.07, and 0.11 +/- 0.02 per 100 cells, respectively), and stable chromosome aberrations (0.74 +/- 0.16, 0.8 +/- 0.1, and 0.63 +/- 0.13 per 100 cells, respectively). The qualitative spectra of the cytogenetic lesions observed in these groups indicate a mutagenic effect of ionizing radiation on chromosomes in the populations studied.

  3. Application of a loading dose of colistin methanesulfonate in critically ill patients: population pharmacokinetics, protein binding, and prediction of bacterial kill.

    Science.gov (United States)

    Mohamed, Ami F; Karaiskos, Ilias; Plachouras, Diamantis; Karvanen, Matti; Pontikis, Konstantinos; Jansson, Britt; Papadomichelakis, Evangelos; Antoniadou, Anastasia; Giamarellou, Helen; Armaganidis, Apostolos; Cars, Otto; Friberg, Lena E

    2012-08-01

    A previous pharmacokinetic study on dosing of colistin methanesulfonate (CMS) at 240 mg (3 million units [MU]) every 8 h indicated that colistin has a long half-life, resulting in insufficient concentrations for the first 12 to 48 h after initiation of treatment. A loading dose would therefore be beneficial. The aim of this study was to evaluate CMS and colistin pharmacokinetics following a 480-mg (6-MU) loading dose in critically ill patients and to explore the bacterial kill following the use of different dosing regimens obtained by predictions from a pharmacokinetic-pharmacodynamic model developed from an in vitro study on Pseudomonas aeruginosa. The unbound fractions of colistin A and colistin B were determined using equilibrium dialysis and considered in the predictions. Ten critically ill patients (6 males; mean age, 54 years; mean creatinine clearance, 82 ml/min) with infections caused by multidrug-resistant Gram-negative bacteria were enrolled in the study. The pharmacokinetic data collected after the first and eighth doses were analyzed simultaneously with the data from the previous study (total, 28 patients) in the NONMEM program. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.026 and 2.2 h, respectively. For colistin, a one-compartment model was sufficient and the estimated half-life was 18.5 h. The unbound fractions of colistin in the patients were 26 to 41% at clinical concentrations. Colistin A, but not colistin B, had a concentration-dependent binding. The predictions suggested that the time to 3-log-unit bacterial kill for a 480-mg loading dose was reduced to half of that for the dose of 240 mg.

  4. Development of a population pharmacokinetic model to predict brain distribution and dopamine D2 receptor occupancy of raclopride in non-anesthetized rat.

    Science.gov (United States)

    Wong, Yin Cheong; Ilkova, Trayana; van Wijk, Rob C; Hartman, Robin; de Lange, Elizabeth C M

    2018-01-01

    Raclopride is a selective antagonist of the dopamine D2 receptor. It is one of the most frequently used in vivo D2 tracers (at low doses) for assessing drug-induced receptor occupancy (RO) in animals and humans. It is also commonly used as a pharmacological blocker (at high doses) to occupy the available D2 receptors and antagonize the action of dopamine or drugs on D2 in preclinical studies. The aims of this study were to comprehensively evaluate its pharmacokinetic (PK) profiles in different brain compartments and to establish a PK-RO model that could predict the brain distribution and RO of raclopride in the freely moving rat using a LC-MS based approach. Rats (n=24) received a 10-min IV infusion of non-radiolabeled raclopride (1.61μmol/kg, i.e. 0.56mg/kg). Plasma and the brain tissues of striatum (with high density of D2 receptors) and cerebellum (with negligible amount of D2 receptors) were collected. Additional microdialysis experiments were performed in some rats (n=7) to measure the free drug concentration in the extracellular fluid of the striatum and cerebellum. Raclopride concentrations in all samples were analyzed by LC-MS. A population PK-RO model was constructed in NONMEM to describe the concentration-time profiles in the unbound plasma, brain extracellular fluid and brain tissue compartments and to estimate the RO based on raclopride-D2 receptor binding kinetics. In plasma raclopride showed a rapid distribution phase followed by a slower elimination phase. The striatum tissue concentrations were consistently higher than that of cerebellum tissue throughout the whole experimental period (10-h) due to higher non-specific tissue binding and D2 receptor binding in the striatum. Model-based simulations accurately predicted the literature data on rat plasma PK, brain tissue PK and D2 RO at different time points after intravenous or subcutaneous administration of raclopride at tracer dose (RO 30%). For the first time a predictive model that could describe

  5. A cancer research UK pharmacokinetic study of BPA-mannitol in patients with high grade glioma to optimise uptake parameters for clinical trials of BNCT

    Energy Technology Data Exchange (ETDEWEB)

    Cruickshank, G.S. [University of Birmingham and University Hospital Birmingham, Birmingham (United Kingdom)], E-mail: garth.cruickshank@uhb.nhs.uk; Ngoga, D.; Detta, A.; Green, S.; James, N.D.; Wojnecki, C.; Doran, J.; Hardie, J.; Chester, M.; Graham, N.; Ghani, Z. [University of Birmingham and University Hospital Birmingham, Birmingham (United Kingdom); Halbert, G.; Elliot, M.; Ford, S. [CR-UK Formulation Unit, University of Strathclyde, Glasgow (United Kingdom); Braithwaite, R.; Sheehan, T.M.T. [Regional Laboratory for Toxicology, Sandwell and West Birmingham Hospitals Trust, Birmingham (United Kingdom); Vickerman, J.; Lockyer, N. [Surface Analysis Research Centre, University of Manchester, Manchester (United Kingdom); Steinfeldt, H.; Croswell, G. [CR-UK Drug Development Office, London (United Kingdom)] (and others)

    2009-07-15

    This paper describes results to-date from a human pharmacokinetic study which began recruitment in December 2007. Results are presented for a single patient recruited in December 2007. A second patient was recruited in July 2008 but detailed data are not available at the time of writing. The trial is an open-label, non-comparative, non-therapeutic study of BPA-mannitol in patients with high-grade glioma, who will be undergoing stereotactic brain biopsy as part of the diagnostic process before definitive treatment. The study investigates the route of infusion (intra-venous (IV) or intra-carotid artery) and in each case will assess the effect of administration of mannitol as a blood-brain barrier disrupter. All cohorts will receive a 2 h infusion of BPA-mannitol, and for some cohorts an additional mannitol bolus will be administered at the beginning of this infusion. Measurements are made by inductively coupled plasma mass spectrometry (ICP-MS) of {sup 10}B concentration in samples of blood, urine, extra-cellular fluid in normal brain (via a dialysis probe), brain tissue around tumour and tumour tissue. Additional analysis of the tumour tissue is performed using secondary ion mass spectrometry (SIMS). The first patient was part of the cohort having intra-venous infusion without mannitol bolus. No serious clinical problems were experienced and the assay results can be compared with available patient data from other BNCT centres. In particular we note that the peak {sup 10}B concentration in blood was 28.1 mg/ml for a total BPA administration of 350 mg/kg which is very consistent with the previous experience with BPA-fructose reported by the Helsinki group.

  6. A cancer research UK pharmacokinetic study of BPA-mannitol in patients with high grade glioma to optimise uptake parameters for clinical trials of BNCT

    International Nuclear Information System (INIS)

    Cruickshank, G.S.; Ngoga, D.; Detta, A.; Green, S.; James, N.D.; Wojnecki, C.; Doran, J.; Hardie, J.; Chester, M.; Graham, N.; Ghani, Z.; Halbert, G.; Elliot, M.; Ford, S.; Braithwaite, R.; Sheehan, T.M.T.; Vickerman, J.; Lockyer, N.; Steinfeldt, H.; Croswell, G.

    2009-01-01

    This paper describes results to-date from a human pharmacokinetic study which began recruitment in December 2007. Results are presented for a single patient recruited in December 2007. A second patient was recruited in July 2008 but detailed data are not available at the time of writing. The trial is an open-label, non-comparative, non-therapeutic study of BPA-mannitol in patients with high-grade glioma, who will be undergoing stereotactic brain biopsy as part of the diagnostic process before definitive treatment. The study investigates the route of infusion (intra-venous (IV) or intra-carotid artery) and in each case will assess the effect of administration of mannitol as a blood-brain barrier disrupter. All cohorts will receive a 2 h infusion of BPA-mannitol, and for some cohorts an additional mannitol bolus will be administered at the beginning of this infusion. Measurements are made by inductively coupled plasma mass spectrometry (ICP-MS) of 10 B concentration in samples of blood, urine, extra-cellular fluid in normal brain (via a dialysis probe), brain tissue around tumour and tumour tissue. Additional analysis of the tumour tissue is performed using secondary ion mass spectrometry (SIMS). The first patient was part of the cohort having intra-venous infusion without mannitol bolus. No serious clinical problems were experienced and the assay results can be compared with available patient data from other BNCT centres. In particular we note that the peak 10 B concentration in blood was 28.1 mg/ml for a total BPA administration of 350 mg/kg which is very consistent with the previous experience with BPA-fructose reported by the Helsinki group.

  7. Assessing Nutritional Parameters of Brown Bear Diets among Ecosystems Gives Insight into Differences among Populations.

    Science.gov (United States)

    López-Alfaro, Claudia; Coogan, Sean C P; Robbins, Charles T; Fortin, Jennifer K; Nielsen, Scott E

    2015-01-01

    Food habit studies are among the first steps used to understand wildlife-habitat relationships. However, these studies are in themselves insufficient to understand differences in population productivity and life histories, because they do not provide a direct measure of the energetic value or nutritional composition of the complete diet. Here, we developed a dynamic model integrating food habits and nutritional information to assess nutritional parameters of brown bear (Ursus arctos) diets among three interior ecosystems of North America. Specifically, we estimate the average amount of digestible energy and protein (per kilogram fresh diet) content in the diet and across the active season by bears living in western Alberta, the Flathead River (FR) drainage of southeast British Columbia, and the Greater Yellowstone Ecosystem (GYE). As well, we estimate the proportion of energy and protein in the diet contributed by different food items, thereby highlighting important food resources in each ecosystem. Bear diets in Alberta had the lowest levels of digestible protein and energy through all seasons, which might help explain the low reproductive rates of this population. The FR diet had protein levels similar to the recent male diet in the GYE during spring, but energy levels were lower during late summer and fall. Historic and recent diets in GYE had the most energy and protein, which is consistent with their larger body sizes and higher population productivity. However, a recent decrease in consumption of trout (Oncorhynchus clarki), whitebark pine nuts (Pinus albicaulis), and ungulates, particularly elk (Cervus elaphus), in GYE bears has decreased the energy and protein content of their diet. The patterns observed suggest that bear body size and population densities are influenced by seasonal availability of protein an energy, likely due in part to nutritional influences on mass gain and reproductive success.

  8. Assessing Nutritional Parameters of Brown Bear Diets among Ecosystems Gives Insight into Differences among Populations.

    Directory of Open Access Journals (Sweden)

    Claudia López-Alfaro

    Full Text Available Food habit studies are among the first steps used to understand wildlife-habitat relationships. However, these studies are in themselves insufficient to understand differences in population productivity and life histories, because they do not provide a direct measure of the energetic value or nutritional composition of the complete diet. Here, we developed a dynamic model integrating food habits and nutritional information to assess nutritional parameters of brown bear (Ursus arctos diets among three interior ecosystems of North America. Specifically, we estimate the average amount of digestible energy and protein (per kilogram fresh diet content in the diet and across the active season by bears living in western Alberta, the Flathead River (FR drainage of southeast British Columbia, and the Greater Yellowstone Ecosystem (GYE. As well, we estimate the proportion of energy and protein in the diet contributed by different food items, thereby highlighting important food resources in each ecosystem. Bear diets in Alberta had the lowest levels of digestible protein and energy through all seasons, which might help explain the low reproductive rates of this population. The FR diet had protein levels similar to the recent male diet in the GYE during spring, but energy levels were lower during late summer and fall. Historic and recent diets in GYE had the most energy and protein, which is consistent with their larger body sizes and higher population productivity. However, a recent decrease in consumption of trout (Oncorhynchus clarki, whitebark pine nuts (Pinus albicaulis, and ungulates, particularly elk (Cervus elaphus, in GYE bears has decreased the energy and protein content of their diet. The patterns observed suggest that bear body size and population densities are influenced by seasonal availability of protein an energy, likely due in part to nutritional influences on mass gain and reproductive success.

  9. Assessing Nutritional Parameters of Brown Bear Diets among Ecosystems Gives Insight into Differences among Populations

    Science.gov (United States)

    López-Alfaro, Claudia; Coogan, Sean C. P.; Robbins, Charles T.; Fortin, Jennifer K.; Nielsen, Scott E.

    2015-01-01

    Food habit studies are among the first steps used to understand wildlife-habitat relationships. However, these studies are in themselves insufficient to understand differences in population productivity and life histories, because they do not provide a direct measure of the energetic value or nutritional composition of the complete diet. Here, we developed a dynamic model integrating food habits and nutritional information to assess nutritional parameters of brown bear (Ursus arctos) diets among three interior ecosystems of North America. Specifically, we estimate the average amount of digestible energy and protein (per kilogram fresh diet) content in the diet and across the active season by bears living in western Alberta, the Flathead River (FR) drainage of southeast British Columbia, and the Greater Yellowstone Ecosystem (GYE). As well, we estimate the proportion of energy and protein in the diet contributed by different food items, thereby highlighting important food resources in each ecosystem. Bear diets in Alberta had the lowest levels of digestible protein and energy through all seasons, which might help explain the low reproductive rates of this population. The FR diet had protein levels similar to the recent male diet in the GYE during spring, but energy levels were lower during late summer and fall. Historic and recent diets in GYE had the most energy and protein, which is consistent with their larger body sizes and higher population productivity. However, a recent decrease in consumption of trout (Oncorhynchus clarki), whitebark pine nuts (Pinus albicaulis), and ungulates, particularly elk (Cervus elaphus), in GYE bears has decreased the energy and protein content of their diet. The patterns observed suggest that bear body size and population densities are influenced by seasonal availability of protein an energy, likely due in part to nutritional influences on mass gain and reproductive success. PMID:26083536

  10. Structural parameters of pikeperch (Sander lucioperca population of the Kyiv reservoir

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    O. Buzevych

    2017-01-01

    Full Text Available Purpose. Analysis of the dynamics of structural parameters as an integral property of the processes of recruitment and elimination of the reproductive and commercial population nuclei of pikeperch of the Kyiv reservoir. Methodology. Ichthyological material was collected during spring-summer period of 2015-2016 from survey catches done with gill nets with mesh sizes of 30-120 mm. Collection and processing of the field materials were carried out using conventional methods. In total, catches of 3.5 thousand net-days were processed during the study period and 1031 individual pikeperch were analyzed. Total mortality coefficient (Z was determined by graphic method based on the dynamics of the natural logarithms of the abundances of different age groups. Statistical processing of data was done in MS Excel. Findings. Commercial landings of pikeperch during last 10 years has a clear trend for a growth: from 20-25 to 80-100 tons. The catch of pikeperch per unit effort of survey gill nets in an interannual aspect is also characterized by a growth. At the same time, there is a certain improvement of the structural parameters of pikeperch population, e.g. an increase in the maximum age and extension of the modal frequency distribution. Age-3 and age-4 fish represented the major part of the population (71.6% in the catches of 2015, while the share of age-5-6 fish was also relatively high (10.8%. It resulted in an increase in the weighed mean age of the pikeperch population to 4.5 years. For 2016, there is a significant shift of the frequency distribution to its left wing – the major part of the population (64.7% was composed of age-2 to age-4 fish. The weighed mean age in 2016 decreased to 2.6 years that was due first of all to abundant recruitment and intensive elimination of middle age groups. Total mortality (Z of pikeperch in 2015-2016 was 0.53-0.56 that corresponded to normal conditions of the formation of the commercial stock of this species and

  11. Fetal biometric parameters: Reference charts for a non-selected risk population from Uberaba, Brazil.

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    Peixoto, Alberto Borges; da Cunha Caldas, Taciana Mara Rodrigues; Dulgheroff, Fernando Felix; Martins, Wellington P; Araujo Júnior, Edward

    2017-03-01

    To establish reference charts for fetal biometric parameters in a non-selected risk population from Uberaba, Southeast of Brazil. A retrospective cross-sectional study was performed among 5656 non-selected risk singleton pregnant women between 14 and 41 weeks of gestation. The ultrasound exams were performed during routine visits of second and third trimesters. Biparietal diameter (BPD) was measured at the level of the thalami and cavum septi pellucidi. Head circumference (HC) was calculated by the following formula: HC = 1.62*(BPD + occipital frontal diameter, OFD). Abdominal circumference (AC) was measured using the following formula: AC = (anteroposterior diameter + transverse abdominal diameter) × 1.57. Femur diaphysis length (FDL) was obtained in the longest axis of femur without including the distal femoral epiphysis. The estimated fetal weight (EFW) was obtained by the Hadlock formula. Polynomial regressions were performed to obtain the best-fit model for each fetal biometric parameter as the function of gestational age (GA). The mean, standard deviations ( SD ), minimum and maximum of BPD (cm), HC (cm), AC (cm), FDL (cm) and EFW (g) were 6.9 ± 1.9 (2.3 - 10.5), 24.51 ± 6.61 (9.1 - 36.4), 22.8 ± 7.3 (7.5 - 41.1), 4.9 ± 1.6 (1.2 - 8.1) and 1365 ± 1019 (103 - 4777), respectively. Second-degree polynomial regressions between the evaluated parameters and GA resulted in the following formulas: BPD = -4.044 + 0.540 × GA - 0.0049 × GA 2 ( R 2 = 0.97); HC= -15.420 + 2.024 GA - 0.0199 × GA 2 ( R 2 = 0.98); AC = -9.579 + 1.329 × GA - 0.0055 × GA 2 ( R 2 = 0.97); FDL = -3.778 + 0.416 × GA - 0.0035 × GA 2 ( R 2 = 0.98) and EFW = 916 - 123 × GA + 4.70 × GA 2 ( R 2 = 0.96); respectively. Reference charts for the fetal biometric parameters in a non-selected risk population from Uberaba, Southeast of Brazil, were established.

  12. Fetal biometric parameters: Reference charts for a non-selected risk population from Uberaba, Brazil

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    Alberto Borges Peixoto

    2017-03-01

    Full Text Available Objective: To establish reference charts for fetal biometric parameters in a non-selected risk population from Uberaba, Southeast of Brazil. Methods: A retrospective cross-sectional study was performed among 5656 non-selected risk singleton pregnant women between 14 and 41 weeks of gestation. The ultrasound exams were performed during routine visits of second and third trimesters. Biparietal diameter (BPD was measured at the level of the thalami and cavum septi pellucidi. Head circumference (HC was calculated by the following formula: HC = 1.62*(BPD + occipital frontal diameter, OFD. Abdominal circumference (AC was measured using the following formula: AC = (anteroposterior diameter + transverse abdominal diameter × 1.57. Femur diaphysis length (FDL was obtained in the longest axis of femur without including the distal femoral epiphysis. The estimated fetal weight (EFW was obtained by the Hadlock formula. Polynomial regressions were performed to obtain the best-fit model for each fetal biometric parameter as the function of gestational age (GA. Results: The mean, standard deviations (SD, minimum and maximum of BPD (cm, HC (cm, AC (cm, FDL (cm and EFW (g were 6.9 ± 1.9 (2.3 – 10.5, 24.51 ± 6.61 (9.1 – 36.4, 22.8 ± 7.3 (7.5 – 41.1, 4.9 ± 1.6 (1.2 – 8.1 and 1365 ± 1019 (103 – 4777, respectively. Second-degree polynomial regressions between the evaluated parameters and GA resulted in the following formulas: BPD = –4.044 + 0.540 × GA – 0.0049 × GA² (R² = 0.97; HC= –15.420 + 2.024 GA – 0.0199 × GA² (R² = 0.98; AC = –9.579 + 1.329 × GA – 0.0055 × GA² (R² = 0.97; FDL = –3.778 + 0.416 × GA – 0.0035 × GA² (R² = 0.98 and EFW = 916 – 123 × GA + 4.70 × GA² (R² = 0.96; respectively. Conclusion: Reference charts for the fetal biometric parameters in a non-selected risk population from Uberaba, Southeast of Brazil, were established.

  13. Dynamic regime of coherent population trapping and optimization of frequency modulation parameters in atomic clocks.

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    Yudin, V I; Taichenachev, A V; Basalaev, M Yu; Kovalenko, D V

    2017-02-06

    We theoretically investigate the dynamic regime of coherent population trapping (CPT) in the presence of frequency modulation (FM). We have formulated the criteria for quasi-stationary (adiabatic) and dynamic (non-adiabatic) responses of atomic system driven by this FM. Using the density matrix formalism for Λ system, the error signal is exactly calculated and optimized. It is shown that the optimal FM parameters correspond to the dynamic regime of atomic-field interaction, which significantly differs from conventional description of CPT resonances in the frame of quasi-stationary approach (under small modulation frequency). Obtained theoretical results are in good qualitative agreement with different experiments. Also we have found CPT-analogue of Pound-Driver-Hall regime of frequency stabilization.

  14. Reproductive and population dynamics parameters of Mbanza-Ngungu's local goat in Democratic Republic of Congo

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    R. Gasigwa Sabimana

    2018-03-01

    Full Text Available Prospects for the development of goat breeding in the Democratic Republic of Congo seem favorable. Knowledge of the characteristics of local goat farming by breeders is a very important factor to control and promote goat production. The objective of this study was to improve the productivity of Mbanza-Ngungu’s local goat by increasing the knowledge of its reproductive performance. To achieve this objective, data were collected by direct observation of the goats. These data were used to simulate reproductive and population dynamics parameters over a five-year period. The study showed the relevance of the model to simulate the reproduction traits of Mbanza-Ngungu’s goats and that it is useless to keep them beyond five years.

  15. [Study on differences between pharmacokinetics and chromatopharmacodynamics for Chinese materia medica formulae].

    Science.gov (United States)

    He, Fuyuan; Deng, Kaiwen; Zou, Huan; Qiu, Yun; Chen, Feng; Zhou, Honghao

    2011-01-01

    To study on the differences between chromatopharmacokinetics (pharmacokinetics with fingerprint chromatography) and chromatopharmacodynamics (pharmacodynamics with fingerprint chromatography) of Chinese materia medica formulae to answer the question whether the pharmacokinetic parameters of multiple composites can be utilized to guide the medication of multiple composites. On the base of established four chromatopharmacology (pharmacology with chromatographic fingerprint), the pharmacokinetics, and pharmacodynamics were analyzed comparably on their mathematical model and parameter definition. On the basis of quantitative pharmacology, the function expressions and total statistical parameters, such as total zero moment, total first moment, total second moment of the pharmacokinetics, and pharmacodynamics were analyzed to the common expressions and elucidated results for single and multiple components in Chinese materia medica formulae. Total quantitative pharmacokinetic, i.e., chromatopharmacokinetic parameter were decided by each component pharmacokinetic parameters, whereas the total quantitative pharmacodynamic, i.e., chromatopharmacodynamic parameter were decided by both of pharmacokinetic and pharmacodynamic parameters of each components. The pharmacokinetic parameters were corresponded to pharmacodynamic parameters with an existing stable effective coefficient when the constitutive ratio of each composite was a constant. The effects of Chinese materia medica were all controlled by pharmacokinetic and pharmacodynamic coefficient. It is a special case that the pharmacokinetic parameter could independently guide the clinical medication for single component whereas the chromatopharmacokinetic parameters are not applied to the multiple drug combination system, and not be used to solve problems of chromatopharmacokinetic of Chinese materia medica formulae.

  16. Comparison of sampling methodologies and estimation of population parameters for a temporary fish ectoparasite

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    J.M. Artim

    2016-08-01

    Full Text Available Characterizing spatio-temporal variation in the density of organisms in a community is a crucial part of ecological study. However, doing so for small, motile, cryptic species presents multiple challenges, especially where multiple life history stages are involved. Gnathiid isopods are ecologically important marine ectoparasites, micropredators that live in substrate for most of their lives, emerging only once during each juvenile stage to feed on fish blood. Many gnathiid species are nocturnal and most have distinct substrate preferences. Studies of gnathiid use of habitat, exploitation of hosts, and population dynamics have used various trap designs to estimate rates of gnathiid emergence, study sensory ecology, and identify host susceptibility. In the studies reported here, we compare and contrast the performance of emergence, fish-baited and light trap designs, outline the key features of these traps, and determine some life cycle parameters derived from trap counts for the Eastern Caribbean coral-reef gnathiid, Gnathia marleyi. We also used counts from large emergence traps and light traps to estimate additional life cycle parameters, emergence rates, and total gnathiid density on substrate, and to calibrate the light trap design to provide estimates of rate of emergence and total gnathiid density in habitat not amenable to emergence trap deployment.

  17. Phthalate exposure and reproductive parameters in young men from the general Swedish population.

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    Axelsson, Jonatan; Rylander, Lars; Rignell-Hydbom, Anna; Jönsson, Bo A G; Lindh, Christian H; Giwercman, Aleksander

    2015-12-01

    In animals, exposure to certain phthalates negatively affects the male reproductive function. Human results are conflicting and mostly based on subfertile males, in whom the association between exposure and reproductive function may differ from the general population. To study if levels of phthalate metabolites were associated with semen quality and reproductive hormones in general Swedish men. We recruited 314 young men delivering semen, urine and blood samples at the same visit. We analyzed reproductive hormones and several semen parameters including progressive motility and high DNA stainability (HDS)-a marker for sperm immaturity. In urine, we analyzed metabolites of phthalates, including diethylhexyl phthalate (DEHP). We studied associations between urinary levels of the metabolites and seminal as well as serum reproductive parameters, accounting for potential confounders. DEHP metabolite levels, particularly urinary mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), were negatively associated with progressive sperm motility, which was 11 (95% CI: 5.0-17) percentage points lower in the highest quartile of MECPP than in the lowest. Further, men in the highest quartile of the DEHP metabolite monoethylhexyl phthalate had 27% (95% CI: 5.5%-53%) higher HDS than men in the lowest quartile. DEHP metabolite levels seemed negatively associated with sperm motility and maturation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Population Growth Parameters of Tuta absoluta (Lepidoptera: Gelechiidae) on Tomato Plant Using Organic Substrate and Biofertilizers.

    Science.gov (United States)

    Mohamadi, P; Razmjou, J; Naseri, B; Hassanpour, M

    2017-01-01

    The tomato leafminer, Tuta absoluta (Meyrick) is a devastating pest associated with tomato. In this study, effects of tomato plants treated with vermicompost (20, 40, and 60%), humic fertilizer (2, 4 and 6 g/kg soil) and plant growth promoting rhizobacteria (Pseudomonas fluorescens and Bacillus subtilis) were investigated on the life table parameters of T. absoluta in a growth chamber at 25 ± 2 °C, 65 ± 5% RH, and 16:8 (L:D) h. Significant differences were found for the total developmental time, fecundity, and oviposition period of T. absoluta on the treatments tested. The net reproductive rate (R0), intrinsic rate of natural increase (rm), finite rate of increase (λ), mean generation time (T), and doubling time (DT) of T. absoluta were significantly different among treatments tested. We found that in all vermicompost, humic fertilizer and plant growth promoting rhizobacteria treatments, values of R0, rm, and λ were lower than control treatment. However, the lowest values of these parameters were obtained on 2 g/kg humic fertilizer and 40% vermicompost. Furthermore, T. absoluta had longest T and DT values on 2 g/kg humic fertilizer treatment. Data obtained showed that the addition of 2 g/kg humic fertilizer and 40% vermicompost to the growing soil reduced T. absoluta populations in tomato cultures. In addition, these levels of fertilizers improved growth parameters of tomato seedlings (plant height, wet weight, and dry weight) compared with other treatments. These results could be useful in improving the sustainable management of the moth. © The Author 2017. Published by Oxford University Press on behalf of the Entomological Society of America.

  19. Estimating Finite Rate of Population Increase for Sharks Based on Vital Parameters.

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    Kwang-Ming Liu

    Full Text Available The vital parameter data for 62 stocks, covering 38 species, collected from the literature, including parameters of age, growth, and reproduction, were log-transformed and analyzed using multivariate analyses. Three groups were identified and empirical equations were developed for each to describe the relationships between the predicted finite rates of population increase (λ' and the vital parameters, maximum age (Tmax, age at maturity (Tm, annual fecundity (f/Rc, size at birth (Lb, size at maturity (Lm, and asymptotic length (L∞. Group (1 included species with slow growth rates (0.034 yr(-1 < k < 0.103 yr(-1 and extended longevity (26 yr < Tmax < 81 yr, e.g., shortfin mako Isurus oxyrinchus, dusky shark Carcharhinus obscurus, etc.; Group (2 included species with fast growth rates (0.103 yr(-1 < k < 0.358 yr(-1 and short longevity (9 yr < Tmax < 26 yr, e.g., starspotted smoothhound Mustelus manazo, gray smoothhound M. californicus, etc.; Group (3 included late maturing species (Lm/L∞ ≧ 0.75 with moderate longevity (Tmax < 29 yr, e.g., pelagic thresher Alopias pelagicus, sevengill shark Notorynchus cepedianus. The empirical equation for all data pooled was also developed. The λ' values estimated by these empirical equations showed good agreement with those calculated using conventional demographic analysis. The predictability was further validated by an independent data set of three species. The empirical equations developed in this study not only reduce the uncertainties in estimation but also account for the difference in life history among groups. This method therefore provides an efficient and effective approach to the implementation of precautionary shark management measures.

  20. Analytic Investigation Into Effect of Population Heterogeneity on Parameter Ratio Estimates

    International Nuclear Information System (INIS)

    Schinkel, Colleen; Carlone, Marco; Warkentin, Brad; Fallone, B. Gino

    2007-01-01

    Purpose: A homogeneous tumor control probability (TCP) model has previously been used to estimate the α/β ratio for prostate cancer from clinical dose-response data. For the ratio to be meaningful, it must be assumed that parameter ratios are not sensitive to the type of tumor control model used. We investigated the validity of this assumption by deriving analytic relationships between the α/β estimates from a homogeneous TCP model, ignoring interpatient heterogeneity, and those of the corresponding heterogeneous (population-averaged) model that incorporated heterogeneity. Methods and Materials: The homogeneous and heterogeneous TCP models can both be written in terms of the geometric parameters D 50 and γ 50 . We show that the functional forms of these models are similar. This similarity was used to develop an expression relating the homogeneous and heterogeneous estimates for the α/β ratio. The expression was verified numerically by generating pseudo-data from a TCP curve with known parameters and then using the homogeneous and heterogeneous TCP models to estimate the α/β ratio for the pseudo-data. Results: When the dominant form of interpatient heterogeneity is that of radiosensitivity, the homogeneous and heterogeneous α/β estimates differ. This indicates that the presence of this heterogeneity affects the value of the α/β ratio derived from analysis of TCP curves. Conclusions: The α/β ratio estimated from clinical dose-response data is model dependent-a heterogeneous TCP model that accounts for heterogeneity in radiosensitivity will produce a greater α/β estimate than that resulting from a homogeneous TCP model

  1. Diets of differentially processed wheat alter ruminal fermentation parameters and microbial populations in beef cattle.

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    Jiang, S Z; Yang, Z B; Yang, W R; Li, Z; Zhang, C Y; Liu, X M; Wan, F C

    2015-11-01

    The influences of differently processed wheat products on rumen fermentation, microbial populations, and serum biochemistry profiles in beef cattle were studied. Four ruminally cannulated Limousin × Luxi beef cattle (400 ± 10 kg) were used in the experiment with a 4 × 4 Latin square design. The experimental diets contained (on a DM basis) 60% corn silage as a forage source and 40% concentrate with 4 differently processed wheat products (extruded, pulverized, crushed, and rolled wheat). Concentrations of ruminal NH-N and microbial protein (MCP) in cattle fed crushed and rolled wheat were greater ( Ruminal concentrations of total VFA and acetate and the ratio of acetate to propionate decreased ( 0.05). Our findings suggest that the method of wheat processing could have a significant effect on ruminal fermentation parameters and microbial populations in beef cattle and that crushed and rolled processing is better in terms of ruminal NH-N and MCP content, acetate-to-propionate ratio, and relative abundance of rumen microorganisms.

  2. Respiratory tract dose calculation considering physiological parameters from samples of Brazilian population

    International Nuclear Information System (INIS)

    Reis, A.; Lopes, R.; Lourenco, M.; Cardoso, J.

    2006-01-01

    The Human Respiratory Tract Model proposed by the ICRP Publication 66 accounts for the morphology and physiology of the respiratory tract. The ICRP 66 presents deposition fraction in the respiratory tract regions considering reference values from Caucasian man. However, in order to obtain a more accurate assessment of intake and dose the ICRP recommends the use of specific information when they are available. The application of parameters from Brazilian population in the deposition and in the clearance model shows significant variations in the deposition fractions and in the fraction of inhaled activity transferred to blood. The main objective of this study is to evaluate the influence in dose calculation to each region of the respiratory tract when physiological parameters from Brazilian population are applied in the model. The purpose of the dosimetric model is to evaluate dose to each tissues of respiratory tract that are potentially risk from inhaled radioactive materials. The committed equivalent dose, H.T., is calculated by the product of the total number of transformations of the radionuclide in tissue source S over a period of fifty years after incorporation and of the energy absorbed per unit mass in the target tissue T, for each radiation emitted per transformation in tissue source S. The dosimetric model of Human Respirator y Tract was implemented in the software Excel for Windows (version 2000) and H.T. was determined in two stages. First it was calculated the number of total transformations, US, considering the fractional deposition of activity in each source tissue and then it was calculated the total energy absorbed per unit mass S.E.E., in the target tissue. It was assumed that the radionuclide emits an alpha particle with average energy of 5.15 MeV. The variation in the fractional deposition in the compartments of the respiratory tract in changing the physiological parameters from Caucasian to Brazilian adult man causes variation in the number of

  3. Associations between urinary phthalate concentrations and semen quality parameters in a general population

    Science.gov (United States)

    Bloom, M.S.; Whitcomb, B.W.; Chen, Z.; Ye, A.; Kannan, K.; Buck Louis, G.M.

    2015-01-01

    STUDY QUESTION Are urinary phthalate concentrations associated with altered semen quality parameters among males recruited from the general population? SUMMARY ANSWER Urinary levels of metabolites of phthalate diesters are associated with lower total sperm counts, larger sperm head sizes, and higher percentages of morphologically abnormal sperm. WHAT IS KNOWN ALREADY High dose experiments in rats implicate phthalates as anti-androgens. Studies involving infertile men seeking care suggest that phthalates influence measures of semen quality raising concern about the implications for men in the general population. STUDY DESIGN, SIZE, DURATION This prospective cohort study comprised 501 male partners in couples discontinuing contraception to become pregnant, who were recruited from 16 US counties using population-based sampling frameworks from 2005 to 2009. PARTICIPANTS/MATERIALS, SETTING, METHODS Urine and semen samples were obtained at baseline from 473 (94%) men, of whom 378 (80%) men provided a second sample the following month. Urine was analyzed for 14 monoester metabolites of phthalate diesters by high-performance liquid chromatography coupled to tandem mass spectrometry. Semen samples were analyzed for 34 quality parameters categorized as general, motility, morphology, sperm head and sperm chromatin structure. MAIN RESULTS AND THE ROLE OF CHANCE Urinary mono-[2-(carboxymethyl) hexyl] phthalate (MCMHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-benzyl phthalate (MBzP), and mono-isononyl phthalate (MNP) were significantly associated with lower total sperm counts and concentrations, larger sperm head sizes, higher proportions of megalo head sperm morphology, and/or other morphological changes. Urinary mono-methyl phthalate (MMP) and mono-cyclohexyl phthalate (MCPP) were significantly associated with lower sperm motility, and urine mono-2-ethylhexyl phthalate (MEHP) was significantly associated with higher sperm motility. LIMITATIONS, REASONS FOR

  4. Application of Physiologically-Based Pharmacokinetic Modeling for the Prediction of Tofacitinib Exposure in Japanese.

    Science.gov (United States)

    Suzuki, Misaki; Tse, Susanna; Hirai, Midori; Kurebayashi, Yoichi

    2017-05-09

    Tofacitinib (3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3 -oxopropanenitrile) is an oral Janus kinase inhibitor that is approved in countries including Japan and the United States for the treatment of rheumatoid arthritis, and is being developed across the globe for the treatment of inflammatory diseases. In the present study, a physiologically-based pharmacokinetic model was applied to compare the pharmacokinetics of tofacitinib in Japanese and Caucasians to assess the potential impact of ethnicity on the dosing regimen in the two populations. Simulated plasma concentration profiles and pharmacokinetic parameters, i.e. maximum concentration and area under plasma concentration-time curve, in Japanese and Caucasian populations after single or multiple doses of 1 to 30 mg tofacitinib were in agreement with clinically observed data. The similarity in simulated exposure between Japanese and Caucasian populations supports the currently approved dosing regimen in Japan and the United States, where there is no recommendation for dose adjustment according to race. Simulated results for single (1 to 100 mg) or multiple doses (5 mg twice daily) of tofacitinib in extensive and poor metabolizers of CYP2C19, an enzyme which has been shown to contribute in part to tofacitinib elimination and is known to exhibit higher frequency in Japanese compared to Caucasians, were also in support of no recommendation for dose adjustment in CYP2C19 poor metabolizers. This study demonstrated a successful application of physiologically-based pharmacokinetic modeling in evaluating ethnic sensitivity in pharmacokinetics at early stages of development, presenting its potential value as an efficient and scientific method for optimal dose setting in the Japanese population.

  5. What Population Reveals about Individual Cell Identity: Single-Cell Parameter Estimation of Models of Gene Expression in Yeast.

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    Artémis Llamosi

    2016-02-01

    Full Text Available Significant cell-to-cell heterogeneity is ubiquitously observed in isogenic cell populations. Consequently, parameters of models of intracellular processes, usually fitted to population-averaged data, should rather be fitted to individual cells to obtain a population of models of similar but non-identical individuals. Here, we propose a quantitative modeling framework that attributes specific parameter values to single cells for a standard model of gene expression. We combine high quality single-cell measurements of the response of yeast cells to repeated hyperosmotic shocks and state-of-the-art statistical inference approaches for mixed-effects models to infer multidimensional parameter distributions describing the population, and then derive specific parameters for individual cells. The analysis of single-cell parameters shows that single-cell identity (e.g. gene expression dynamics, cell size, growth rate, mother-daughter relationships is, at least partially, captured by the parameter values of gene expression models (e.g. rates of transcription, translation and degradation. Our approach shows how to use the rich information contained into longitudinal single-cell data to infer parameters that can faithfully represent single-cell identity.

  6. Population Growth Parameters of Rose Aphid, Macrosiphum rosae (Hemiptera: Aphididae) on Different Rose Cultivars.

    Science.gov (United States)

    Golizadeh, A; Jafari-Behi, V; Razmjou, J; Naseri, B; Hassanpour, M

    2017-02-01

    The rose aphid, Macrosiphum rosae (L.), is one of the most important pests on rose plants (Rosa spp.) with a worldwide distribution. As resistance indices, the development, survivorship, and reproduction of this aphid were evaluated on 10 rose cultivars, including Bella Vita, Cool Water, Dolce Vita, Maroussia, Orange Juice, Pinkpromise, Roulette, Tea, Valentine, and Persian Yellow in laboratory at 25 ± 1°C, 65 ± 5% relative humidity, and photoperiod of 16:8 (L/D) h. Rose aphid successfully survived on all 10 rose cultivars, although mortality rate was higher on Tea and Bella Vita. The number of offspring per female differed significantly among the tested rose cultivars, and ranged from 9.2 on Tea to 38.7 nymphs on Orange Juice. Population growth parameters were significantly affected by rose cultivars. The longest mean generation time (T) was observed on Bella Vita (14.8 days) and Tea (14.7 days) and the shortest on Orange Juice (10.0 days). The net reproductive rate (R 0 ) ranged from 6.9 on Tea to 33.2 nymphs on Orange Juice cultivar. Correspondingly, the highest value of intrinsic rate of increase (r m ) was observed on Orange Juice (0.348 day -1 ) and lower values on Tea (0.131 day -1 ) followed by Bella Vita (0.154 day -1 ). Cluster analysis of all the measured parameters of rose aphid on different rose cultivars revealed that Tea and Bella Vita were relatively resistant to M. rosae. These findings could be useful in developing an integrated pest management (IPM) program for this aphid in urbanized areas and commercial rose potting.

  7. Pharmacokinetics of mitragynine in man

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    Trakulsrichai S

    2015-04-01

    the study without adverse reactions. The median duration of abuse was 1.75 years. We analyzed one subject separately due to the abnormal behavior of blood concentration. From data of nine subjects, the pharmacokinetic parameters established were time to reach the maximum plasma concentration (0.83±0.35 hour, terminal half-life (23.24±16.07 hours, and the apparent volume of distribution (38.04±24.32 L/kg. The urine excretion of unchanged form was 0.14%. The pharmacokinetics were observed to be oral two-compartment model. Conclusion: This was the first pharmacokinetic study in humans, which demonstrated linearity and was consistent with the oral two-compartment model with a terminal half-life of about 1 day. The pharmacokinetic linearity and parameters reported are necessary pharmacological information of Kratom, and there is a possibility for it to be developed medically as a pain killer or better opioid substitute in the future. Keywords: kratom, human, pharmacokinetics

  8. Genetic parameters for residual feed intake in a random population of Pekin duck

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    Yunsheng Zhang

    2017-02-01

    Full Text Available Objective The feed intake (FI and feed efficiency are economically important traits in ducks. To obtain insight into this economically important trait, we designed an experiment based on the residual feed intake (RFI and feed conversion ratio (FCR of a random population Pekin duck. Methods Two thousand and twenty pedigreed random population Pekin ducks were established from 90 males mated to 450 females in two hatches. Traits analyzed in the study were body weight at the 42th day (BW42, 15 to 42 days average daily gain (ADG, 15 to 42 days FI, 15 to 42 days FCR, and 15 to 42 days RFI to assess their genetic inter-relationships. The genetic parameters for feed efficiency traits were estimated using restricted maximum likelihood (REML methodology applied to a sire-dam model for all traits using the ASREML software. Results Estimates heritability of BW42, ADG, FI, FCR, and RFI were 0.39, 0.38, 0.33, 0.38, and 0.41, respectively. The genetic correlation was high between RFI and FI (0.77 and moderate between RFI and FCR (0.54. The genetic correlation was high and moderate between FCR and ADG (−0.80, and between FCR and BW42 (−0.64, and between FCR and FI (0.49, respectively. Conclusion Thus, selection on RFI was expected to improve feed efficiency, and reduce FI. Selection on RFI thus improves the feed efficiency of animals without impairing their FI and increase growth rate.

  9. Reproductive and population parameters of spiny dogfish Squalus acanthias in the south-western Atlantic Ocean.

    Science.gov (United States)

    Colonello, J H; Cortés, F; Belleggia, M; Massa, A M

    2016-05-01

    The objective of this study was to estimate reproductive and population parameters of the spiny dogfish Squalus acanthias for the south-western Atlantic Ocean. In total, 2714 specimens (1616 males and 1098 females) were collected from surveys carried out using research vessels. Males ranged from 225 to 861 mm total length (LT ) and females from 235 to 925 mm LT . The size at maturity of females (651 mm) was significantly greater than that of males (565 mm). The maximum proportion of mature individuals (Pmax ) of the gestation ogive was 156 mm). The temporal and spatial co-occurrence of non-gravid adult females at different stages of ovarian development, as well as gravid females at all embryonic development stages would indicate that the female reproductive cycle in the south-western Atlantic Ocean is asynchronous. The results indicate that S. acanthias is susceptible to fishing pressure on account of its length at maturity, extended reproductive cycles and low fecundity. © 2016 The Fisheries Society of the British Isles.

  10. Mating system parameters in a high density population of andirobas in the Amazon forest

    Directory of Open Access Journals (Sweden)

    Tatiana de Campos

    2013-05-01

    Full Text Available The objective of this work was to estimate the mating system parameters of a andiroba (Carapa guianensis population using microsatellite markers and the mixed and correlated mating models. Twelve open‑pollinated progeny arrays of 15 individuals were sampled in an area with C. guianensis estimated density of 25.7 trees per hectare. Overall, the species has a mixed reproductive system, with a predominance of outcrossing. The multilocus outcrossing rate (t m = 0.862 was significantly lower than the unity, indicating that self‑pollination occurred. The rate of biparental inbreeding was substantial (t m ‑ t s = 0.134 and significantly different from zero. The correlation of selfing within progenies was high (r s = 0.635, indicating variation in the individual outcrossing rate. Consistent with this result, the estimate of the individual outcrossing rate ranged from 0.598 to 0.978. The multilocus correlation of paternity was low (r p(m = 0.081, but significantly different from zero, suggesting that the progenies contain full‑sibs. The coancestry within progenies (Θ = 0.185 was higher and the variance effective size (Ne(v = 2.7 was lower than expected for true half‑sib progenies (Θ = 0.125; Ne(v = 4. These results suggest that, in order to maintain a minimum effective size of 150 individuals for breeding, genetic conservation, and environmental reforestation programs, seeds from at least 56 trees must be collected.

  11. Spatially explicit inference for open populations: estimating demographic parameters from camera-trap studies.

    Science.gov (United States)

    Gardner, Beth; Reppucci, Juan; Lucherini, Mauro; Royle, J Andrew

    2010-11-01

    We develop a hierarchical capture-recapture model for demographically open populations when auxiliary spatial information about location of capture is obtained. Such spatial capture-recapture data arise from studies based on camera trapping, DNA sampling, and other situations in which a spatial array of devices records encounters of unique individuals. We integrate an individual-based formulation of a Jolly-Seber type model with recently developed spatially explicit capture-recapture models to estimate density and demographic parameters for survival and recruitment. We adopt a Bayesian framework for inference under this model using the method of data augmentation which is implemented in the software program WinBUGS. The model was motivated by a camera trapping study of Pampas cats Leopardus colocolo from Argentina, which we present as an illustration of the model in this paper. We provide estimates of density and the first quantitative assessment of vital rates for the Pampas cat in the High Andes. The precision of these estimates is poor due likely to the sparse data set. Unlike conventional inference methods which usually rely on asymptotic arguments, Bayesian inferences are valid in arbitrary sample sizes, and thus the method is ideal for the study of rare or endangered species for which small data sets are typical.

  12. Population parameters for dose calculations: initial estimates of municipal, city and provincial age group population within 20, 50 and 80 kilometers of the PNPP-1

    International Nuclear Information System (INIS)

    Ramirez, R.A.

    1985-01-01

    The study attempts to determine the total population and population growth rates of four (4) age groups per municipality/city within twenty (20), fifty (50) and eighty (80) kilometers from the Philippine Nuclear Power Plant (PNPP-1). The population estimates were done at five (5) year intervals covering the next fifty years. The latest National Census and Statistics Office (NCSO) population projections at the provincial level under the assumption of moderate fertility and moderate mentality decline (series no. 2) were used to derive the estimates of the total population and population growth rates at the minicipality/city levels. The Bureau of Coastal and Geodetic Survey (BCGS) and the NCSO maps served as the bases for delineating the geographic and political boundaries covered by the study. The results will complement the findings of the PAEC project on agricultural parameters for radiation dose calculations and useful for related environmental studies. (author)

  13. Sequential updating of a new dynamic pharmacokinetic model for caffeine in premature neonates.

    Science.gov (United States)

    Micallef, Sandrine; Amzal, Billy; Bach, Véronique; Chardon, Karen; Tourneux, Pierre; Bois, Frédéric Y

    2007-01-01

    Caffeine treatment is widely used in nursing care to reduce the risk of apnoea in premature neonates. To check the therapeutic efficacy of the treatment against apnoea, caffeine concentration in blood is an important indicator. The present study was aimed at building a pharmacokinetic model as a basis for a medical decision support tool. In the proposed model, time dependence of physiological parameters is introduced to describe rapid growth of neonates. To take into account the large variability in the population, the pharmacokinetic model is embedded in a population structure. The whole model is inferred within a Bayesian framework. To update caffeine concentration predictions as data of an incoming patient are collected, we propose a fast method that can be used in a medical context. This involves the sequential updating of model parameters (at individual and population levels) via a stochastic particle algorithm. Our model provides better predictions than the ones obtained with models previously published. We show, through an example, that sequential updating improves predictions of caffeine concentration in blood (reduce bias and length of credibility intervals). The update of the pharmacokinetic model using body mass and caffeine concentration data is studied. It shows how informative caffeine concentration data are in contrast to body mass data. This study provides the methodological basis to predict caffeine concentration in blood, after a given treatment if data are collected on the treated neonate.

  14. [Advances on pharmacokinetics of traditional Chinese medicine under disease states].

    Science.gov (United States)

    Gong, Zi-peng; Chen, Ying; Zhang, Rui-jie; Yang, Qing; Zhu, Xiao-xin

    2015-01-01

    In recent years, more and more research shows that the pharmacokinetic parameter of traditional Chinese medicine can be affected by the disease states. It's possible that drug metabolic enzymes, transporters, cell membrane permeability and the change of microbes group could be interfered with physiological and pathological changes, which enables the pharmacokinetics of traditional Chinese medicine in the body to be altered, including the process of absorption, distribution, metabolism and excretion, and then the pharmacokinetic parameters of traditional chinese medicine are altered. It's found that investigating the pharmacokinetic of traditional Chinese medicine in the pathological state is more useful than that of in normal state because the great part of traditional Chinese medicine is mainly used to treat disease. This article reflects the latest research on the pharmacokinetic of traditional Chinese medicine in the disease state such as diabete, cerebral ischemia, liver injury, inflammatory disease, nervous system disorders and fever in order to provide certain reference for clinicians designing reasonable administration dose.

  15. Pharmacokinetics of terbutaline in chronic kidney disease.

    Science.gov (United States)

    Bastiansen, Anders; Eggert, Sarah; Pedersen, Erland

    2013-11-01

    In healthy individuals upwards of 90 % of an injected dose of terbutaline is excreted in the urine. The purpose of this study is to determine the pharmacokinetic properties of terbutaline in patients with severe renal impairment as defined by a glomerular filtration rate (GFR) below 30 mL/min. Ten patients were included in the study. GFR was measured with Cr-EDTA clearance. They were given an intravenous injection of 0.500 mg of terbutaline. Blood samples were collected at intervals for 60 h and urine samples were collected for 96 h. The concentration of terbutaline in the blood and in the urine was used to calculate pharmacokinetic parameters. In patients with normal renal function the total clearance of terbutaline is 2.23-3 mL/min/kg. In our population the total clearance of terbutaline was found to be 1.72 (SD: 0.49) mL/min/kg of which approximately 15 % (0.25 mL/min/kg) was renal clearance. We calculated a distribution volume at steady state of 0.74 (SD: 0.22) L/kg with a terminal half-life of 7.93 (SD: 4.06) hours. The mean residence time (MRT) was 8.35 (SD: 4.93) hours. In healthy individuals the excretion of terbutaline is foremost renal but this study shows that severe renal impairment does not lower the total clearance of terbutaline to a degree that might be expected from the Cr-EDTA clearance. However, more research is needed to determine if dosage adjustment is warranted in patients with CKD.

  16. Importance of ethnicity, CYP2B6 and ABCB1 genotype for efavirenz pharmacokinetics and treatment outcomes: a parallel-group prospective cohort study in two sub-Saharan Africa populations.

    Directory of Open Access Journals (Sweden)

    Eliford Ngaimisi

    Full Text Available We evaluated the importance of ethnicity and pharmacogenetic variations in determining efavirenz pharmacokinetics, auto-induction and immunological outcomes in two African populations.ART naïve HIV patients from Ethiopia (n = 285 and Tanzania (n = 209 were prospectively enrolled in parallel to start efavirenz based HAART. CD4+ cell counts were determined at baseline, 12, 24 and 48 weeks. Plasma and intracellular efavirenz and 8-hydroxyefvairenz concentrations were determined at week 4 and 16. Genotyping for common functional CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 variant alleles were done.Patient country, CYP2B6*6 and ABCB1 c.4036A>G (rs3842A>G genotype were significant predictors of plasma and intracellular efavirenz concentration. CYP2B6*6 and ABCB1 c.4036A>G (rs3842 genotype were significantly associated with higher plasma efavirenz concentration and their allele frequencies were significantly higher in Tanzanians than Ethiopians. Tanzanians displayed significantly higher efavirenz plasma concentration at week 4 (pG genotype. Within country analyses indicated a significant decrease in the mean plasma efavirenz concentration by week 16 compared to week 4 in Tanzanians (p = 0.006, whereas no significant differences in plasma concentration over time was observed in Ethiopians (p = 0.84. Intracellular efavirenz concentration and patient country were significant predictors of CD4 gain during HAART.We report substantial differences in efavirenz pharmacokinetics, extent of auto-induction and immunologic recovery between Ethiopian and Tanzanian HIV patients, partly but not solely, due to pharmacogenetic variations. The observed inter-ethnic variations in efavirenz plasma exposure may possibly result in varying clinical treatment outcome or adverse event profiles between populations.

  17. [Distribution, population parameters, and diet of Astropecten marginatus (Asteroidea: Astropectinidae) in the Venezuelan Atlantic coast].

    Science.gov (United States)

    Ortega, Ileana; Martín, Alberto; Díaz, Yusbelly

    2011-03-01

    Astropecten marginatus is a sea star widely distributed in Northern and Eastern South America, found on sandy and muddy bottoms, in shallow and deep waters. To describe some of its ecological characteristics, we calculated it spatial-temporal distribution, population parameters (based on size and weight) and diet in the Orinoco Delta ecoregion (Venezuela). The ecoregion was divided in three sections: Golfo de Paria, Boca de Serpiente and Plataforma Deltana. Samples for the rainy and dry seasons came from megabenthos surveys of the "Línea Base Ambiental Plataforma Deltana (LBAPD)" and "Corocoro Fase I (CFI)" projects. The collected sea stars were measured, weighted and dissected by the oral side to extract their stomach and identify the preys consumed. A total of 570 sea stars were collected in LBAPD project and 306 in CFI one. The highest densities were found during the dry season in almost all sections. In LBAPD project the highest density was in "Plataforma Deltana" section (0.007 +/- 0.022 ind/m2 in dry season and 0.014 +/- 0.06 ind/m2 in rainy season) and in the CFI project the densities in "Golfo de Paria" section were 0.705 +/- 0.829 ind/m2 in rainy season and 1.027 +/- 1.107 ind/m2 in dry season. The most frequent size range was 3.1-4.6cm. The highest biomass was found in "Golfo de Paria" section (7.581 +/- 0.018 mg/m2 in dry season and 0.005 +/- 6.542 x 10(-06) mg/m2 in rainy season for 2004-2005 and 3.979 +/- 4.024 mg/m2 in dry season; and 3.117 +/- 3.137 mg/m2 in rainy season for 2006). A linear relationship was found between the sea star size and its weight but no relationship was observed between its size and the depth where it was collected. Mollusks are dominant in the sea star diet (47.4% in abundance). The diet in any of the sections, seasons or between projects or size class was heterogeneous, using multivariate ordinations (MDS) and SIMPER analysis and there was no difference in the prey number or food elements that a sea star can eat. Although A

  18. Pharmacokinetics: curiosity or cure

    International Nuclear Information System (INIS)

    Notari, R.E.

    1979-01-01

    What is the fate of a drug from the time of its introduction into the body to the end of its duration. Pharmacokinetic studies are often designed to provide an answer to this question. But this question may be asked of any drug and research that is limited to answering it will remain empirical. Pharmacokinetic studies can provide answers to many other drug-related questions. In doing so pharmacokinetic research has the potential of improving drug therapy as well as the design and evaluation of drugs. While significant contributions can be cited, the future of pharmacokinetics depends upon its increased impact on clinical practice and drug design. How can a molecule be tailored for site specificity. Can chemical modification selectively alter absorption, distribution, metabolism, binding or excretion. In what new ways can pharmacokinetic information increase the predictability of drug therapy. Such questions, to which pharmacokinetics should provide answers, are numerous and easily identified. But the definitive studies are difficult both to create and conduct. Whether or not pharmacokinetics can achieve its full potential will depend upon the extent to which it can provide answers to these currently unanswered questions

  19. Lisdexamfetamine: A pharmacokinetic review.

    Science.gov (United States)

    Comiran, Eloisa; Kessler, Félix Henrique; Fröehlich, Pedro Eduardo; Limberger, Renata Pereira

    2016-06-30

    Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used to treat Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED) symptoms. The in vivo pharmacodynamics of LDX is the same as that of its active product d-AMPH, although there are a few qualitative and quantitative differences due to pharmacokinetics. Due to the specific pharmacokinetics of the long-acting stimulants, this article revises the pharmacokinetic studies on LDX, the newest amphetamine pro-drug. The Medline/Pubmed, Science Direct and Biblioteca Virtual em Saúde (Lilacs and Ibecs) (2007-2016) databases were searched for articles and their list of references. As for basic pharmacokinetics studies, since LDX is a newly developed medication, there are few results concerning biotransformation, distribution and the use of different biological matrices for analysis. This is the first robust review on this topic, gathering data from all clinical pharmacokinetics studies available in the literature. The particular pharmacokinetics of LDX plays a major role in studying this pro-drug, since this knowledge was essential to understand some reports on clinical effects in literature, e.g. the small likelihood of reducing the effect by interactions, the effect of long duration use and the still questionable reduction of the potential for abuse. In general the already well-known pharmacokinetic properties of amphetamine make LDX relatively predictable, simplifying the use of LDX in clinical practice. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Sex hormones and quantitative ultrasound parameters at the heel in men and women from the general population

    Directory of Open Access Journals (Sweden)

    Konrad Pätzug

    2017-12-01

    Conclusions: This cross-sectional population-based study revealed independent associations of DHEAS and FT with QUS parameters in men, suggesting a potential influence on male bone metabolism. The predictive role of DHEAS and FT as a marker for osteoporosis in men warrants further investigation in clinical trials and large-scale observational studies.

  1. An interactive program for pharmacokinetic modeling.

    Science.gov (United States)

    Lu, D R; Mao, F

    1993-05-01

    A computer program, PharmK, was developed for pharmacokinetic modeling of experimental data. The program was written in C computer language based on the high-level user-interface Macintosh operating system. The intention was to provide a user-friendly tool for users of Macintosh computers. An interactive algorithm based on the exponential stripping method is used for the initial parameter estimation. Nonlinear pharmacokinetic model fitting is based on the maximum likelihood estimation method and is performed by the Levenberg-Marquardt method based on chi 2 criterion. Several methods are available to aid the evaluation of the fitting results. Pharmacokinetic data sets have been examined with the PharmK program, and the results are comparable with those obtained with other programs that are currently available for IBM PC-compatible and other types of computers.

  2. Inference of some pharmacokinetic parameters of the C mitomycin, through the analysis of its micro nucleate polychromatic erythrocytes induction kinetics; Inferencia de algunos parametros farmacocineticos de la mitomicina C, mediante el analisis de su cinetica de induccion de eritrocitos policromaticos micronucleados

    Energy Technology Data Exchange (ETDEWEB)

    Morales R, P.; Vallarino K, T.; Cruz V, V.; Delgadillo H, A. [ININ, 52045 Ocoyoacac, Estado de Mexico (Mexico)

    2003-07-01

    The objective of the present work was to establish pharmacokinetic parameters of the C Mitomycin (MMC) in vivo, comparing its kinetics of induction of polychromatic micro nucleate erythrocytes (EPGMN) with that of the gamma radiation. The used doses were of 0.75; 1.5 and 3. 0 {mu}moles/kg of MMC. It was observed that the MMC produces MN in the first cycle of cellular division and it is independent of the cytotoxic effect. This agent requires of a relatively long period of latency that is not compatible with her great reactivity, for what the pharmacokinetic values obtained in fact reflect the time that takes the processing of leisure in the DNA and the subsequent induction of ruptures that produce MN. (Author)

  3. Inference from some pharmacokinetic and pharmacodynamic parameters of busulfan through the analysis of its induction kinetics of micronuclei polychromated erythrocytes; Inferencia de algunos parametros farmacocineticos y farmacodinamicos de busulfan, mediante el analisis de su cinetica de induccion de eritrocitos policromaticos micronucleados

    Energy Technology Data Exchange (ETDEWEB)

    Lopez I, M.R.; Vallarino K, T.; Morales R, P. [Instituto Nacional de Investigaciones Nucleares, A.P. 18-1027, 11801 Mexico D.F. (Mexico)

    2001-07-01

    The induction kinetics of micronuclei polychromated eritrocites (EPC-MN) which is produced by busulfan and compared with that produced by the ionizing radiation, allows to make inferences over the pharmacokinetics and pharmacodynamics of busulfan. Observing two induction mechanisms of MN, this one early at low doses and other later at high doses, this last is presented to a critical dose being very sheer and associated with an increase of the cytotoxicity. The data suggest the transformation or dependence between these two types of leisures, which to determine the narrow therapeutical margin of busulfan. The pharmacokinetic parameters determined in the early mechanisms kinetics indicate a latency period, a time of effective activity and of half life 5.7, 5.2 and 2.6 h respectively. (Author)

  4. [FINDRISC Test: Relationship between cardiovascular risk parameters and scales in Spanish Mediterranean population].

    Science.gov (United States)

    López-González, Ángel Arturo; García-Agudo, Sheila; Tomás-Salvá, Matías; Vicente-Herrero, María Teófila; Queimadelos-Carmona, Milagros; Campos-González, Irene

    2017-01-01

    The Finnish Diabetes Risk Score (FINDRISC) questionnaire has been used to assess the risk of type 2 diabetes and metabolic syndrome. The objetive was to assess the relationship between different scales related to cardiovascular risk and FINDRISC questionnaire. Values of different anthropometric and clinical parameters (body mass index, waist circumference, waist to height ratio, blood pressure), analytical parameters (lipid profile, blood glucose) and scales related to cardiovascular risk (atherogenic index, metabolic syndrome, REGICOR, SCORE, heart age and vascular age) were determined on the basis of the value of the FINDRISC questionnaire. All analyzed parameters related to cardiovascular risk were getting worse at the same time that the value of the FINDRISC questionnaire increased. There is a close relationship between FINDRISC questionnaire values and those obtained in the different parameters by which cardiovascular risk was measured directly or indirectly.

  5. Derivation of cell population kinetic parameters from clinical statistical data (program RAD3)

    International Nuclear Information System (INIS)

    Cohen, L.

    1978-01-01

    Cellular lethality models generally require up to 6 parameters to simulate a clinical course of fractionated radiation therapy and to derive an estimate of the cellular surviving fraction for a given treatment scheme. These parameters are the mean cellular lethal dose, the extrapolation number, the ratio of sublethal to irreparable events, the regeneration rate, the repopulation limit (cell cycles), and a field-size or tumor-volume factor. A computer program (RAD3) was designed to derive best-fitting values for these parameters in relation to available clinical data based on the assumption that if a number of different fractionation schemes yield similar reactions, the cellular surviving fractions will be about equal in each instance. Parameters were derived for a variety of human tissues from which realistic iso-effect functions could be generated

  6. COMPARATIVE DESCRIPTION OF POPULATION PARAMETERS OF THE LIFE QUALITY OF INHABITANTS OF DAKHADAEV DISTRICT, REPUBLIC OF DAGESTAN

    Directory of Open Access Journals (Sweden)

    Patimat Asadullamagomedowna Bekshokova

    2015-01-01

    Full Text Available The study presents the population indices of the life quality of inhabitants of Dakhadaev district, Republic of Dagestan. The study was conducted using a questionnaire SF-36. The regularities of the age-and gender changes of parameters of the life quality were identified. The highest rate in the analyzed settlements was marked on a scale of social functioning, the lowest – on the scale of overall health. The integral indexes of men were higher in all age groups than those of women. The highest parameters of the integral index of the male and female population were fixed in the age-group to 35. The most gender differences are noted on the scale of the role-physical functioning, the least on the scale of social functioning. In whole with age increasing we saw lowering parameters of indices of the life quality as in male group, so in female one. Besides the most changes in indices of the life quality were on the scale of role-physical functioning. Minimal differences in age groups were observed on the scales of social functioning and mental health. Women have more age lowering of indices of the life quality than men exceptthe role-physical functioning and social functioning. The highest parameter of the integral index of the life quality was observed in Zilbachi administrative settlement, the lowest one – in Kharbuk settlement of Dakhadaev district, Republic of Dagestan. The data of population study of the life quality give the information about indices of the life quality of population, reflecting in such a way the degree of its physical, psychological and social wellbeing. This information allows to estimate the efficiency of realization different medical and social and economic programs, aiming to improvement of the life quality of the population, rising the level of its wellbeing.Aim. The aim of this work was a pilot study of population indices of the life quality of inhabitants of Dakhadaev district, Republic of Dagestan

  7. Influence of Chemical Parameters on Artemia sp. (Crustacea: Anostraca Population in Al Wathba Lake in the Abu Dhabi Emirate, UAE

    Directory of Open Access Journals (Sweden)

    Anitha Saji

    2016-04-01

    Full Text Available Long term monitoring programme on Brine shrimp (Artemia sp. is being carried out by the Environment Agency, Abu Dhabi, United Arab Emirates (EAD with the prime purpose of understanding the population dynamics, ecology and habitat requirements of Artemia at Al Wathba Lake, situated within Al Wathba Wetland Reserve, which is an artificial wetland near Abu Dhabi City. The present study, being a component of this programme, intends to understand the influence of chemical parameters such as dissolved oxygen, nitrate, nitrite, phosphate, ammonia and total organic carbon on Artemia biomass and cyst production at different sites of the Al Wathba Lake. The study was carried out by sampling lake water quarterly for a period of 5 years from 2010 to 2014. The Artemia population was found to have direct impact of the above mentioned parameters on its abundance. The abundance was highest during the year 2010. Further, temperature, dissolved oxygen, nitrate and cadmium were found to be the most crucial parameters for production of Artemia. The study further aimed to determine the significant relationship between physico-chemical parameters and Artemia sp. population dynamics and cyst production.

  8. Application of new genetic approaches to obtain population vital rate parameters in leatherbacks

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — This project addresses major gaps in knowledge on vital rates such as age to maturity, survival, sex ratios, and population size (including the males)whcih have made...

  9. Influence of Population Variation of Physiological Parameters in Computational Models of Space Physiology

    Science.gov (United States)

    Myers, J. G.; Feola, A.; Werner, C.; Nelson, E. S.; Raykin, J.; Samuels, B.; Ethier, C. R.

    2016-01-01

    The earliest manifestations of Visual Impairment and Intracranial Pressure (VIIP) syndrome become evident after months of spaceflight and include a variety of ophthalmic changes, including posterior globe flattening and distension of the optic nerve sheath. Prevailing evidence links the occurrence of VIIP to the cephalic fluid shift induced by microgravity and the subsequent pressure changes around the optic nerve and eye. Deducing the etiology of VIIP is challenging due to the wide range of physiological parameters that may be influenced by spaceflight and are required to address a realistic spectrum of physiological responses. Here, we report on the application of an efficient approach to interrogating physiological parameter space through computational modeling. Specifically, we assess the influence of uncertainty in input parameters for two models of VIIP syndrome: a lumped-parameter model (LPM) of the cardiovascular and central nervous systems, and a finite-element model (FEM) of the posterior eye, optic nerve head (ONH) and optic nerve sheath. Methods: To investigate the parameter space in each model, we employed Latin hypercube sampling partial rank correlation coefficient (LHSPRCC) strategies. LHS techniques outperform Monte Carlo approaches by enforcing efficient sampling across the entire range of all parameters. The PRCC method estimates the sensitivity of model outputs to these parameters while adjusting for the linear effects of all other inputs. The LPM analysis addressed uncertainties in 42 physiological parameters, such as initial compartmental volume and nominal compartment percentage of total cardiac output in the supine state, while the FEM evaluated the effects on biomechanical strain from uncertainties in 23 material and pressure parameters for the ocular anatomy. Results and Conclusion: The LPM analysis identified several key factors including high sensitivity to the initial fluid distribution. The FEM study found that intraocular pressure and

  10. [Research progress on current pharmacokinetic evaluation of Chinese herbal medicines].

    Science.gov (United States)

    Li, Guofu; Zhao, Haoru; Yang, Jin

    2011-03-01

    In order to prove safety and efficacy, herbal medicines must undergo the rigorous scientific researches such as pharmacokinetic and bioavailability, before they are put on the market in the foreign countries. Botanical Drug Products promulgated by the US FDA could guide industry sponsors to develop herbal drugs, which was also an important reference for investigating Chinese herbal medicines. This paper reviews and discusses novel approaches for how to assess systemic exposure and pharmacokinetic of Chinese herbal medicines, which were in line with FDA guidance. This mainly focus on identifying pharmacokinetic markers of botanical products, integral pharmacokinetic study of multiple components, Biopharmaceutics drug disposition classification system, and population pharmacokinetic-pharmacodynamic study in herb-drug interaction.

  11. Pharmacokinetics of Snake Venom

    OpenAIRE

    Suchaya Sanhajariya; Stephen B. Duffull; Geoffrey K. Isbister

    2018-01-01

    Understanding snake venom pharmacokinetics is essential for developing risk assessment strategies and determining the optimal dose and timing of antivenom required to bind all venom in snakebite patients. This review aims to explore the current knowledge of snake venom pharmacokinetics in animals and humans. Literature searches were conducted using EMBASE (1974–present) and Medline (1946–present). For animals, 12 out of 520 initially identified studies met the inclusion criteria. In general, ...

  12. [Role of "Health" National project in improvement of health parameters in working population].

    Science.gov (United States)

    Bykovskaia, T Iu

    2011-01-01

    The author analyzed results of "Health" National project accomplishment in Rostov region over 2006-2009. Findings are that quality of primary medical care has improved, material and technical basis of municipal health care institutions has progressed, salary of primary health care division specialists has increased. Over this period, infant mortality and mortality among able-bodied population in the region has decreased, birth rate has increased, coefficient of natural loss of population has reduced, life expectancy has increased.

  13. Analysis of changes of demographic parameters in different groups of Chernigiv region population

    International Nuclear Information System (INIS)

    Gridzhuk, M.Yu.

    1998-01-01

    To perform comparison of the changes in different social and age groups of the population of Chernigiv region, Kozeletsky district in particular, which was exposed to considerable radioactive contamination, during the recent 20 years (beginning from 1977). The Chernobyl accident together with social and other unfavorable factors caused negative demographic changes in the contaminated districts. Reduction in the number of different social groups of the population is expected

  14. Population pharmacokinetics of busulfan in pediatric and young adult patients undergoing hematopoietic cell transplant: a model-based dosing algorithm for personalized therapy and implementation into routine clinical use.

    Science.gov (United States)

    Long-Boyle, Janel R; Savic, Rada; Yan, Shirley; Bartelink, Imke; Musick, Lisa; French, Deborah; Law, Jason; Horn, Biljana; Cowan, Morton J; Dvorak, Christopher C

    2015-04-01

    Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared with conventional dose guidelines. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration at steady state) and implement a simple model-based tool for the initial dosing of busulfan in children undergoing hematopoietic cell transplantation. Model development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone hematopoietic cell transplantation with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the nonlinear mixed effects modeling software, NONMEM. The final population PK model was implemented into a clinician-friendly Microsoft Excel-based tool and used to recommend initial doses of busulfan in a group of 21 pediatric patients prospectively dosed based on the population PK model. Modeling of busulfan time-concentration data indicates that busulfan clearance displays nonlinearity in children, decreasing up to approximately 20% between the concentrations of 250-2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan clearance were actual body weight and age. The percentage of individuals achieving a therapeutic concentration at steady state was significantly higher in subjects receiving initial doses based on the population PK model (81%) than in historical controls dosed on conventional guidelines (52%) (P = 0.02). When compared with the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in

  15. Uncertainty in population growth rates: determining confidence intervals from point estimates of parameters.

    Directory of Open Access Journals (Sweden)

    Eleanor S Devenish Nelson

    Full Text Available BACKGROUND: Demographic models are widely used in conservation and management, and their parameterisation often relies on data collected for other purposes. When underlying data lack clear indications of associated uncertainty, modellers often fail to account for that uncertainty in model outputs, such as estimates of population growth. METHODOLOGY/PRINCIPAL FINDINGS: We applied a likelihood approach to infer uncertainty retrospectively from point estimates of vital rates. Combining this with resampling techniques and projection modelling, we show that confidence intervals for population growth estimates are easy to derive. We used similar techniques to examine the effects of sample size on uncertainty. Our approach is illustrated using data on the red fox, Vulpes vulpes, a predator of ecological and cultural importance, and the most widespread extant terrestrial mammal. We show that uncertainty surrounding estimated population growth rates can be high, even for relatively well-studied populations. Halving that uncertainty typically requires a quadrupling of sampling effort. CONCLUSIONS/SIGNIFICANCE: Our results compel caution when comparing demographic trends between populations without accounting for uncertainty. Our methods will be widely applicable to demographic studies of many species.

  16. Detecting recent changes in the demographic parameters of drosophilid populations from western and central Africa

    Science.gov (United States)

    Bouiges, Axelle; Yassin, Amir; Ikogou, Maya; Lelarge, Clément; Sikoa, Axelle-Rolande; Mona, Stefano; Veuille, Michel

    2013-07-01

    Previous genetic studies showing evidence of past demographic changes in African drosophilids suggested that these populations had strongly responded to Quaternary climate changes. We surveyed nine species of Zaprionus, a drosophilid genus mostly present in Africa, in forests located between southern Senegal and Gabon. The mitochondrial COI gene showed contrasted levels of sequence variation across species. Populations of the only cosmopolitan species of the genus, Z. indianus, and of its closely related sibling species, Z. africanus, are highly polymorphic and appear to have undergone a continuous population expansion beginning about 130,000 years ago. Five less variable species probably underwent a population expansion beginning only about 20,000-30,000 years ago. One of them, Z. taronus, was significantly structured between forest blocks. The last two species were nearly monomorphic, probably due to infection by Wolbachia. These results are similar to those obtained in three species from the melanogaster subgroup, and may be typical of the responses of African drosophilid populations to glacial cycles.

  17. Numerical solution of a logistic growth model for a population with Allee effect considering fuzzy initial values and fuzzy parameters

    Science.gov (United States)

    Amarti, Z.; Nurkholipah, N. S.; Anggriani, N.; Supriatna, A. K.

    2018-03-01

    Predicting the future of population number is among the important factors that affect the consideration in preparing a good management for the population. This has been done by various known method, one among them is by developing a mathematical model describing the growth of the population. The model usually takes form in a differential equation or a system of differential equations, depending on the complexity of the underlying properties of the population. The most widely used growth models currently are those having a sigmoid solution of time series, including the Verhulst logistic equation and the Gompertz equation. In this paper we consider the Allee effect of the Verhulst’s logistic population model. The Allee effect is a phenomenon in biology showing a high correlation between population size or density and the mean individual fitness of the population. The method used to derive the solution is the Runge-Kutta numerical scheme, since it is in general regarded as one among the good numerical scheme which is relatively easy to implement. Further exploration is done via the fuzzy theoretical approach to accommodate the impreciseness of the initial values and parameters in the model.

  18. Application of morphological and physiological parameters representative of a sample Brazilian population in the human respiratory tract model

    International Nuclear Information System (INIS)

    Reis, A.A.; Cardoso, J.C.S.; Lourenco, M.C.

    2005-01-01

    Full text: The Human Respiratory Tract Model (HRTM) proposed in ICRP Publication 66 account for the morphology and physiology of the respiratory tract. The characteristics of air drawn into the lungs and exhaled are greatly influenced by the morphology of the respiratory tract, which causes numerous changes in pressure, flow rate, direction and humidity as air moves into and out of the lungs. These changing characteristics can influence the rates and the sites of deposition. Concerning the respiratory physiological parameters the breathing characteristics influence the volume, the inhalation rate of air and the portion that enters through the nose and the mouth. These characteristics are important to determine the fractional deposition. The HRTM model uses morphological and physiological parameters from the Caucasian man to establish deposition fractions in the respiratory tract regions. lt is known that the morphology and physiology are influenced by environmental, occupational and economic conditions. The ICRP recommends for a reliable evaluation of the regional deposition the use of parameters from a local population when information is available. The main purpose of this study is to verify the influence in using the morphology and physiology parameters representative of a sample of the Brazilian population on the deposition model of ICRP Publication 66. The morphological and physiological data were obtained from the literature. The software EXCEL for Windows (version 2000) was used in order to implement the deposition model and also to allow the changes in parameters of interest. Initially, the implemented model was checked using the parameters defined in ICRP and the results of the fraction deposition in the respiratory tract compartments were compared. Finally, morphological and physiological parameters from Brazilian adult male were applied and the fractional deposition calculated. The respiratory values at different levels of activity for ages varying from

  19. Application of morphological and physiological parameters representative of a Brazilian population sample in the respiratory tract model

    International Nuclear Information System (INIS)

    Dos Reis, A. A.; Cardoso, J. C. S.; Lourenco, M. C.

    2007-01-01

    The human respiratory tract model (HRTM) adopted by ICRP in its Publication 66 accounts for the morphology and physiology of the respiratory tract. The characteristics of air drawn into the lungs and exhaled are greatly influenced by the morphology of the respiratory tract, which causes numerous changes in pressure, flow rate, direction and humidity as air moves into and out of the lungs. These characteristics are important to determine the fractional deposition. It is known that the morphology and physiology are influenced by environmental, occupational and economic conditions. The ICRP recommends, for a reliable evaluation of the regional deposition, the use of parameters from a local population wherever such information is available. The main purpose of this study is to verify the influence of using the morphology and physiology parameters representative of a sample of the Brazilian population on the deposition model of the ICRP Publication 66 model. (authors)

  20. Connection between Dynamically Derived Initial Mass Function Normalization and Stellar Population Parameters

    NARCIS (Netherlands)

    McDermid, Richard M.; Cappellari, Michele; Alatalo, Katherine; Bayet, Estelle; Blitz, Leo; Bois, Maxime; Bournaud, Frédéric; Bureau, Martin; Crocker, Alison F.; Davies, Roger L.; Davis, Timothy A.; de Zeeuw, P. T.; Duc, Pierre-Alain; Emsellem, Eric; Khochfar, Sadegh; Krajnović, Davor; Kuntschner, Harald; Morganti, Raffaella; Naab, Thorsten; Oosterloo, Tom; Sarzi, Marc; Scott, Nicholas; Serra, Paolo; Weijmans, Anne-Marie; Young, Lisa M.

    We report on empirical trends between the dynamically determined stellar initial mass function (IMF) and stellar population properties for a complete, volume-limited sample of 260 early-type galaxies from the ATLAS3D project. We study trends between our dynamically derived IMF normalization αdyn ≡

  1. Food intake, nutritional anthropometry and blood chemical parameters in 3 selected Dutch schoolchildren populations

    NARCIS (Netherlands)

    Haar, van der F.; Kromhout, D.

    1978-01-01

    The major health problems in populations of economically developed countries at the present time are of a chronic nature with, as their main clinical characteristic, the frequently occurring premature coronary heart disease. When food intake data are to be evaluated, it would be incorrect

  2. Constitution and anthropometric parameters in indigenous population of Southern Altai Mountains.

    Science.gov (United States)

    Sayapin, V S; Schmidt, I R; Podkhomutnikova, O V; Van, V Ch; Van, L V; Malevik, V F; Zhestikova, M G

    2003-03-01

    Analysis of anthropometric parameters of 645 indigenous residents of Southern Altai Mountains belonging to two subethnic groups (165 Telengites and 480 Altai-Kizhi) revealed constitutional characteristics distinguishing these groups from each other and from Europeans. Differences in body length and weight, distribution by constitution types, sexual dimorphism, and AB0 blood groups were detected. The specific features of constitution together with environmental factors can determine predisposition of individuals belonging of these subethnic groups to some diseases.

  3. Pharmacokinetics, efficacy prediction indexes and residue depletion of antibacterial drugs.

    Directory of Open Access Journals (Sweden)

    Arturo Anadón

    2016-06-01

    Full Text Available Pharmacokinetics behaviour of the antibacterial in food producing animals, provides information on the rates of absorption and elimination, half-life in plasma and tissue, elimination pathways and metabolism. The dose and the dosing interval of the antimicrobial can be justified by considering the pharmacokinetic/pharmacodynamic (PK/PD relationship, if established, as well as the severity of the disease, whereas the number of administrations should be in line with the nature of the disease. The target population for therapy should be well defined and possible to identify under field conditions. Based on in vitro susceptibility data, and target animal PK data, an analysis for the PK/PD relationship may be used to support dose regimen selection and interpretation criteria for a clinical breakpoint. Therefore, for all antibacterials with systemic activity, the MIC data collected should be compared with the concentration of the compound at the relevant biophase following administration at the assumed therapeutic dose as recorded in the pharmacokinetic studies. Currently, the most frequently used parameters to express the PK/PD relationship are Cmax/MIC (maximum serum concentration/MIC, %T > MIC (fraction of time in which concentration exceeds MIC and AUC/MIC (area under the inhibitory concentration– time curve/MIC. Furthermore, the pharmacokinetic parameters provide the first indication of the potential for persistent residues and the tissues in which they may occur. The information on residue depletion in food-producing animals, provides the data on which MRL recommendations will be based. A critical factor in the antibacterial medication of all food-producing animals is the mandatory withdrawal period, defined as the time during which drug must not be administered prior to the slaughter of the animal for consumption. The withdrawal period is an integral part of the regulatory authorities’ approval process and is designed to ensure that no

  4. Assessment of chronic kidney disease using skin texture as a key parameter: for South Indian population.

    Science.gov (United States)

    Udhayarasu, Madhanlal; Ramakrishnan, Kalpana; Periasamy, Soundararajan

    2017-12-01

    Periodical monitoring of renal function, specifically for subjects with history of diabetic or hypertension would prevent them from entering into chronic kidney disease (CKD) condition. The recent increase in numbers may be due to food habits or lack of physical exercise, necessitates a rapid kidney function monitoring system. Presently, it is determined by evaluating glomerular filtration rate (GFR) that is mainly dependent on serum creatinine value and demographic parameters and ethnic value. Attempted here is to develop ethnic parameter based on skin texture for every individual. This value when used in GFR computation, the results are much agreeable with GFR obtained through standard modification of diet in renal disease and CKD epidemiology collaboration equations. Once correlation between CKD and skin texture is established, classification tool using artificial neural network is built to categorise CKD level based on demographic values and parameter obtained through skin texture (without using creatinine). This network when tested gives almost at par results with the network that is trained with demographic and creatinine values. The results of this Letter demonstrate the possibility of non-invasively determining kidney function and hence for making a device that would readily assess the kidney function even at home.

  5. [Population genetic study of Russian cosmonauts and test subjects: genetic demographic parameters and immunogenetic markers].

    Science.gov (United States)

    Kurbatova, O L; Pobedonostseva, E Iu; Prokhorovskaia, V D; Kholod, O N; Evsiukov, A N; Bogomolov, V V; Voronkov, Iu I; Filatova, L M; Larina, O N; Sidorenko, L A; Morgun, V V; Kasparanskiĭ, R R; Altukhov, Iu P

    2006-10-01

    Genetic demographic characteristics and immunogenetic markers (blood groups ABO, Rhesus, MNSs, P, Duffy, Kidd, and Kell) have been studied in a group of 132 Russian cosmonauts and test subjects (CTSG). Analysis of pedigrees has shown a high exogamy in the preceding generations: almost half of the subjects have mixed ethnic background. According to the results of genetic demographic analysis, a sample from the Moscow population was used as control group (CG). Comparison between the CTSG and CG has demonstrated significant differences in genotype frequencies for several blood group systems. The CTSG is characterized by a decreased proportion of rare interlocus genotypic combinations and an increased man heterozygosity. Analysis of the distributions of individual heterozygosity for loci with codominant expression of alleles has shown that highly heterozygous loci are more frequent in the CTSG. Taking into account that the CTSG has been thoroughly selected from the general population, it is concluded that heterozygosity is related to successful adaptation to a space flight.

  6. Population Parameters of Blainville’s and Cuvier’s Beaked Whales

    Science.gov (United States)

    2014-09-30

    waters, they are usually difficult to study. El Hierro (Canary Islands) holds resident populations of Blainville’s and Cuvier’s beaked whales in...surveys off El Hierro , according to plan. Four of these cruises took place since the last report in September 2013, summing 38 days of fieldwork performed...marks as to be individually recognizable. 3 Publication of results of the ONR funded cetacean research in El Hierro in 2014 Peer reviewed

  7. Estimation of demographic parameters in a tiger population from long-term camera trap data

    Science.gov (United States)

    Karanth, K. Ullas; Nichols, James D.; O'Connell, Allan F.; Nichols, James D.; Karanth, K. Ullas

    2011-01-01

    Chapter 7 (Karanth et al.) illustrated the use of camera trapping in combination with closed population capture–recapture (CR) models to estimate densities of tigers Panthera tigris. Such estimates can be very useful for investigating variation across space for a particular species (e.g., Karanth et al. 2004) or variation among species at a specific location. In addition, estimates of density continued at the same site(s) over multiple years are very useful for understanding and managing populations of large carnivores. Such multi-year studies can yield estimates of rates of change in abundance. Additionally, because the fates of marked individuals are tracked through time, biologists can delve deeper into factors driving changes in abundance such as rates of survival, recruitment and movement (Williams et al. 2002). Fortunately, modern CR approaches permit the modeling of populations that change between sampling occasions as a result of births, deaths, immigration and emigration (Pollock et al. 1990; Nichols 1992). Some of these early “open population” models focused on estimation of survival rates and, to a lesser extent, abundance, but more recent models permit estimation of recruitment and movement rates as well.

  8. UNCERTAINTIES IN TRICHLOROETHYLENE PHARMACOKINETIC MODELS

    Science.gov (United States)

    Understanding the pharmacokinetics of a chemical¯its absorption, distribution, metabolism, and excretion in humans and laboratory animals ¯ is critical to the assessment of its human health risks. For trichloroethylene (TCE), numerous physiologically-based pharmacokinetic (PBPK)...

  9. Steady-State Clozapine and Norclozapine Pharmacokinetics in Maori and European Patients.

    Science.gov (United States)

    Menkes, David B; Glue, Paul; Gale, Christopher; Lam, Frederic; Hung, Cheung-Tak; Hung, Noelyn

    2018-01-01

    Clozapine is the most effective drug for treatment-resistant schizophrenia, but its use is limited by toxicity. Because ethnicity has been reported to affect clozapine metabolism, we compared its steady state pharmacokinetics in New Zealand Maori and European patients. Clozapine and norclozapine steady state bioavailability was assessed over 24h under fasting and fed conditions in 12 Maori and 16 European patients treated for chronic psychotic illnesses with stable once-daily clozapine doses. Plasma clozapine and norclozapine concentrations were assessed using liquid chromatography with tandem mass spectrometry; pharmacokinetic parameters were calculated using standard non-compartmental methods, and compared using unpaired t-tests. Mean pharmacokinetic parameters (AUC, C max and C min ) for clozapine and norclozapine were virtually identical in Maori and European subjects, under both fed and fasted conditions. Clozapine bioavailability does not vary between Maori and European patients, and thus does not need to be considered in prescribing decisions. Additional studies are needed to identify if there are differences between Maori and European populations for drugs metabolized by other enzyme pathways. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  10. Population Structures in Russia: Optimality and Dependence on Parameters of Global Evolution

    Directory of Open Access Journals (Sweden)

    Yuri Yegorov

    2016-07-01

    Full Text Available The paper is devoted to analytical investigation of the division of geographical space into urban and rural areas with application to Russia. Yegorov (2005, 2006, 2009 has suggested the role of population density on economics. A city has an attractive potential based on scale economies. The optimal city size depends on the balance between its attractive potential and the cost of living that can be approximated by equilibrium land rent and commuting cost. For moderate scale effects optimal population of a city depends negatively on transport costs that are related positively with energy price index. The optimal agricultural density of population can also be constructed. The larger is a land slot per peasant, the higher will be the output from one unit of his labour force applied to this slot. But at the same time, larger farm size results in increase of energy costs, related to land development, collecting the crop and bringing it to the market. In the last 10 years we have observed substantial rise of both food and energy prices at the world stock markets. However, the income of farmers did not grow as fast as food price index. This can shift optimal rural population density to lower level, causing migration to cities (and we observe this tendency globally. Any change in those prices results in suboptimality of existing spatial structures. If changes are slow, the optimal infrastructure can be adjusted by simple migration. If the shocks are high, adaptation may be impossible and shock will persist. This took place in early 1990es in the former USSR, where after transition to world price for oil in domestic markets existing spatial infrastructure became suboptimal and resulted in persistent crisis, leading to deterioration of both industry and agriculture. Russia is the largest country but this is also its problem. Having large resource endowment per capita, it is problematic to build sufficient infrastructure. Russia has too low population

  11. Population Pharmacokinetic Characteristics of Amikacin in Suspected Cases of Neonatal Sepsis in a Low-Resource African Setting: A Prospective Nonrandomized Single-Site Study

    Directory of Open Access Journals (Sweden)

    Seth K. Amponsah, PhD

    2017-01-01

    Conclusions: The V and half-life of amikacin in this cohort varied from that reported in non-African populations, and the high trough and low peak amikacin concentrations in both term and preterm neonates suggest strategies to optimize amikacin dosing are required in this population.

  12. Prediction of the Pharmacokinetics, Pharmacodynamics, and Efficacy of a Monoclonal Antibody, Using a Physiologically Based Pharmacokinetic FcRn Model

    Science.gov (United States)

    Chetty, Manoranjenni; Li, Linzhong; Rose, Rachel; Machavaram, Krishna; Jamei, Masoud; Rostami-Hodjegan, Amin; Gardner, Iain

    2015-01-01

    Although advantages of physiologically based pharmacokinetic models (PBPK) are now well established, PBPK models that are linked to pharmacodynamic (PD) models to predict pharmacokinetics (PK), PD, and efficacy of monoclonal antibodies (mAbs) in humans are uncommon. The aim of this study was to develop a PD model that could be linked to a physiologically based mechanistic FcRn model to predict PK, PD, and efficacy of efalizumab. The mechanistic FcRn model for mAbs with target-mediated drug disposition within the Simcyp population-based simulator was used to simulate the pharmacokinetic profiles for three different single doses and two multiple doses of efalizumab administered to virtual Caucasian healthy volunteers. The elimination of efalizumab was modeled with both a target-mediated component (specific) and catabolism in the endosome (non-specific). This model accounted for the binding between neonatal Fc receptor (FcRn) and efalizumab (protective against elimination) and for changes in CD11a target concentration. An integrated response model was then developed to predict the changes in mean Psoriasis Area and Severity Index (PASI) scores that were measured in a clinical study as an efficacy marker for efalizumab treatment. PASI scores were approximated as continuous and following a first-order asymptotic progression model. The reported steady state asymptote (Y ss) and baseline score [Y (0)] was applied and parameter estimation was used to determine the half-life of progression (Tp) of psoriasis. Results suggested that simulations using this model were able to recover the changes in PASI scores (indicating efficacy) observed during clinical studies. Simulations of both single dose and multiple doses of efalizumab concentration-time profiles as well as suppression of CD11a concentrations recovered clinical data reasonably well. It can be concluded that the developed PBPK FcRn model linked to a PD model adequately predicted PK, PD, and efficacy of efalizumab. PMID

  13. Sex hormones and quantitative ultrasound parameters at the heel in men and women from the general population.

    Science.gov (United States)

    Pätzug, Konrad; Friedrich, Nele; Kische, Hanna; Hannemann, Anke; Völzke, Henry; Nauck, Matthias; Keevil, Brian G; Haring, Robin

    2017-12-01

    The present study investigates potential associations between liquid chromatography-mass spectrometry (LC-MS) measured sex hormones, dehydroepiandrosterone sulphate, sex hormone-binding globulin (SHBG) and bone ultrasound parameters at the heel in men and women from the general population. Data from 502 women and 425 men from the population-based Study of Health in Pomerania (SHIP-TREND) were used. Cross-sectional associations of sex hormones including testosterone (TT), calculated free testosterone (FT), dehydroepiandrosterone sulphate (DHEAS), androstenedione (ASD), estrone (E1) and SHBG with quantitative ultrasound (QUS) parameters at the heel, including broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (SI) were examined by analysis of variance (ANOVA) and multivariable quantile regression models. Multivariable regression analysis showed a sex-specific inverse association of DHEAS with SI in men (Beta per SI unit = - 3.08, standard error (SE) = 0.88), but not in women (Beta = - 0.01, SE = 2.09). Furthermore, FT was positively associated with BUA in men (Beta per BUA unit = 29.0, SE = 10.1). None of the other sex hormones (ASD, E1) or SHBG was associated with QUS parameters after multivariable adjustment. This cross-sectional population-based study revealed independent associations of DHEAS and FT with QUS parameters in men, suggesting a potential influence on male bone metabolism. The predictive role of DHEAS and FT as a marker for osteoporosis in men warrants further investigation in clinical trials and large-scale observational studies.

  14. Pharmacokinetic study of mycophenolic acid in Iranian kidney transplant patients

    Directory of Open Access Journals (Sweden)

    Saeed Rezaee

    2013-02-01

    Full Text Available Background: The purpose of this study was to characterize the pharmacokinetic parameters of mycophenolic acid (MPA in Iranian kidney transplant patients. Methods: Plasma MPA concentration of mycophenolate mofetile (MMF 1 gram two times a day was measured in 21 Iranian kidney transplant recipients receiving treatment. Patients who entered the study had been transplanted for more than 3 months and their drug level was supposed to be at steady state. MMF concentration was measured with high-performance liquid chromatography (HPLC. Results: The plasma MPA concentration-time curve was characterized by an early sharp peak at about 1 hour postdose. The mean Area Under Curve (AUC, Cmax and Tmax were 47.0±18.3 µg.h/ml, 18.6±8.5 µg/ml and 1.0±0.5 hours respectively. Conclusion: The plasma MPA concentration-time curve pattern of Iranian patients was similar and consistent with previously reported profiles in other populations taking the same dose. Keywords: Mycophenolate mofetil, Mycophenolic acid, Pharmacokinetics, Area Under Curve, Kidney transplantation

  15. Dose selection based on physiologically based pharmacokinetic (PBPK) approaches.

    Science.gov (United States)

    Jones, Hannah M; Mayawala, Kapil; Poulin, Patrick

    2013-04-01

    Physiologically based pharmacokinetic (PBPK) models are built using differential equations to describe the physiology/anatomy of different biological systems. Readily available in vitro and in vivo preclinical data can be incorporated into these models to not only estimate pharmacokinetic (PK) parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. They provide a mechanistic framework to understand and extrapolate PK and dose across in vitro and in vivo systems and across different species, populations and disease states. Using small molecule and large molecule examples from the literature and our own company, we have shown how PBPK techniques can be utilised for human PK and dose prediction. Such approaches have the potential to increase efficiency, reduce the need for animal studies, replace clinical trials and increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however some limitations need to be addressed to realise its application and utility more broadly.

  16. The relationship between anthropometric parameters and bone mineral density in an Iranian referral population.

    Directory of Open Access Journals (Sweden)

    Akbar Soltani

    2014-07-01

    Full Text Available Osteoporosis is a common health concern in both developed and developing countries. In this study the association between anthropometric measures and osteoporosis was investigated in 3630 males and females visiting BMD clinic of Shariati Hospital, Tehran, Iran, a teaching hospital and referral center for osteoporosis affiliated to the Tehran University of Medical Sciences. Anthropometric measurements obtained and also Bone Mineral Density (BMD measurement was done using a Lunar DPXMD densitometer. Data were analyzed using SPSS with Chi-square and ANOVA with post-hoc tests. Results showed that the weight, BMI and age had the strongest correlation with the BMD values in the studied people. While age is negatively correlated with BMD in all the studied people, a positive association was noted between weight, height and BMI and BMD parameters (P<0.01. It was concluded that certain anthropometric parameters (BMI and weight can considerably affect one's risk of developing osteoporosis. Further research on the effect of these variables on the association of weight and BMD is needed.

  17. Absorption and pharmacokinetics of grapefruit flavanones in beagles

    OpenAIRE

    Mata Bilbao, María de Lourdes; Andrés Lacueva, Ma. Cristina; Roura Carvajal, Elena; Jáuregui Pallarés, Olga; Escribano Ferrer, Elvira; Torre, Celina; Lamuela Raventós, Rosa Ma.

    2007-01-01

    The present study evaluated the pharmacokinetics of three different grapefruit flavanone forms in dog plasma and demonstrated their absorption after an oral intake of a grapefruit extract; pharmacokinetic parameters of these forms were also determined. Ten healthy beagles were administered 70 mg citrus flavonoids as a grapefruit extract contained in capsules, while two additional dogs were used as controls and given an excipient. The grapefruit flavanone naringin, along with its metabolites n...

  18. HPLC assay for ethiofos in plasma: Application to pharmacokinetics in the beagle dog

    International Nuclear Information System (INIS)

    Swynnerton, N.F.; Mangold, D.J.; Ludden, T.M.

    1985-01-01

    An HPLC assay for ethiofos [S-2-(3-amino-propylamino)ethyl phosphorothioate, WR 2727] in plasma is presented. Its application to the development of pharmacokinetic parameters following IV administration of the drug to beagle dogs is demonstrated and preliminary pharmacokinetics of four dosings will be presented. Following a dose of 150 mg kg -1 , the plasma concentration versus time profile was best described by a two-compartment pharmacokinetics model. Mean pharmacokinetic parameters were: terminal elimination half-life = 16.0 minutes, volume of central compartment = 129 mL kg -1 , and clearance = 11.0 mL min -1 kg -1

  19. Gamma-radiation effect on the parameters of the population recovery of plants

    Directory of Open Access Journals (Sweden)

    N.I. Ivanishvili

    2016-12-01

    Full Text Available Investigation of the effects of different physic-chemical factors on the ecosystems is one of the important scientific tasks. From this perspective, it is to be mentioned an effect of such a strong damaging factor as ionizing radiation. Radiation damage is reflected differently in relation to the levels of organization of living organisms. On the relatively early stage of radiation damage determination of post-irradiation regeneration indicators on population level gives possibility to forecast the sustainability of ecosystems. In order to determine the indicators of post-irradiation regeneration of plant populations we have used as a model water plant – Lemna minor L. During the exposure of radiation on different levels of organization differences are identified not only according to qualitative features but also by the character of direction of the development of the processes of postradiation regeneration. A conclusion is made that if during the acute radiation it is possible to determine radioresistance of certain plants, which is based on the plant potential to post-radiation regeneration, the investigation carried out through chronic irradiation gives the possibility to determine the indicators of the ability of the plant to adapt to the radiation.

  20. Periodontal disease in a remote Asian population: association between clinical and microbiological parameters.

    Science.gov (United States)

    Kvarnvik, Christine; Söljegård, Emelie; Charalampakis, Georgios; Suksu-Art, Narong; Dahlén, Gunnar

    2016-08-01

    The aim was to clinically and microbiologically describe the periodontal conditions in a remote adult Asian population with poor oral hygiene. The subjects were 30-60-year-old adults of Karen Hill tribes with no access to dental care. Eighty-six subjects were selected randomly. Clinical registrations included number of remaining teeth, plaque index (PlI), bleeding on probing (BoP), clinical attachment loss (CAL), and probing pocket depth (PPD). Subgingival plaque samples were collected and analyzed with the checkerboard method. Subjects of the study group had mean number of remaining teeth of 26.5 despite the abundant plaque and a high bleeding score. Severe periodontitis (CAL ≥ 7 mm) was recorded in 12.9% of the youngest age group (30-39 years) while it was significantly higher (52%) in the middle group (40-49 years) and (60%) in the eldest age group (50-60 years). Pathological pocketing (PPD ≥ 7 mm) was significantly lower in all age groups. Age, betel chewing, and a microbiological cluster including at least one of Prevotella tannerae, Filifactor alocis and Porphyromonas endodontalis significantly correlated with the severity of periodontal disease. Age, betel chewing, and a new bacterial complex other than the "red complex" correlated to periodontal breakdown in this remote adult Asian population. © 2015 Wiley Publishing Asia Pty Ltd.

  1. A comprehensive physiologically based pharmacokinetic ...

    Science.gov (United States)

    Published physiologically based pharmacokinetic (PBPK) models from peer-reviewed articles are often well-parameterized, thoroughly-vetted, and can be utilized as excellent resources for the construction of models pertaining to related chemicals. Specifically, chemical-specific parameters and in vivo pharmacokinetic data used to calibrate these published models can act as valuable starting points for model development of new chemicals with similar molecular structures. A knowledgebase for published PBPK-related articles was compiled to support PBPK model construction for new chemicals based on their close analogues within the knowledgebase, and a web-based interface was developed to allow users to query those close analogues. A list of 689 unique chemicals and their corresponding 1751 articles was created after analysis of 2,245 PBPK-related articles. For each model, the PMID, chemical name, major metabolites, species, gender, life stages and tissue compartments were extracted from the published articles. PaDEL-Descriptor, a Chemistry Development Kit based software, was used to calculate molecular fingerprints. Tanimoto index was implemented in the user interface as measurement of structural similarity. The utility of the PBPK knowledgebase and web-based user interface was demonstrated using two case studies with ethylbenzene and gefitinib. Our PBPK knowledgebase is a novel tool for ranking chemicals based on similarities to other chemicals associated with existi

  2. A Comparison of Grizzly Bear Demographic Parameters Estimated from Non-Spatial and Spatial Open Population Capture-Recapture Models.

    Science.gov (United States)

    Whittington, Jesse; Sawaya, Michael A

    2015-01-01

    Capture-recapture studies are frequently used to monitor the status and trends of wildlife populations. Detection histories from individual animals are used to estimate probability of detection and abundance or density. The accuracy of abundance and density estimates depends on the ability to model factors affecting detection probability. Non-spatial capture-recapture models have recently evolved into spatial capture-recapture models that directly include the effect of distances between an animal's home range centre and trap locations on detection probability. Most studies comparing non-spatial and spatial capture-recapture biases focussed on single year models and no studies have compared the accuracy of demographic parameter estimates from open population models. We applied open population non-spatial and spatial capture-recapture models to three years of grizzly bear DNA-based data from Banff National Park and simulated data sets. The two models produced similar estimates of grizzly bear apparent survival, per capita recruitment, and population growth rates but the spatial capture-recapture models had better fit. Simulations showed that spatial capture-recapture models produced more accurate parameter estimates with better credible interval coverage than non-spatial capture-recapture models. Non-spatial capture-recapture models produced negatively biased estimates of apparent survival and positively biased estimates of per capita recruitment. The spatial capture-recapture grizzly bear population growth rates and 95% highest posterior density averaged across the three years were 0.925 (0.786-1.071) for females, 0.844 (0.703-0.975) for males, and 0.882 (0.779-0.981) for females and males combined. The non-spatial capture-recapture population growth rates were 0.894 (0.758-1.024) for females, 0.825 (0.700-0.948) for males, and 0.863 (0.771-0.957) for both sexes. The combination of low densities, low reproductive rates, and predominantly negative population growth

  3. A Comparison of Grizzly Bear Demographic Parameters Estimated from Non-Spatial and Spatial Open Population Capture-Recapture Models.

    Directory of Open Access Journals (Sweden)

    Jesse Whittington

    Full Text Available Capture-recapture studies are frequently used to monitor the status and trends of wildlife populations. Detection histories from individual animals are used to estimate probability of detection and abundance or density. The accuracy of abundance and density estimates depends on the ability to model factors affecting detection probability. Non-spatial capture-recapture models have recently evolved into spatial capture-recapture models that directly include the effect of distances between an animal's home range centre and trap locations on detection probability. Most studies comparing non-spatial and spatial capture-recapture biases focussed on single year models and no studies have compared the accuracy of demographic parameter estimates from open population models. We applied open population non-spatial and spatial capture-recapture models to three years of grizzly bear DNA-based data from Banff National Park and simulated data sets. The two models produced similar estimates of grizzly bear apparent survival, per capita recruitment, and population growth rates but the spatial capture-recapture models had better fit. Simulations showed that spatial capture-recapture models produced more accurate parameter estimates with better credible interval coverage than non-spatial capture-recapture models. Non-spatial capture-recapture models produced negatively biased estimates of apparent survival and positively biased estimates of per capita recruitment. The spatial capture-recapture grizzly bear population growth rates and 95% highest posterior density averaged across the three years were 0.925 (0.786-1.071 for females, 0.844 (0.703-0.975 for males, and 0.882 (0.779-0.981 for females and males combined. The non-spatial capture-recapture population growth rates were 0.894 (0.758-1.024 for females, 0.825 (0.700-0.948 for males, and 0.863 (0.771-0.957 for both sexes. The combination of low densities, low reproductive rates, and predominantly negative

  4. Clinical pharmacokinetics of melatonin

    DEFF Research Database (Denmark)

    Harpsøe, Nathja Groth; Andersen, Lars Peter Holst; Gögenur, Ismail

    2015-01-01

    was performed in PubMed and Embase databases. The pharmacokinetic variables included maximal plasma/serum concentration (Cmax), time to maximal plasma/serum concentration (Tmax), elimination half-life (T1/2), area-under-the-curve plasma/serum concentrations (AUC), clearance (Cl), volume of distribution (VD......) and 1602 L (4 mg, oral). Bioavailability of oral melatonin ranged from 9 to 33%. Pharmacokinetics was affected by age, caffeine, smoking, oral contraceptives, feeding status, and fluvoxamine. Critically ill patients displayed accelerated absorption and compromised elimination. CONCLUSIONS: Despite...

  5. Insulin-like growth factor I and anthropometric parameters in a Danish population

    DEFF Research Database (Denmark)

    Friedrich, N; Jørgensen, Torben; Juul, A

    2012-01-01

    study was to analyse the associations between anthropometric measures and IGF-I levels in a population-based sample. From the Danish cross-sectional Health2006 study 3,328 subjects (1,835 women; 1,493 men) aged 19-72 years were included in the analyses. Serum IGF-I levels were determined...... consumption, smoking and physical activity. Our large cross-sectional study suggests that IGF-I may serve as the link between obesity and mortality although any causal relation cannot be inferred and longitudinal analyses are needed to clarify the causal relation.......During the last decade several studies indicated that low insulin-like growth factor (IGF) I levels are related to higher risk of cardiovascular disease and mortality. Obesity represents one further main cardiovascular risk factor which might also be related to IGF-I. The objective of the present...

  6. Factors influencing the selected body parameters and hippometric indexes in donkey’s population

    Directory of Open Access Journals (Sweden)

    Martina Kosťuková

    2012-01-01

    Full Text Available The main focus of our work was to collect basic body measurements of donkey population in Czech republic and determine the factors that influence these body measurements and hipometric indexes. The following measurements were recorded: height at withers, chest circumference and metacarpus interference. Based on the collected data, we were able to calculate the hipometric indexes: index of boniness, skeleton strength index, body mass index and coup height index. From a total of 331 individuals of donkey species living in Czech republic we managed to collect 50 samples. These were subjected to a general linear model (GLM and multiplex comparison statistical analysis. We managed to prove a statistically significant difference between donkeys born in Czech republic and the ones born abroad for all the measurements. Specifically the metacarpus circumference the gender dependency was also proved, having its impact on the hipometric indexes as well; the boniness index and skeleton strength index were also proved to be gender – dependent.

  7. Helicobacter pylori infection and metabolic parameters: Is there an association in elderly population?

    Directory of Open Access Journals (Sweden)

    Narges Sotuneh

    2014-01-01

    Full Text Available Background: The association between Helicobacter pylori (HP, as one of the most prevalent infections, and serum glucose level was inconsistent with previous studies. Moreover, there are contradictory reports about the relationship between HP infection and lipid profile. The purpose of this study was to determine the relationship between HP infection with glycemic and lipid profiles in elderly people. Methods: This cross-sectional study was conducted on 1,300 subjects over 60 years in Amirkola Health and Ageing Project. After using a standard questionnaire, the venous sampling was done to determine FBS, triglyceride (TG, cholesterol, low density lipoprotein (LDL, high-density lipoprotein (HDL and IgG anti-HP after a 12-h overnight fast. The information about the individuals was analyzed using SPSS-17. The P < 0.05 was considered statistically significant. Results: The prevalence of HP infection in diabetic and nondiabetic subjects was 77.5% and 75.7%, respectively, which had no statistically significant difference. Also, there was no significant difference between the serum lipid level including TG, LDL and HDL cholesterol with levels of anti-HP antibodies. The rate of HP infection in patients with hypertension was 75% and 78.3% in healthy patients, in which the difference was not statistically significant. In terms of body mass index (BMI, the prevalence of infection in the group with normal BMI was 77.3% and for the overweight and obese elderly population, it was 74.7%, and 77.5%, respectively (P = 0.445. Conclusions: The findings revealed that in a large population of elderly in the northern part of Iran, HP infection is not associated with BMI, serum glucose and lipid profile as well as blood pressure.

  8. Population Pharmacokinetic Analysis of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Healthy Subjects, Subjects with Various Degrees of Renal Function, and Patients with Complicated Urinary Tract Infection or Acute Uncomplicated Pyelonephritis.

    Science.gov (United States)

    Kawaguchi, Nao; Katsube, Takayuki; Echols, Roger; Wajima, Toshihiro

    2018-02-01

    Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. The aim of this study was to perform a population pharmacokinetic (PK) analysis based on plasma cefiderocol concentrations in healthy subjects, subjects with various degrees of renal function, and patients with complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis (AUP) caused by Gram-negative pathogens and to calculate the fraction of the time during the dosing interval where the free drug concentration in plasma exceeds the MIC ( fT MIC ). Population PK models were developed with three renal function markers, body surface area-adjusted estimated glomerular filtration rate (eGFR), absolute eGFR, and creatinine clearance, on the basis of 2,571 plasma concentrations from 91 subjects without infection and 238 patients with infection. The population PK models with each renal function marker adequately described the plasma cefiderocol concentrations. Clear relationships of total clearance (CL) to all renal function markers were observed. Body weight and disease status (with or without infection) were also significant covariates. The CL in patients with infection was 26% higher than that in subjects without infection. The fT MIC values were more than 75% in all patients (and were 100% in most patients), suggesting that a sufficient exposure to cefiderocol was provided by the tested dose regimens (2 g every 8 h as the standard dose regimen) for the treatment of cUTI or AUP caused by Gram-negative pathogens. Copyright © 2018 Kawaguchi et al.

  9. Ethnic differences in lens parameters measured by ocular biometry in a cataract surgery population.

    Science.gov (United States)

    Wang, Dajiang; Amoozgar, Behzad; Porco, Travis; Wang, Zhen; Lin, Shan C

    2017-01-01

    To investigate whether differences exist in lens position and other lens parameters among major ethnic groups with cataractous eyes, which may help explain racial differences in angle closure risk. This retrospective, cross-sectional study included 807 adult patients who had cataract surgery between years 2014 and 2016 at the University of California, San Francisco (UCSF). Adult patients of white, Asian, Hispanic and African-American ethnicity were included. Lens position (LP), defined as anterior chamber depth (ACD) + 1/2 lens thickness (LT), was assessed using measurements from optical biometry. Other assessed biometric parameters included axial length (AL), relative lens position (RLP) (defined as LP/AL), and anterior chamber depth (ACD). A total of 807 patients and 1361 eyes were included in this study from a database of patients having cataract surgery. Mean age was 69.2 years (age range from 18 to 101 years old), and 60.3% of patients were women. The mean LP measurements were 5.54±0.32 mm for white, 5.38±0.32 mm for Asian, 5.32±0.30 mm for Hispanic, and 5.40±0.28 mm for African-American participants. After adjusting for age, sex, and AL, significant differences were found when comparing LP in paired comparisons among White cohort with Asians (P<0.001), Hispanics (P<0.001) and African-Americans (P = 0.003). Additionally, when comparing RLP, similar significant results were found when comparing Whites with Asians (P<0.001), Hispanics (P<0.001) and African-Americans (P = 0.002). Lastly, pair-wise comparison of LT between ethnic groups showed significant differences while comparing Asians with Whites (P = 0.001) and Asians with African-Americans (P<0.001). The results of this study suggest that the LP of Hispanic, Asian, and African-American patients are significantly smaller than that of White patients, and among all ethnic groups, Hispanics and after Asians have the smallest LP (P<0.001) and RLP (P<0.001). These findings may have implications for the

  10. Estimating Population Parameters using the Structured Serial Coalescent with Bayesian MCMC Inference when some Demes are Hidden

    Directory of Open Access Journals (Sweden)

    Allen Rodrigo

    2006-01-01

    Full Text Available Using the structured serial coalescent with Bayesian MCMC and serial samples, we estimate population size when some demes are not sampled or are hidden, ie ghost demes. It is found that even with the presence of a ghost deme, accurate inference was possible if the parameters are estimated with the true model. However with an incorrect model, estimates were biased and can be positively misleading. We extend these results to the case where there are sequences from the ghost at the last time sample. This case can arise in HIV patients, when some tissue samples and viral sequences only become available after death. When some sequences from the ghost deme are available at the last sampling time, estimation bias is reduced and accurate estimation of parameters associated with the ghost deme is possible despite sampling bias. Migration rates for this case are also shown to be good estimates when migration values are low.

  11. Estimation of genetic parameters for morphological and functional traits in a Menorca horse population

    Directory of Open Access Journals (Sweden)

    Marina Solé

    2014-01-01

    Full Text Available Functional conformation and performance in Classic and Menorca Dressage are the main selection criteria in the Menorca Horse breeding program. Menorca Dressage is an alternative Classical Dressage discipline which is exclusive of the Menorca Island, but including a series of movements that the animals perform in the traditional festivities called “Jaleo Menorquín”. One of these movements involves the horse raising its forelimbs and standing or walking on its hindlimbs, which is called “el bot”. To make the Menorca horse breed more competitive in the equestrian market, it is necessary to understand the genetic background that characterizes the aptitude for Menorca Dressage and its relationship with conformation traits. The analysed data consisted of 15 conformation traits from 347 Menorca horses (200 males and 147 females, with 1,550 performance records in Menorca Dressage competitions. Genetic parameters were estimated using linear and threshold animal models. The heritabilities for heights and lengths were high (0.45-0.76, those for angulations and binary conformation traits were low to moderate (0.10-0.36 as were the scores for dressage performance (0.13-0.21. The results suggest that the analyzed traits could be used as an efficient tool for selecting breeding horses.

  12. Estimation of genetic parameters for morphological and functional traits in a Menorca horse population

    Energy Technology Data Exchange (ETDEWEB)

    Sole, M.; Cervantes, I.; Gutierrez, J. P.; Gomez, M. D.; Valera, M.

    2014-06-01

    Functional conformation and performance in Classic and Menorca Dressage are the main selection criteria in the Menorca Horse breeding program. Menorca Dressage is an alternative Classical Dressage discipline which is exclusive of the Menorca Island, but including a series of movements that the animals perform in the traditional festivities called Jaleo Menorquin. One of these movements involves the horse raising its forelimbs and standing or walking on its hindlimbs, which is called el bot. To make the Menorca horse breed more competitive in the equestrian market, it is necessary to understand the genetic background that characterizes the aptitude for Menorca Dressage and its relationship with conformation traits. The analysed data consisted of 15 conformation traits from 347 Menorca horses (200 males and 147 females), with 1,550 performance records in Menorca Dressage competitions. Genetic parameters were estimated using linear and threshold animal models. The heritabilities for heights and lengths were high (0.45-0.76), those for angulations and binary conformation traits were low to moderate (0.10-0.36) as were the scores for dressage performance (0.13-0.21). The results suggest that the analyzed traits could be used as an efficient tool for selecting breeding horses. (Author)

  13. A population-based study of the associations of stroke occurrence with weather parameters in Siberia, Russia (1982-92).

    Science.gov (United States)

    Feigin, V L; Nikitin, Y P; Bots, M L; Vinogradova, T E; Grobbee, D E

    2000-03-01

    Previous studies have established a seasonal variation in stroke occurrence, but none have assessed the influence of inclement weather conditions on stroke incidence in a general population of Russia. We performed a stroke population-based study in the Oktiabrsky District of Novosibirsk, Siberia, Russia. Included in the analysis were 1929 patients with their first occurrence of ischemic stroke (IS), 215 patients with their first occurrence of intracerebral hemorrhage (ICH) and 64 patients with their first occurrence of subarachnoid hemorrhage (SAH): all patients were aged between 25 and 74 years. The cumulative daily occurrence of total strokes and stroke subtypes was evaluated in relation to aggregated daily mean values of ambient temperature, relative humidity and air pressure by means of Poisson regression analysis to estimate the rate ratio (RR) with corresponding confidence interval (CI) and to identify the weather parameters of most importance. In a multivariate analysis, with adjustment for the effects of season, solar and geomagnetic activity, and age of the patients, low ambient temperature (RR 1.32; 95% CI 1.05-1.66) and mean value of air pressure (RR 0.986; 95% CI 0.972-0.999) were important predictors of IS occurrence, while mild ambient temperature (RR 1.52; 95% CI 1. 04-2.22) was an important predictor of ICH occurrence. No relationship between SAH occurrence and any one of the weather parameters studied was revealed. There was no interaction between any meteorological variables that was statistically significant. Inclement weather conditions are associated with the occurrence of IS and ICH in Siberia, Russia. Among the meteorological parameters studied, low ambient temperature and mean air pressure are the most important predictors of IS occurrence, whereas the occurrence of ICH is associated with mild ambient temperature. There is no association between any one of the weather parameters studied and the occurrence of SAH.

  14. Pharmacokinetics of dexmedetomidine administered to patients with end-stage renal failure and secondary hyperparathyroidism undergoing general anaesthesia.

    Science.gov (United States)

    Zhong, W; Zhang, Y; Zhang, M-Z; Huang, X-H; Li, Y; Li, R; Liu, Q-W

    2018-06-01

    The primary objective of this study was to compare the pharmacokinetics of dexmedetomidine in patients with end-stage renal failure and secondary hyperparathyroidism with those in normal individuals. Fifteen patients with end-stage renal failure and secondary hyperparathyroidism (Renal-failure Group) and 8 patients with normal renal and parathyroid gland function (Control Group) received intravenous 0.6 μg/kg dexmedetomidine for 10 minutes before anaesthesia induction. Arterial blood samples for plasma dexmedetomidine concentration analysis were drawn at regular intervals after the infusion was stopped. The pharmacokinetics were analysed using a nonlinear mixed-effect model with NONMEM software. The statistical significance of covariates was examined using the objective function (-2 log likelihood). In the forward inclusion and backward deletion, covariates (age, weight, sex, height, lean body mass [LBM], body surface area [BSA], body mass index [BMI], plasma albumin and grouping factor [renal failure or not]) were tested for significant effects on pharmacokinetic parameters. The validity of our population model was also evaluated using bootstrap simulations. The dexmedetomidine concentration-time curves fitted best with the principles of a two-compartmental pharmacokinetic model. No covariate of systemic clearance further improved the model. The final pharmacokinetic parameter values were as follows: V 1  = 60.6 L, V 2  = 222 L, Cl 1  = 0.825 L/min and Cl 2  = 4.48 L/min. There was no influence of age, weight, sex, height, LBM, BSA, BMI, plasma albumin and grouping factor (renal failure or not) on pharmacokinetic parameters. Although the plasma albumin concentrations (35.46 ± 4.13 vs 44.10 ± 1.12 mmol/L, respectively, P Renal-failure Group than in the Control Group (81.68 ± 18.08 vs 63.07 ± 13.45 μg/kg/min, respectively, P renal failure and hyperparathyroidism were similar to those in patients with normal renal function. Further

  15. Identifying key demographic parameters of a small island–associated population of Indo-Pacific bottlenose dolphins (Reunion, Indian Ocean)

    Science.gov (United States)

    Estrade, Vanessa; Fayan, Jacques

    2017-01-01

    Photo-identification surveys of Indo-Pacific bottlenose dolphins were conducted from 2009 to 2014 off Reunion Island (55°E33’/21°S07’), in the Indian Ocean. Robust Design models were applied to produce the most reliable estimate of population abundance and survival rate, while accounting for temporary emigration from the survey area (west coast). The sampling scheme consisted of a five-month (June–October) sampling period in each year of the study. The overall population size at Reunion was estimated to be 72 individuals (SE = 6.17, 95%CI = 61–85), based on a random temporary emigration (γ”) of 0.096 and a proportion of 0.70 (SE = 0.03) distinct individuals. The annual survival rate was 0.93 (±0.018 SE, 95%CI = 0.886–0.958) and was constant over time and between sexes. Models considering gender groups indicated different movement patterns between males and females. Males showed null or quasi-null temporary emigration (γ” = γ’ < 0.01), while females showed a random temporary emigration (γ”) of 0.10, suggesting that a small proportion of females was outside the survey area during each primary sampling period. Sex-specific temporary migration patterns were consistent with movement and residency patterns observed in other areas. The Robust Design approach provided an appropriate sampling scheme for deriving island-associated population parameters, while allowing to restrict survey effort both spatially (i.e. west coast only) and temporally (five months per year). Although abundance and survival were stable over the six years, the small population size of fewer than 100 individuals suggested that this population is highly vulnerable. Priority should be given to reducing any potential impact of human activity on the population and its habitat. PMID:28640918

  16. Identifying key demographic parameters of a small island-associated population of Indo-Pacific bottlenose dolphins (Reunion, Indian Ocean).

    Science.gov (United States)

    Dulau, Violaine; Estrade, Vanessa; Fayan, Jacques

    2017-01-01

    Photo-identification surveys of Indo-Pacific bottlenose dolphins were conducted from 2009 to 2014 off Reunion Island (55°E33'/21°S07'), in the Indian Ocean. Robust Design models were applied to produce the most reliable estimate of population abundance and survival rate, while accounting for temporary emigration from the survey area (west coast). The sampling scheme consisted of a five-month (June-October) sampling period in each year of the study. The overall population size at Reunion was estimated to be 72 individuals (SE = 6.17, 95%CI = 61-85), based on a random temporary emigration (γ") of 0.096 and a proportion of 0.70 (SE = 0.03) distinct individuals. The annual survival rate was 0.93 (±0.018 SE, 95%CI = 0.886-0.958) and was constant over time and between sexes. Models considering gender groups indicated different movement patterns between males and females. Males showed null or quasi-null temporary emigration (γ" = γ' < 0.01), while females showed a random temporary emigration (γ") of 0.10, suggesting that a small proportion of females was outside the survey area during each primary sampling period. Sex-specific temporary migration patterns were consistent with movement and residency patterns observed in other areas. The Robust Design approach provided an appropriate sampling scheme for deriving island-associated population parameters, while allowing to restrict survey effort both spatially (i.e. west coast only) and temporally (five months per year). Although abundance and survival were stable over the six years, the small population size of fewer than 100 individuals suggested that this population is highly vulnerable. Priority should be given to reducing any potential impact of human activity on the population and its habitat.

  17. Identifying key demographic parameters of a small island-associated population of Indo-Pacific bottlenose dolphins (Reunion, Indian Ocean.

    Directory of Open Access Journals (Sweden)

    Violaine Dulau

    Full Text Available Photo-identification surveys of Indo-Pacific bottlenose dolphins were conducted from 2009 to 2014 off Reunion Island (55°E33'/21°S07', in the Indian Ocean. Robust Design models were applied to produce the most reliable estimate of population abundance and survival rate, while accounting for temporary emigration from the survey area (west coast. The sampling scheme consisted of a five-month (June-October sampling period in each year of the study. The overall population size at Reunion was estimated to be 72 individuals (SE = 6.17, 95%CI = 61-85, based on a random temporary emigration (γ" of 0.096 and a proportion of 0.70 (SE = 0.03 distinct individuals. The annual survival rate was 0.93 (±0.018 SE, 95%CI = 0.886-0.958 and was constant over time and between sexes. Models considering gender groups indicated different movement patterns between males and females. Males showed null or quasi-null temporary emigration (γ" = γ' < 0.01, while females showed a random temporary emigration (γ" of 0.10, suggesting that a small proportion of females was outside the survey area during each primary sampling period. Sex-specific temporary migration patterns were consistent with movement and residency patterns observed in other areas. The Robust Design approach provided an appropriate sampling scheme for deriving island-associated population parameters, while allowing to restrict survey effort both spatially (i.e. west coast only and temporally (five months per year. Although abundance and survival were stable over the six years, the small population size of fewer than 100 individuals suggested that this population is highly vulnerable. Priority should be given to reducing any potential impact of human activity on the population and its habitat.

  18. How good is controlled attenuation parameter and fatty liver index for assessing liver steatosis in general population: correlation with ultrasound.

    Science.gov (United States)

    Carvalhana, Sofia; Leitão, Jorge; Alves, Ana C; Bourbon, Mafalda; Cortez-Pinto, Helena

    2014-07-01

    Liver steatosis measurement by controlled attenuation parameter (CAP) is a non-invasive method for diagnosing steatosis, based on transient elastography. Its usefulness as screening procedure for hepatic steatosis in general population has not been previously evaluated. The aim of this study was to evaluate the diagnostic accuracy of CAP and fatty liver index (FLI) for detection and quantification of steatosis in general population. Recruitment was done from a prospective epidemiological study of the general adult population. Steatosis was evaluated using CAP, FLI and ultrasound (US). Steatosis scored according to Hamaguchi's US scoring, from 0 (S0) to 6 (S6) points. Hepatic steatosis defined by score ≥2 (S≥2) and moderate/severe steatosis by score ≥4 (S≥4). Performance of CAP and FLI for diagnosing steatosis compared with US was assessed using areas under receiver operating characteristic curves (AUROC). From 219 consecutive individuals studied, 13 (5.9%) excluded because of failure/unreliable liver stiffness measurements. Steatosis prevalence: S≥2 38.4% and S≥4 12.1%. CAP significantly correlated with steatosis (ρ = 0.73, P steatosis score (ρ = 0.76; P steatosis quantification in the general population. Larger studies are needed for validation. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Mefloquine pharmacokinetics and mefloquine-artesunate effectiveness in Peruvian patients with uncomplicated Plasmodium falciparum malaria

    Directory of Open Access Journals (Sweden)

    Quezada Wilmer

    2009-04-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT is recommended as a means of prolonging the effectiveness of first-line malaria treatment regimens. Different brands of mefloquine (MQ have been reported to be non-bioequivalent; this could result in sub-therapeutic levels of mefloquine with decreased efficacy. In 2002, mefloquine-artesunate (MQ-AS combination therapy was adopted as the first-line treatment for uncomplicated Plasmodium falciparum malaria in the Amazon region of Peru. Although MQ resistance has yet to be reported from the Peruvian Amazon, it has been reported from other countries in the Amazon Region. Therefore, continuous monitoring is warranted to ensure that the first-line therapy remains efficacious. This study examines the in vivo efficacy and pharmacokinetic parameters through Day 56 of three commercial formulations of MQ (Lariam®, Mephaquin®, and Mefloquina-AC® Farma given in combination with artesunate. Methods Thirty-nine non-pregnant adults with P. falciparum mono-infection were randomly assigned to receive artesunate in combination with either (1 Lariam, (2 Mephaquin, or (3 Mefloquina AC. Patients were assessed on Day 0 (with blood samples for pharmacokinetics at 0, 2, 4, and 8 hours, 1, 2, 3, 7, and then weekly until day 56. Clinical and parasitological outcomes were based on the standardized WHO protocol. Whole blood mefloquine concentrations were determined by high-performance liquid chromatography and pharmacokinetic parameters were determined using non-compartmental analysis of concentration versus time data. Results By day 3, all patients had cleared parasitaemia except for one patient in the AC Farma arm; this patient cleared by day 4. No recurrences of parasitaemia were seen in any of the 34 patients. All three MQ formulations had a terminal half-life of 14–15 days and time to maximum plasma concentration of 45–52 hours. The maximal concentration (Cmax and interquartile range was 2,820 ng

  20. Fasting time and lipid parameters: association with hepatic steatosis — data from a random population sample

    Science.gov (United States)

    2014-01-01

    Background Current guidelines recommend measuring plasma lipids in fasting patients. Recent studies, however, suggest that variation in plasma lipid concentrations secondary to fasting time may be minimal. Objective of the present study was to investigate the impact of fasting time on plasma lipid concentrations (total cholesterol, HDL and LDL cholesterol, triglycerides). A second objective was to determine the effect of non-alcoholic fatty liver disease exerted on the above-mentioned lipid levels. Method Subjects participating in a population-based cross-sectional study (2,445 subjects; 51.7% females) were questioned at time of phlebotomy regarding duration of pre-phlebotomy fasting. Total cholesterol, LDL and HDL cholesterol, and triglycerides were determined and correlated with length of fasting. An upper abdominal ultrasonographic examination was performed and body-mass index (BMI) and waist-to-hip ratio (WHR) were calculated. Subjects were divided into three groups based on their reported fasting periods of 1–4 h, 4–8 h and > 8 h. After application of the exclusion criteria, a total of 1,195 subjects (52.4% females) were included in the study collective. The Kruskal-Wallis test was used for continuous variables and the chi-square test for categorical variables. The effects of age, BMI, WHR, alcohol consumption, fasting time and hepatic steatosis on the respective lipid variables were analyzed using multivariate logistic regression. Results At multivariate analysis, fasting time was associated with elevated triglycerides (p = 0.0047 for 1–4 h and p = 0.0147 for 4–8 h among females; p fasting period. LDL cholesterol and triglycerides exhibit highly significant variability; the greatest impact is seen with the triglycerides. Fasting time represents an independent factor for reduced LDL cholesterol and elevated triglyceride concentrations. There is a close association between elevated lipids and hepatic steatosis. PMID:24447492

  1. Pharmacokinetics of Melatonin

    DEFF Research Database (Denmark)

    Andersen, Lars Peter Holst; Gögenur, Ismail; Rosenberg, Jacob

    2016-01-01

    Despite widespread clinical application of melatonin, several unanswered questions remain regarding the pharmacokinetics of this drug. This lack of knowledge may contribute to the inconsistency of results in previous clinical studies. Currently, a t max value of 30-45 min and a t ½elimination of ...

  2. Pharmacokinetic evaluation of pemetrexed

    DEFF Research Database (Denmark)

    Sørensen, Jens Benn

    2011-01-01

    correlates with renal function and it may be safely used with vitamin supplementation in patients with creatinine clearance ≥ 45 ml/min. The pharmacokinetics of pemetrexed is also largely unchanged in third-space fluids and can be feasibly and safely administered in combination with several other cytotoxic...

  3. Pharmacokinetic evaluation of pemetrexed

    DEFF Research Database (Denmark)

    Sørensen, Jens Benn

    2011-01-01

    correlates with renal function and it may be safely used with vitamin supplementation in patients with creatinine clearance = 45 ml/min. The pharmacokinetics of pemetrexed is also largely unchanged in third-space fluids and can be feasibly and safely administered in combination with several other cytotoxic...

  4. A Multi-Route Model of Nicotine-Cotinine Pharmacokinetics, Pharmacodynamics and Brain Nicotinic Acetylcholine Receptor Binding in Humans

    Energy Technology Data Exchange (ETDEWEB)

    Teeguarden, Justin G.; Housand, Conrad; Smith, Jordan N.; Hinderliter, Paul M.; Gunawan, Rudy; Timchalk, Charles

    2013-02-01

    The pharmacokinetics of nicotine, the pharmacologically active alkaloid in tobacco responsible for addiction, are well characterized in humans. We developed a physiologically based pharmacokinetic/pharmacodynamic model of nicotine pharmacokinetics, brain dosimetry and brain nicotinic acetylcholine receptor (nAChRs) occupancy. A Bayesian framework was applied to optimize model parameters against multiple human data sets. The resulting model was consistent with both calibration and test data sets, but in general underestimated variability. A pharmacodynamic model relating nicotine levels to increases in heart rate as a proxy for the pharmacological effects of nicotine accurately described the nicotine related changes in heart rate and the development and decay of tolerance to nicotine. The PBPK model was utilized to quantitatively capture the combined impact of variation in physiological and metabolic parameters, nicotine availability and smoking compensation on the change in number of cigarettes smoked and toxicant exposure in a population of 10,000 people presented with a reduced toxicant (50%), reduced nicotine (50%) cigarette Across the population, toxicant exposure is reduced in some but not all smokers. Reductions are not in proportion to reductions in toxicant yields, largely due to partial compensation in response to reduced nicotine yields. This framework can be used as a key element of a dosimetry-driven risk assessment strategy for cigarette smoke constituents.

  5. Analysis of blood parameters in relation to the risk of cardiovascular disease for older population in Kelantan

    Science.gov (United States)

    Nabela, Z.; Ramzun, M. R.; Hana, M. M.; Zahirah, N. Z. N.; Ashikin, N. A. R. N. N.; Nursakinah, S.; Azhar, A. R.; Iskandar, S. M.

    2018-04-01

    Cardiovascular disease (CVD) is known to be the leading cause of morbidity and mortality worldwide and its complication is increasing among older people. Blood parameters including blood pressure (BP), glucose (BG), cholesterol (CHL) and uric acid (UA) are important aspects in maintaining a good condition of the cardiovascular system. The aim of this study is to determine the reference values of blood parameters among older population as well as to assess the association of CVD risk factors with the factors of age, gender and body mass index (BMI). Blood samples were collected from 400 older respondents (≥50 years) in Kota Bharu, Kelantan. The findings showed that respondents aged ≥60 years had significantly higher levels of BP and UA, but lower CHL than 50-59 years respondents (p<0.05). The males had significantly higher BP and lower CHL than the females (p<0.05). The respondents with BMI of ≥25 kgm-2 had significantly higher BP and BG than the respondents with BMI of <25 kgm-2 (p<0.05). There were significant associations between BP-BG, BG-UA and CHL-UA. It can be concluded that the levels of blood parameters are affected by the factors of age, gender and BMI.

  6. A probabilistic approach to the assessment of some life history pattern parameters in a Middle Pleistocene human population.

    Science.gov (United States)

    Durand, A I; Ipina, S L; Bermúdez de Castro, J M

    2000-06-01

    Parameters of a Middle Pleistocene human population such as the expected length of the female reproductive period (E(Y)), the expected interbirth interval (E(X)), the survival rate (tau) for females after the expected reproductive period, the rate (phi(2)) of women who, given that they reach first birth, do not survive to the end of the expected reproductive period, and the female infant plus juvenile mortality rate (phi(1)) have been assessed from a probabilistic standpoint provided that such a population were stationary. The hominid sample studied, the Sima de los Huesos (SH) cave site, Sierra de Atapuerca (Spain), is the most exhaustive human fossil sample currently available. Results suggest that the Atapuerca (SH) sample can derive from a stationary population. Further, in the case that the expected reproductive period ends between 37 and 40 yr of age, then 24 less, similarE(Y) less, similar27 yr, E(X)=3 yr, 0.224

  7. An oracle: antituberculosis pharmacokinetics-pharmacodynamics, clinical correlation, and clinical trial simulations to predict the future.

    Science.gov (United States)

    Pasipanodya, Jotam; Gumbo, Tawanda

    2011-01-01

    Antimicrobial pharmacokinetic-pharmacodynamic (PK/PD) science and clinical trial simulations have not been adequately applied to the design of doses and dose schedules of antituberculosis regimens because many researchers are skeptical about their clinical applicability. We compared findings of preclinical PK/PD studies of current first-line antituberculosis drugs to findings from several clinical publications that included microbiologic outcome and pharmacokinetic data or had a dose-scheduling design. Without exception, the antimicrobial PK/PD parameters linked to optimal effect were similar in preclinical models and in tuberculosis patients. Thus, exposure-effect relationships derived in the preclinical models can be used in the design of optimal antituberculosis doses, by incorporating population pharmacokinetics of the drugs and MIC distributions in Monte Carlo simulations. When this has been performed, doses and dose schedules of rifampin, isoniazid, pyrazinamide, and moxifloxacin with the potential to shorten antituberculosis therapy have been identified. In addition, different susceptibility breakpoints than those in current use have been identified. These steps outline a more rational approach than that of current methods for designing regimens and predicting outcome so that both new and older antituberculosis agents can shorten therapy duration.

  8. A review of pharmacokinetic drug-drug interactions with the anthelmintic medications albendazole and mebendazole.

    Science.gov (United States)

    Pawluk, Shane Ashley; Roels, Craig Allan; Wilby, Kyle John; Ensom, Mary H H

    2015-04-01

    Medications indicated for helminthes and other parasitic infections are frequently being used in mass populations in endemic areas. Currently, there is a lack of guidance for clinicians on how to appropriately manage drug interactions when faced with patients requiring short-term anthelmintic therapy with albendazole or mebendazole while concurrently taking other agents. The objective of this review was to systematically summarize and evaluate published literature on the pharmacokinetics of albendazole or mebendazole when taken with other interacting medications. A search of MEDLINE (1946 to October 2014), EMBASE (1974 to October 2014), International Pharmaceutical Abstracts (1970 to October 2014), Google, and Google Scholar was conducted for articles describing the pharmacokinetics of albendazole or mebendazole when given with other medications (and supplemented by a bibliographic review of all relevant articles). Altogether, 17 articles were included in the review. Studies reported data on pharmacokinetic parameters for albendazole or mebendazole when taken with cimetidine, dexamethasone, ritonavir, phenytoin, carbamazepine, phenobarbital, ivermectin, praziquantel, diethylcarbamazine, azithromycin, and levamisole. Cimetidine increased the elimination half-life of albendazole and maximum concentration (Cmax) of mebendazole; dexamethasone increased the area under the plasma concentration-time curve (AUC) of albendazole; levamisole decreased the Cmax of albendazole; anticonvulsants (phenytoin, phenobarbital, carbamazepine) decreased the AUC of albendazole; praziquantel increased the AUC of albendazole; and ritonavir decreased the AUC of both albendazole and mebendazole. No major interactions were found with ivermectin, azithromycin, or diethylcarbamazine. Future research is required to clarify the clinical relevance of the interactions observed.

  9. Anthropometric parameters as indicators of metabolic derangements in schizophrenia patients stabilized on olanzapine in an Indian rural population

    Directory of Open Access Journals (Sweden)

    Jayanta Kumar Rout

    2012-01-01

    Full Text Available Context: For any given body mass, Asian Indians have higher central obesity than Europeans. A periodic measurement of body mass index (BMI and waist hip ratio (WHR is practically more feasible than other parameters of metabolic syndrome by repeated blood collection. However, few studies are available on the relative importance of BMI and WHR as markers of dyslipidemia and insulin resistance in schizophrenia patients stabilized on second generation antipsychotics in Indian population. Aim: We conducted the present study on such patients to examine whether BMI or WHR can better predict dyslipidemia and insulin resistance in these patients in a rural area. Settings and Design: The study was a hospital based case control study under rural settings on 38 schizophrenia patients stabilized on olanzapine and 30 matched controls. Materials and Methods: Fasting concentrations of blood glucose, lipid parameters and serum insulin were assessed. Data for Homeostatic model for assessment of insulin resistance (HOMA-IR, BMI, and WHR were obtained to assess the insulin resistance, overall body fat distribution and abdominal fat dispensation respectively. Statistical analysis used: ′t′ test was performed to assay any difference in corresponding mean values between cases and controls. Dependence of HOMA-IR on key parameters was assessed by analysis of co-variance (ANCOVA study. Results: Cases exhibited significantly higher values for HOMA-IR, serum triglyceride and low density lipoprotein cholesterol (LDLc with a significantly lower high density lipoprotein cholesterol (HDLc level. ANCOVA study reflected that irrespective of age and sex, HOMA-IR was dependent on serum triglyceride level and WHR (F=8.3 and 5.7 respectively, P<0.05, but not on BMI (F<0.001, P=0.997. Conclusions: Central obesity could be more closely associated with the pathogenesis of prediabetic state in our case group. So, WHR is a better anthropometric parameter than BMI for an early

  10. The effect of Yoyo bitters on the pharmacokinetics of single oral ...

    African Journals Online (AJOL)

    Blood samples were collected and analyzed for paracetamol using spectrophotometric method. The values obtained for the pharmacokinetics parameters when paracetamol was administered alone falls within previously reported values. Yoyo bitters did not statistically (P>0.05) affect the pharmacokinetics of paracetamol ...

  11. Tubocurarine and pancuronium: a pharmacokinetic view.

    Science.gov (United States)

    Shanks, C A; Somogyi, A A; Ramzan, M I; Triggs, E J

    1980-02-01

    This review is an attempt to bring together the pharmacokinetic data on d-tubocurarine and pancuronium with clinical observations on relaxant dosage and effect. The modelling techniques used here represent an oversimplification of the relationships between relaxant plasma concentration and response as they do not predict either the time of onset of paralysis or its peak intensity. However, they do enable calculation of a bolus dose of relaxant required to achieve a particular intensity of paralysis for the average patient once pseudo-distribution equilibrium has been achieved. This has been further extended to predict the cumulation of the relaxants with subsequent dosage in average patients. Suggested regimens incorporating bolus and infusion doses of the relaxants to achieve continuous neuromuscular blockade have been calculated also. Averaged pharmacokinetic parameters derived from patients with renal or hepatic dysfunction have been used to predict the likely duration and intensities of paralysis for the relaxants.

  12. Variance Components and Genetic Parameters for Milk Production and Lactation Pattern in an Ethiopian Multibreed Dairy Cattle Population

    Directory of Open Access Journals (Sweden)

    Gebregziabher Gebreyohannes

    2013-09-01

    Full Text Available The objective of this study was to estimate variance components and genetic parameters for lactation milk yield (LY, lactation length (LL, average milk yield per day (YD, initial milk yield (IY, peak milk yield (PY, days to peak (DP and parameters (ln(a and c of the modified incomplete gamma function (MIG in an Ethiopian multibreed dairy cattle population. The dataset was composed of 5,507 lactation records collected from 1,639 cows in three locations (Bako, Debre Zeit and Holetta in Ethiopia from 1977 to 2010. Parameters for MIG were obtained from regression analysis of monthly test-day milk data on days in milk. The cows were purebred (Bos indicus Boran (B and Horro (H and their crosses with different fractions of Friesian (F, Jersey (J and Simmental (S. There were 23 breed groups (B, H, and their crossbreds with F, J, and S in the population. Fixed and mixed models were used to analyse the data. The fixed model considered herd-year-season, parity and breed group as fixed effects, and residual as random. The single and two-traits mixed animal repeatability models, considered the fixed effects of herd-year-season and parity subclasses, breed as a function of cow H, F, J, and S breed fractions and general heterosis as a function of heterozygosity, and the random additive animal, permanent environment, and residual effects. For the analysis of LY, LL was added as a fixed covariate to all models. Variance components and genetic parameters were estimated using average information restricted maximum likelihood procedures. The results indicated that all traits were affected (p<0.001 by the considered fixed effects. High grade B×F cows (3/16B 13/16F had the highest least squares means (LSM for LY (2,490±178.9 kg, IY (10.5±0.8 kg, PY (12.7±0.9 kg, YD (7.6±0.55 kg and LL (361.4±31.2 d, while B cows had the lowest LSM values for these traits. The LSM of LY, IY, YD, and PY tended to increase from the first to the fifth parity. Single-trait analyses

  13. Recovering stellar population parameters via two full-spectrum fitting algorithms in the absence of model uncertainties

    Science.gov (United States)

    Ge, Junqiang; Yan, Renbin; Cappellari, Michele; Mao, Shude; Li, Hongyu; Lu, Youjun

    2018-05-01

    Using mock spectra based on Vazdekis/MILES library fitted within the wavelength region 3600-7350Å, we analyze the bias and scatter on the resulting physical parameters induced by the choice of fitting algorithms and observational uncertainties, but avoid effects of those model uncertainties. We consider two full-spectrum fitting codes: pPXF and STARLIGHT, in fitting for stellar population age, metallicity, mass-to-light ratio, and dust extinction. With pPXF we find that both the bias μ in the population parameters and the scatter σ in the recovered logarithmic values follows the expected trend μ ∝ σ ∝ 1/(S/N). The bias increases for younger ages and systematically makes recovered ages older, M*/Lr larger and metallicities lower than the true values. For reference, at S/N=30, and for the worst case (t = 108yr), the bias is 0.06 dex in M/Lr, 0.03 dex in both age and [M/H]. There is no significant dependence on either E(B-V) or the shape of the error spectrum. Moreover, the results are consistent for both our 1-SSP and 2-SSP tests. With the STARLIGHT algorithm, we find trends similar to pPXF, when the input E(B-V)values, with significantly underestimated dust extinction and [M/H], and larger ages and M*/Lr. Results degrade when moving from our 1-SSP to the 2-SSP tests. The STARLIGHT convergence to the true values can be improved by increasing Markov Chains and annealing loops to the "slow mode". For the same input spectrum, pPXF is about two order of magnitudes faster than STARLIGHT's "default mode" and about three order of magnitude faster than STARLIGHT's "slow mode".

  14. Pharmacokinetics of thiamphenicol in dogs.

    Science.gov (United States)

    Castells, G; Intorre, L; Franquelo, C; Cristòfol, C; Pérez, B; Martí, G; Arboix, M

    1998-11-01

    To determine pharmacokinetic parameters of thiamphenicol (TAP) after IV and IM administration in dogs. 6 healthy 2- to 3-year-old male Beagles. IN a crossover design study, 3 dogs were given TAP IV, and 3 dogs were given TAP IM, each at a dosage of 40 mg/kg of body weight. Three weeks later, the same dogs were given a second dose by the opposite route. At preestablished times after TAP administration, blood samples were collected through a catheter placed in the cephalic vein, and TAP concentration was determined by use of a high-performance liquid chromatography. Results-Kinetics of TAP administered IV were fitted by a biexponential equation with a rapid first disposition phase followed by a slower disposition phase. Elimination half-life was short (1.7+/-0.3 hours), volume of distribution at steady state was 0.66+/-0.05 L/kg, and plasma clearance was 5.3+/-0.7 ml/min/kg. After IM administration, absorption was rapid. Peak plasma concentration (25.1+/-10.3 microg/ml) was reached about 45 minutes after drug administration. The apparent elimination half-life after IM administration (5.6+/-4.6 hours) was longer than that after IV administration probably because of the slow absorption rate from the muscle. Mean bioavailability after IM administration was 96+/-7%. The pharmacokinetic profile of TAP in dogs suggests that it may be therapeutically useful against susceptible microorganisms involved in the most common infections in dogs, such as tracheobronchitis, enterocolitis, mastitis, and urinary tract infections.

  15. [Pharmacokinetics of crocetin in rats].

    Science.gov (United States)

    Liu, Tong-zheng; Qian, Zhi-yu

    2002-05-01

    To develop an HPLC method for the determination of crocetin in rat plasma and study the pharmacokinetics in rats. Hypersil C18 column (5 microns, 4.6 mm x 200 mm) was used at column temperature 30 degrees C. The mobile phase consisted of methanol-water-acetic acid (75:24.5:0.5) at the flow rate of 1.0 mL.min-1. The UV detection wave length was 423 nm. The calibration curve was linear (gamma = 0.9996) in the range from 0.49 microgram.mL-1 to 7.87 micrograms.mL-1 for crocetin. The mean recovery was 105.2%. The lowest detectable concentration of crocetin was 0.14 microgram.mL-1 (S/N = 3). The RSDs of within-day and between-day were all less than 5%. The plasma crocetin was steady. The HPLC method of determination of crocetin in the plasma was established. After single dose of 50 mg.kg-1 ig in 10 rats, the main pharmacokinetic parameters were estimated as follows: T1/2 alpha (30 +/- 6) min, Tmax(65 +/- 16) min, Cmax(5.0 +/- 1.0) microgram.mL-1, AUC0-T(845 +/- 109) microgram.min.mL-1, Vd(5.0 +/- 0.8) L.kg-1. Crocetin was shown to be absorbed into the blood through the gastrointestinal tract. This method is quick, precise and reliable. Crocetin was shown to be quickly absorbed in rats.

  16. Phase 2, Randomized, Double-Blind, Dose-Ranging Study Evaluating the Safety, Tolerability, Population Pharmacokinetics, and Efficacy of Oral Torezolid Phosphate in Patients with Complicated Skin and Skin Structure Infections▿ † ‡

    Science.gov (United States)

    Prokocimer, P.; Bien, P.; Surber, J.; Mehra, P.; DeAnda, C.; Bulitta, J. B.; Corey, G. R.

    2011-01-01

    Torezolid (TR-700) is the active moiety of the prodrug torezolid phosphate ([TP] TR-701), a second-generation oxazolidinone with 4- to 16-fold greater potency than linezolid against Gram-positive species including methicillin-resistant Staphylococcus aureus (MRSA). A double-blind phase 2 study evaluated three levels (200, 300, or 400 mg) of oral, once-daily TP over 5 to 7 days for complicated skin and skin structure infections (cSSSI). Patients 18 to 75 years old with cSSSI caused by suspected or confirmed Gram-positive pathogens were randomized 1:1:1. Of 188 treated patients, 76.6% had abscesses, 17.6% had extensive cellulitis, and 5.9% had wound infections. S. aureus, the most common pathogen, was isolated in 90.3% of patients (139/154) with a baseline pathogen; 80.6% were MRSA. Cure rates in clinically evaluable patients were 98.2% at 200 mg, 94.4% at 300 mg, and 94.4% at 400 mg. Cure rates were consistent across diagnoses, regardless of lesion size or the presence of systemic signs of infection. Clinical cure rates in patients with S. aureus isolated at baseline were 96.6% overall and 96.8% for MRSA. TP was safe and well tolerated at all dose levels. No patients discontinued treatment due to an adverse event. Three-stage hierarchical population pharmacokinetic modeling yielded a geometric mean clearance of 8.28 liters/h (between-patient variability, 32.3%), a volume of the central compartment of 71.4 liters (24.0%), and a volume of the peripheral compartment of 27.9 liters (35.7%). Results of this study show a high degree of efficacy at all three dose levels without significant differences in the safety profile and support the continued evaluation of TP for the treatment of cSSSI in phase 3 trials. PMID:21115795

  17. Pharmacokinetics of linezolid in critically ill patients.

    Science.gov (United States)

    Sazdanovic, Predrag; Jankovic, Slobodan M; Kostic, Marina; Dimitrijevic, Aleksandra; Stefanovic, Srdjan

    2016-06-01

    Linezolid is an oxazolidinone antibiotic active against Gram-positive bacteria, and is most commonly used to treat life-threatening infections in critically ill patients. The pharmacokinetics of linezolid are profoundly altered in critically ill patients, partly due to decreased function of vital organs, and partly because life-sustaining drugs and devices may change the extent of its excretion. This article is summarizes key changes in the pharmacokinetics of linezolid in critically ill patients. The changes summarized are clinically relevant and may serve as rationale for dosing recommendations in this particular population. While absorption and penetration of linezolid to tissues are not significantly changed in critically ill patients, protein binding of linezolid is decreased, volume of distribution increased, and metabolism may be inhibited leading to non-linear kinetics of elimination; these changes are responsible for high inter-individual variability of linezolid plasma concentrations, which requires therapeutic plasma monitoring and choice of continuous venous infusion as the administration method. Acute renal or liver failure decrease clearance of linezolid, but renal replacement therapy is capable of restoring clearance back to normal, obviating the need for dosage adjustment. More population pharmacokinetic studies are necessary which will identify and quantify the influence of various factors on clearance and plasma concentrations of linezolid in critically ill patients.

  18. Development of a physiologically based pharmacokinetic model for assessment of human exposure to bisphenol A

    International Nuclear Information System (INIS)

    Yang, Xiaoxia; Doerge, Daniel R.; Teeguarden, Justin G.; Fisher, Jeffrey W.

    2015-01-01

    A previously developed physiologically based pharmacokinetic (PBPK) model for bisphenol A (BPA) in adult rhesus monkeys was modified to characterize the pharmacokinetics of BPA and its phase II conjugates in adult humans following oral ingestion. Coupled with in vitro studies on BPA metabolism in the liver and the small intestine, the PBPK model was parameterized using oral pharmacokinetic data with deuterated-BPA (d 6 -BPA) delivered in cookies to adult humans after overnight fasting. The availability of the serum concentration time course of unconjugated d 6 -BPA offered direct empirical evidence for the calibration of BPA model parameters. The recalibrated PBPK adult human model for BPA was then evaluated against published human pharmacokinetic studies with BPA. A hypothesis of decreased oral uptake was needed to account for the reduced peak levels observed in adult humans, where d 6 -BPA was delivered in soup and food was provided prior to BPA ingestion, suggesting the potential impact of dosing vehicles and/or fasting on BPA disposition. With the incorporation of Monte Carlo analysis, the recalibrated adult human model was used to address the inter-individual variability in the internal dose metrics of BPA for the U.S. general population. Model-predicted peak BPA serum levels were in the range of pM, with 95% of human variability falling within an order of magnitude. This recalibrated PBPK model for BPA in adult humans provides a scientific basis for assessing human exposure to BPA that can serve to minimize uncertainties incurred during extrapolations across doses and species. - Highlights: • A PBPK model predicts the kinetics of bisphenol A (BPA) in adult humans. • Serum concentrations of aglycone BPA are available for model calibration. • Model predicted peak BPA serum levels for adult humans were in the range of pM. • Model predicted 95% of human variability fell within an order of magnitude.

  19. Development of a physiologically based pharmacokinetic model for assessment of human exposure to bisphenol A

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Xiaoxia, E-mail: xiaoxia.yang@fda.hhs.gov [Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Doerge, Daniel R. [Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Teeguarden, Justin G. [Health Effects and Exposure Science, Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331 (United States); Fisher, Jeffrey W. [Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States)

    2015-12-15

    A previously developed physiologically based pharmacokinetic (PBPK) model for bisphenol A (BPA) in adult rhesus monkeys was modified to characterize the pharmacokinetics of BPA and its phase II conjugates in adult humans following oral ingestion. Coupled with in vitro studies on BPA metabolism in the liver and the small intestine, the PBPK model was parameterized using oral pharmacokinetic data with deuterated-BPA (d{sub 6}-BPA) delivered in cookies to adult humans after overnight fasting. The availability of the serum concentration time course of unconjugated d{sub 6}-BPA offered direct empirical evidence for the calibration of BPA model parameters. The recalibrated PBPK adult human model for BPA was then evaluated against published human pharmacokinetic studies with BPA. A hypothesis of decreased oral uptake was needed to account for the reduced peak levels observed in adult humans, where d{sub 6}-BPA was delivered in soup and food was provided prior to BPA ingestion, suggesting the potential impact of dosing vehicles and/or fasting on BPA disposition. With the incorporation of Monte Carlo analysis, the recalibrated adult human model was used to address the inter-individual variability in the internal dose metrics of BPA for the U.S. general population. Model-predicted peak BPA serum levels were in the range of pM, with 95% of human variability falling within an order of magnitude. This recalibrated PBPK model for BPA in adult humans provides a scientific basis for assessing human exposure to BPA that can serve to minimize uncertainties incurred during extrapolations across doses and species. - Highlights: • A PBPK model predicts the kinetics of bisphenol A (BPA) in adult humans. • Serum concentrations of aglycone BPA are available for model calibration. • Model predicted peak BPA serum levels for adult humans were in the range of pM. • Model predicted 95% of human variability fell within an order of magnitude.

  20. Analysis of the diffusion tensor imaging parameters of a normal cervical spinal cord in a healthy population.

    Science.gov (United States)

    Wei, Liang-Feng; Wang, Shou-Sen; Zheng, Zhao-Cong; Tian, Jun; Xue, Liang

    2017-05-01

    Diffusion tensor imaging (DTI) shows great advantage in the diagnosis of brain diseases, including cervical spinal cord (CSC) disease. This study aims to obtain the normal values of the DTI parameters for a healthy population and to establish a baseline for CSC disease diagnosis using DTI. A total of 36 healthy adults were subjected to magnetic resonance imaging (MRI) for the entire CSC using the Siemens 3.0 T MR System. Sagittal DTI acquisition was carried out with a single-shot spin-echo echo-planar imaging (EPI) sequence along 12 non-collinear directions. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were determined at different cervical levels using a region of interest (ROI) method, following which they were correlated with parameters, like age and sex. Further, diffusion tensor tracking (DTT) was carried out to reconstruct the white matter fiber bundles of the CSC. The full and complete fiber bundle structure of a normal CSC was confirmed in both the T2-weighted and DTI images. The FA and ADC values were significantly negatively correlated with each other and showed strongly negative and positive correlations with age, respectively, but not with sex. Additionally, there was no significant difference between the FA and the ADC values at different cervical levels. The DTI technique can act as an important supplement to the conventional MRI technique for CSC observation. Moreover, the FA and ADC values can be used as sensitive parameters in the DTI study on the CSC by taking the effects of age into consideration.

  1. Influence of Renal Impairment on the Pharmacokinetics of Afatinib: An Open-Label, Single-Dose Study.

    Science.gov (United States)

    Wiebe, Sabrina; Schnell, David; Külzer, Raimund; Gansser, Dietmar; Weber, Anne; Wallenstein, Gudrun; Halabi, Atef; Conrad, Anja; Wind, Sven

    2017-06-01

    Afatinib is an oral irreversible ErbB-Family Blocker indicated for treatment of patients with EGFR mutation positive advanced non-small cell lung cancer. This trial assessed whether renal impairment influences the pharmacokinetics and safety of afatinib. This was an open-label, single-dose study. Pharmacokinetic parameters after afatinib 40 mg were investigated in subjects with moderate (n = 8) or severe (n = 8) renal impairment (estimated glomerular filtration rate 30-59 mL/min/1.73 m 2 and 15-29 mL/min/1.73 m 2 , respectively) and healthy matched controls (n = 14). Plasma and urine samples were collected before and up to 14 days after dosing for pharmacokinetic and plasma protein-binding assessment. Primary endpoints were area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUC last ) and maximum plasma concentration (C max ) between subjects with renal impairment and healthy matched controls. Pharmacokinetic profiles and plasma protein binding were similar in all groups. The extent of exposure, as indicated by AUC last and C max , was generally similar between the matched treatment groups, with the exception of the geometric mean ratio of AUC last for subjects with severe renal impairment, which showed a trend towards a higher value compared with matched healthy subjects (150.0 % [90 % CI 105.3-213.7]) Inter-individual variability was moderate (geometric mean coefficient of variation 28-39 % for moderate impairment, 34-42 % for severe impairment). Afatinib was well tolerated and urinary excretion was minimal. Moderate-to-severe renal impairment had a minor influence on the pharmacokinetics of afatinib that was within the observed inter-individual variability, suggesting that afatinib treatment can be considered in this patient population. Registered at ClinicalTrials.gov as NCT02096718.

  2. Human physiologically based pharmacokinetic model for propofol

    Directory of Open Access Journals (Sweden)

    Schnider Thomas W

    2005-04-01

    Full Text Available Abstract Background Propofol is widely used for both short-term anesthesia and long-term sedation. It has unusual pharmacokinetics because of its high lipid solubility. The standard approach to describing the pharmacokinetics is by a multi-compartmental model. This paper presents the first detailed human physiologically based pharmacokinetic (PBPK model for propofol. Methods PKQuest, a freely distributed software routine http://www.pkquest.com, was used for all the calculations. The "standard human" PBPK parameters developed in previous applications is used. It is assumed that the blood and tissue binding is determined by simple partition into the tissue lipid, which is characterized by two previously determined set of parameters: 1 the value of the propofol oil/water partition coefficient; 2 the lipid fraction in the blood and tissues. The model was fit to the individual experimental data of Schnider et. al., Anesthesiology, 1998; 88:1170 in which an initial bolus dose was followed 60 minutes later by a one hour constant infusion. Results The PBPK model provides a good description of the experimental data over a large range of input dosage, subject age and fat fraction. Only one adjustable parameter (the liver clearance is required to describe the constant infusion phase for each individual subject. In order to fit the bolus injection phase, for 10 or the 24 subjects it was necessary to assume that a fraction of the bolus dose was sequestered and then slowly released from the lungs (characterized by two additional parameters. The average weighted residual error (WRE of the PBPK model fit to the both the bolus and infusion phases was 15%; similar to the WRE for just the constant infusion phase obtained by Schnider et. al. using a 6-parameter NONMEM compartmental model. Conclusion A PBPK model using standard human parameters and a simple description of tissue binding provides a good description of human propofol kinetics. The major advantage of a

  3. The pharmacokinetics of cytarabine administered subcutaneously, combined with prednisone, in dogs with meningoencephalomyelitis of unknown etiology.

    Science.gov (United States)

    Pastina, B; Early, P J; Bergman, R L; Nettifee, J; Maller, A; Bray, K Y; Waldron, R J; Castel, A M; Munana, K R; Papich, M G; Messenger, K M

    2018-05-15

    The objective of this study was to describe the pharmacokinetics (PK) of cytarabine (CA) after subcutaneous (SC) administration to dogs with meningoencephalomyelitis of unknown etiology (MUE). Twelve dogs received a single SC dose of CA at 50 mg/m 2 as part of treatment of MUE. A sparse sampling technique was used to collect four blood samples from each dog from 0 to 360 min after administration. All dogs were concurrently receiving prednisone (0.5-2 mg kg -1 day -1 ). Plasma CA concentrations were measured by HPLC, and pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling (NLME). Plasma drug concentrations ranged from 0.05 to 2.8 μg/ml. The population estimate (CV%) for elimination half-life and Tmax of cytarabine in dogs was 1.09 (21.93) hr and 0.55 (51.03) hr, respectively. The volume of distribution per fraction absorbed was 976.31 (10.85%) ml/kg. Mean plasma concentration of CA for all dogs was above 1.0 μg/ml at the 30-, 60-, 90-, and 120-min time points. In this study, the pharmacokinetics of CA in dogs with MUE after a single 50 mg/m 2 SC injection in dogs was similar to what has been previously reported in healthy beagles; there was moderate variability in the population estimates in this clinical population of dogs. © 2018 John Wiley & Sons Ltd.

  4. Clinical Pharmacokinetics of Paclitaxel Monotherapy

    DEFF Research Database (Denmark)

    Stage, Tore B; Bergmann, Troels K; Kroetz, Deanna L

    2018-01-01

    Paclitaxel is an anticancer agent efficacious in the treatment of ovarian, breast, and lung cancer. Due to a strong link between the pharmacokinetics and therapeutic efficacy of paclitaxel, we reviewed the literature on paclitaxel pharmacokinetics. Systematic data mining was performed to extract ...

  5. The association of Mediterranean diet and exercise modifications with anthropometric parameters in a psychiatric community population: A pilot study

    Directory of Open Access Journals (Sweden)

    Rosaria Di Lorenzo

    2018-03-01

    Full Text Available Weight gain and related metabolic syndrome (MS are major current issues in public health. MS consists of abdominal fat, atherogenic dyslipidemia, hypertension, hyperglycemia, insulin resistance, pro-inflammatory and pro-thrombotic state, and accounts for both cardiovascular diseases and type II diabetes mellitus risk factors. Patients affected by psychiatric illness present a prevalence of 35–40% of MS. Many studies have shown that Mediterranean diet is associated with the reduction of mortality due to cardiovascular and malignant diseases, potentially preventing both obesity and type II diabetes mellitus. Our pilot study explores the effects of a 12-month healthy lifestyle program (Mediterranean diet and mild physical activity on metabolic and anthropometric parameters of patients affected by chronic psychiatric disorders who live in a psychiatric community facility. A Mediterranean diet was provided by a senior nutritional clinician and adapted by two dieticians, according to the needs and preferences of the community population. Concomitantly, a program of moderate physical activity, consisting in 30-min walks on level ground 4days a week, and psycho-educational group sessions with educational and therapeutic purposes were implemented. The metabolic and anthropometric parameters of our patients improved after both 6 (T6 and 12 (T12 months. Body Max Index was statistically significantly reduced at T6 and T12, with patients perceiving good quality of life. These positive outcomes suggest that a low-cost healthy lifestyle program can produce good adherence and feasibility even among patients with chronic psychiatric diseases, reducing their risk for MS, cardiovascular diseases and other complications. Keywords: Weight gain and metabolic syndrome, Antipsychotic drugs, Chronic psychiatric disorders, Rehabilitative community, Mediterranean diet and mild physical activity

  6. Pharmacokinetics of Snake Venom

    Directory of Open Access Journals (Sweden)

    Suchaya Sanhajariya

    2018-02-01

    Full Text Available Understanding snake venom pharmacokinetics is essential for developing risk assessment strategies and determining the optimal dose and timing of antivenom required to bind all venom in snakebite patients. This review aims to explore the current knowledge of snake venom pharmacokinetics in animals and humans. Literature searches were conducted using EMBASE (1974–present and Medline (1946–present. For animals, 12 out of 520 initially identified studies met the inclusion criteria. In general, the disposition of snake venom was described by a two-compartment model consisting of a rapid distribution phase and a slow elimination phase, with half-lives of 5 to 48 min and 0.8 to 28 h, respectively, following rapid intravenous injection of the venoms or toxins. When the venoms or toxins were administered intramuscularly or subcutaneously, an initial absorption phase and slow elimination phase were observed. The bioavailability of venoms or toxins ranged from 4 to 81.5% following intramuscular administration and 60% following subcutaneous administration. The volume of distribution and the clearance varied between snake species. For humans, 24 out of 666 initially identified publications contained sufficient information and timed venom concentrations in the absence of antivenom therapy for data extraction. The data were extracted and modelled in NONMEM. A one-compartment model provided the best fit, with an elimination half-life of 9.71 ± 1.29 h. It is intended that the quantitative information provided in this review will provide a useful basis for future studies that address the pharmacokinetics of snakebite in humans.

  7. Use of the robust design to estimate seasonal abundance and demographic parameters of a coastal bottlenose dolphin (Tursiops aduncus population.

    Directory of Open Access Journals (Sweden)

    Holly C Smith

    Full Text Available As delphinid populations become increasingly exposed to human activities we rely on our capacity to produce accurate abundance estimates upon which to base management decisions. This study applied mark-recapture methods following the Robust Design to estimate abundance, demographic parameters, and temporary emigration rates of an Indo-Pacific bottlenose dolphin (Tursiops aduncus population off Bunbury, Western Australia. Boat-based photo-identification surveys were conducted year-round over three consecutive years along pre-determined transect lines to create a consistent sampling effort throughout the study period and area. The best fitting capture-recapture model showed a population with a seasonal Markovian temporary emigration with time varying survival and capture probabilities. Abundance estimates were seasonally dependent with consistently lower numbers obtained during winter and higher during summer and autumn across the three-year study period. Specifically, abundance estimates for all adults and juveniles (combined varied from a low of 63 (95% CI 59 to 73 in winter of 2007 to a high of 139 (95% CI 134 to148 in autumn of 2009. Temporary emigration rates (γ' for animals absent in the previous period ranged from 0.34 to 0.97 (mean  =  0.54; ±SE 0.11 with a peak during spring. Temporary emigration rates for animals present during the previous period (γ'' were lower, ranging from 0.00 to 0.29, with a mean of 0.16 (± SE 0.04. This model yielded a mean apparent survival estimate for juveniles and adults (combined of 0.95 (± SE 0.02 and a capture probability from 0.07 to 0.51 with a mean of 0.30 (± SE 0.04. This study demonstrates the importance of incorporating temporary emigration to accurately estimate abundance of coastal delphinids. Temporary emigration rates were high in this study, despite the large area surveyed, indicating the challenges of sampling highly mobile animals which range over large spatial areas.

  8. Gap analysis of pharmacokinetics and pharmacodynamics in burn patients: a review.

    Science.gov (United States)

    Steele, Amanda N; Grimsrud, Kristin N; Sen, Soman; Palmieri, Tina L; Greenhalgh, David G; Tran, Nam K

    2015-01-01

    Severe burn injury results in a multifaceted physiological response that significantly alters drug pharmacokinetics and pharmacodynamics (PK/PD). This response includes hypovolemia, increased vascular permeability, increased interstitial hydrostatic pressure, vasodilation, and hypermetabolism. These physiologic alterations impact drug distribution and excretion-thus varying the drug therapeutic effect on the body or microorganism. To this end, in order to optimize critical care for the burn population it is essential to understand how burn injury alters PK/PD parameters. The purpose of this article is to describe the relationship between burn injury and drug PK/PD. We conducted a literature review via PubMed and Google to identify burn-related PK/PD studies. Search parameters included "pharmacokinetics," "pharmacodynamics," and "burns." Based on our search parameters, we located 38 articles that studied PK/PD parameters specifically in burns. Twenty-seven articles investigated PK/PD of antibiotics, 10 assessed analgesics and sedatives, and one article researched an antacid. Out of the 37 articles, there were 19 different software programs used and eight different control groups. The mechanisms behind alterations in PK/PD in burns remain poorly understood. Dosing techniques must be adapted based on burn injury-related changes in PK/PD parameters in order to ensure drug efficacy. Although several PK/PD studies have been undertaken in the burn population, there is wide variation in the analytical techniques, software, and study sample sizes used. In order to refine dosing techniques in burns and consequently improve patient outcomes, there must be harmonization among PK/PD analyses.

  9. Pharmacokinetic modelling of intravenous tobramycin in adolescent and adult patients with cystic fibrosis using the nonparametric expectation maximization (NPEM) algorithm.

    Science.gov (United States)

    Touw, D J; Vinks, A A; Neef, C

    1997-06-01

    The availability of personal computer programs for individualizing drug dosage regimens has stimulated the interest in modelling population pharmacokinetics. Data from 82 adolescent and adult patients with cystic fibrosis (CF) who were treated with intravenous tobramycin because of an exacerbation of their pulmonary infection were analysed with a non-parametric expectation maximization (NPEM) algorithm. This algorithm estimates the entire discrete joint probability density of the pharmacokinetic parameters. It also provides traditional parametric statistics such as the means, standard deviation, median, covariances and correlations among the various parameters. It also provides graphic-2- and 3-dimensional representations of the marginal densities of the parameters investigated. Several models for intravenous tobramycin in adolescent and adult patients with CF were compared. Covariates were total body weight (for the volume of distribution) and creatinine clearance (for the total body clearance and elimination rate). Because of lack of data on patients with poor renal function, restricted models with non-renal clearance and the non-renal elimination rate constant fixed at literature values of 0.15 L/h and 0.01 h-1 were also included. In this population, intravenous tobramycin could be best described by median (+/-dispersion factor) volume of distribution per unit of total body weight of 0.28 +/- 0.05 L/kg, elimination rate constant of 0.25 +/- 0.10 h-1 and elimination rate constant per unit of creatinine clearance of 0.0008 +/- 0.0009 h-1/(ml/min/1.73 m2). Analysis of populations of increasing size showed that using a restricted model with a non-renal elimination rate constant fixed at 0.01 h-1, a model based on a population of only 10 to 20 patients, contained parameter values similar to those of the entire population and, using the full model, a larger population (at least 40 patients) was needed.

  10. Population pharmacokinetics of vancomycin in Jordanian patients ...

    African Journals Online (AJOL)

    Tropical Journal of Pharmaceutical Research. Journal Home · ABOUT THIS JOURNAL · Advanced Search · Current Issue · Archives · Journal Home > Vol 17, No 2 (2018) >. Log in or Register to get access to full text downloads.

  11. Population pharmacokinetics of vancomycin in Jordanian patients

    African Journals Online (AJOL)

    predictors of vancomycin clearance include: weight, serum creatinine, chronic renal ... (http://www.budapestopenaccessinitiative.org/read), which permit ... reproduction in any medium, provided the original work is properly credited. ... fluid balance; and albumin levels]); (3) .... vancomycin half-life is prolonged in patients with.

  12. Pharmacokinetics of enterolignans in healthy men and women consuming a single dose of secoisolariciresinol diglucoside

    NARCIS (Netherlands)

    Kuijsten, A.; Arts, I.C.W.; Vree, T.B.; Hollman, P.C.H.

    2005-01-01

    High concentrations of enterolignans in plasma are associated with a lower risk of acute coronary events. However, little is known about the absorption and excretion of enterolignans. The pharmacokinetic parameters and urinary excretion of enterodiol and enterolactone were evaluated after

  13. Grey-Box Modelling of Pharmacokinetic /Pharmacodynamic Systems

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Jacobsen, Judith L.; Pedersen, Oluf

    2004-01-01

    Grey-box pharmacokinetic/pharmacodynamic (PK/PD) modelling is presented as a promising way of modelling PK/PD systems. The concept behind grey-box modelling is based on combining physiological knowledge along with information from data in the estimation of model parameters. Grey-box modelling...

  14. Two-Compartment Pharmacokinetic Models for Chemical Engineers

    Science.gov (United States)

    Kanneganti, Kumud; Simon, Laurent

    2011-01-01

    The transport of potassium permanganate between two continuous-stirred vessels was investigated to help chemical and biomedical engineering students understand two-compartment pharmacokinetic models. Concepts of modeling, mass balance, parameter estimation and Laplace transform were applied to the two-unit process. A good agreement was achieved…

  15. Low heritability in pharmacokinetics of talinolol

    DEFF Research Database (Denmark)

    Matthaei, Johannes; Tzvetkov, Mladen V; Gal, Valerie

    2016-01-01

    BACKGROUND: Efflux transporters like MDR1 and MRP2 may modulate the pharmacokinetics of about 50 % of all drugs. It is currently unknown how much of the variation in the activities of important drug membrane transporters like MDR1 or MRP2 is determined by genetic or by environmental factors...... of talinolol was predefined as the primary parameter. Heritability was analyzed by structural equation modeling and by within- and between-subject variance and talinolol clearance was correlated with polymorphisms in MDR1, MRP2, BCRP, MDR5, OATP1B1, and OCT1. RESULTS: Talinolol clearance varied approximately...

  16. Pharmacokinetic modeling of gentamicin in treatment of infective endocarditis : Model development and validation of existing models

    NARCIS (Netherlands)

    Gomes, Anna; van der Wijk, Lars; Proost, Johannes H; Sinha, Bhanu; Touw, Daan J

    2017-01-01

    Gentamicin shows large variations in half-life and volume of distribution (Vd) within and between individuals. Thus, monitoring and accurately predicting serum levels are required to optimize effectiveness and minimize toxicity. Currently, two population pharmacokinetic models are applied for

  17. Temperature dependent development parameters and population life table of beet armyworm, Spodoptera exigua (Hübner (Lepidoptera: Noctuidae

    Directory of Open Access Journals (Sweden)

    HonQing Dai

    2017-12-01

    Full Text Available Beet armyworm, Spodoptera exigua (Hübner, is an important insect pest fed on many crops. Temperature and host plant dependent development, survival, and population parameters of S. exigua were studied in present article. The results showed that the generation duration of S. exigua at temperatures 20, 25, 27, 30, and 35 ℃ were 37.61, 30.78, 22.40, 18.57, and 13.74 days, respectively. S. exigua could not survive at 38 ℃. The generation duration of S. exigua, feeding on Lactuca sativa, Lactuca Sativa L., Raphanus sativus L., and Allium fistulosum at 27 ℃, were 18.86, 20.10, 22.67, and 22.50 days respectively. And the generation survivorship was 30.91, 29.00, 22.00, and 27.50% respectively, far less than observed 81.91% feeding on artificial diet. S. exigua feeding on L. sativa showed the highest net reproduction rate (216.29, intrinsic rate for increase (0.34, population trend index (76.59, finite rate for increase (1.33, and fecundity (606.5 eggs, while these values were the lowest when it fed on A. fistulosum. Relationship between development rate and temperature was fitted with three models, the linear model, Logistic model and Wang model, and Wang model produced the best fitting goodness. Wang model showed that for the egg, the 1st-5th instar larvae, pupa and adult of S. exigua, the upper limit temperatures for development are 45, 44.5, 44.4, 40.3, 43.6, 38.9, 38, and 38 ℃, resepctively; the lower limit temperatures for development are 7.5, 7.2, 13.4, 7.3, 6.6, 5.3, 5.6, and 5.6 ℃, respectively, and the optimum temperatures for development are 21.9, 28.9, 25.5, 24.5, 26, 31.6, 30.6, and 29.1 ℃, respectively. The upper limit, lower limit and optimum temperatures for development of the entire generation are 38, 5.7 and 30 ℃, resepctively.

  18. Pediatric Pharmacokinetic Data: Implications for Environmental Risk Assessment for Children

    Science.gov (United States)

    Pharmacology and toxicology share a common interest in pharmacokinetic data, especially as it is available in pediatric populations. These data have been critical to the clinical pharmacologist for many years in designing age-specific dosing regimens. Now they are being used incr...

  19. PHARMACOKINETIC-PHARMACODYNAMIC DRUG-INTERACTIONS WITH NONSTEROIDAL ANTIINFLAMMATORY DRUGS

    NARCIS (Netherlands)

    BROUWERS, JRBJ; DESMET, PAGM

    1994-01-01

    The nonsteroidal anti-inflammatory drugs (NSAIDs) are very commonly prescribed, especially in the elderly population. In many countries more than 10 different NSAIDs are available. As the older pyrazole compounds like phenylbutazone, oxyphenbutazone and azapropazone are most prone to pharmacokinetic

  20. The effect of food on the absorption and pharmacokinetics of rivaroxaban.

    Science.gov (United States)

    Stampfuss, Jan; Kubitza, Dagmar; Becka, Michael; Mueck, Wolfgang

    2013-07-01

    Doses of 10 mg, 15 mg, and 20 mg of rivaroxaban are approved for the treatment and prevention of thromboembolic disorders in adult patients. In six Phase I studies, the pharmacokinetics, safety, and tolerability of 2.5 mg, 5 mg, 10 mg, 15 mg, and 20 mg rivaroxaban were investigated in healthy male subjects, and the influence of food on these parameters was investigated for the 10 mg, 15 mg, and 20 mg tablet doses. In addition, an oral suspension containing 1 mg/ml rivaroxaban, which is under investigation for future use in the pediatric population, was investigated at doses of 10 mg and 20 mg. Rivaroxaban was obtained from Bayer Pharma AG, Wuppertal, Germany. Six independent, single-dose, cross-over studies were performed in healthy male subjects (between 13 and 24 subjects were enrolled in each study) to determine the pharmacokinetics, safety, and tolerability of rivaroxaban under fasting and fed conditions. Study 1 was an absolute bioavailability study that compared 5 mg and 20 mg tablet doses with a 1 mg intravenous solution. Studies 2 and 3 were confirmatory food-effect studies that assessed 10 mg and 20 mg tablet doses, respectively, under fed and fasting conditions. Study 4 was a formulation study that evaluated oral suspensions of 10 mg (fasting) and 20 mg (fasting and fed) rivaroxaban vs. a 10 mg tablet (fasted). Study 5 was a dose-proportionality study that assessed 2.5 mg, 5 mg, and 10 mg tablets under fasting conditions. Study 6 was a dose-proportionality study that assessed tablet doses of 10 mg, 15 mg, and 20 mg under fed conditions. Pharmacokinetic parameters, including the area under the plasma concentration-time curve after a single dose, the maximum drug concentration in plasma after a single dose, dose-adjusted values of area under the plasma concentration-time curve and maximum drug concentration in plasma after a single dose, half-life associated with the terminal slope, and time to maximum concentration in plasma after a single dose were

  1. Estimation of genetic parameters and genetic trends for weight and body measurements at birth in sheep populations in Thailand

    Directory of Open Access Journals (Sweden)

    China Supakorn

    2013-02-01

    Full Text Available The main objective of this study was to estimate the genetic parameters and genetic trends for birth weight (BW,heart girth (HG, and body length (BL at birth of sheep populations in Thailand. Data were collected during 1998 to 2011 fromfour livestock research and testing stations. Fixed effect testing showed that sex, herd, contemporary group and breed groupgreatly influenced on the investigated traits (P<0.05. The log likelihood ratio test showed that all traits significantly affectedby maternal additive genetic effect as well as covariance between animal effects. Estimated direct heritabilities from multivariate analysis of the model for BW, HG and BL were 0.32, 0.52 and 0.54, while estimated maternal heritabilities were 0.23,0.14 and 0.14, respectively. Positive correlations were found among direct additive genetic (0.29 to 0.97, maternal additivegenetic (0.23 to 0.95, and phenotype (0.18 to 0.96. Direct-maternal correlations within traits (-0.68 for BW, -0.92 for HG and-0.89 for BL and between traits (-0.89 to -0.08 were antagonistic effect. Direct additive genetic trends for BW, HG and BL inthe second period (2005 to 2011 were significantly increased (0.02 kg/year, 0.89 and 0.73 cm/year while maternal additivegenetic trends characteristically depicted significantly decreased (-0.01 kg/year, -0.92 and -0.72 cm/year.

  2. The pharmacokinetics of propofol in ICU patients undergoing long-term sedation.

    Science.gov (United States)

    Smuszkiewicz, Piotr; Wiczling, Paweł; Przybyłowski, Krzysztof; Borsuk, Agnieszka; Trojanowska, Iwona; Paterska, Marta; Matysiak, Jan; Kokot, Zenon; Grześkowiak, Edmund; Bienert, Agnieszka

    2016-11-01

    The aim of this study was to characterize the pharmacokinetics (PK) of propofol in ICU patients undergoing long-term sedation and to assess the influence of routinely collected covariates on the PK parameters. Propofol concentration-time profiles were collected from 29 patients. Non-linear mixed-effects modelling in NONMEM 7.2 was used to analyse the observed data. The propofol pharmacokinetics was best described with a three-compartment disposition model. Non-parametric bootstrap and a visual predictive check were used to evaluate the adequacy of the developed model to describe the observations. The typical value of the propofol clearance (1.46 l/min) approximated the hepatic blood flow. The volume of distribution at steady state was high and was equal to 955.1 l, which is consistent with other studies involving propofol in ICU patients. There was no statistically significant covariate relationship between PK parameters and opioid type, SOFA score on the day of admission, APACHE II, predicted death rate, reason for ICU admission (sepsis, trauma or surgery), gender, body weight, age, infusion duration and C-reactive protein concentration. The population PK model was developed successfully to describe the time-course of propofol concentration in ICU patients undergoing prolonged sedation. Despite a very heterogeneous group of patients, consistent PK profiles were observed. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  3. Effects of husbandry parameters on the life-history traits of the apple snail, Marisa cornuarietis: effects of temperature, photoperiod, and population density

    OpenAIRE

    Aufderheide, John; Warbritton, Ryan; Pounds, Nadine; File-Emperador, Sharon; Staples, Charles; Caspers, Norbert; Forbes, Valery

    2006-01-01

    These experiments are part of a larger study designed to investigate the influence of husbandry parameters on the life history of the apple snail, Marisa cornuarietis. The overall objective of the program is to identify suitable husbandry conditions for maintaining multi-generation populations of this species in the laboratory for use in ecotoxicological testing. In this article, we focus on the effects of photoperiod, temperature, and population density on adult fecundity and juvenile growth...

  4. Effects of temperature and population density on von Bertalanffy growth parameters in Atlantic herring: a macro-ecological analysis

    NARCIS (Netherlands)

    Brunel, T.P.A.; Dickey-Collas, M.

    2010-01-01

    The effect of temperature and population density on the growth of Atlantic herring Clupea harengus was studied using a comparative approach applied to 15 North Atlantic populations. The von Bertalanffy (VB) equation was applied to describe mean growth of individuals in each population, both averaged

  5. Atomoxetine pharmacogenetics: associations with pharmacokinetics, treatment response and tolerability.

    Science.gov (United States)

    Brown, Jacob T; Bishop, Jeffrey R

    2015-01-01

    Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder and is predominantly metabolized by the CYP2D6 enzyme. Differences in pharmacokinetic parameters as well as clinical treatment outcomes across CYP2D6 genotype groups have resulted in dosing recommendations within the product label, but clinical studies supporting the use of genotype guided dosing are currently lacking. Furthermore, pharmacokinetic and clinical studies have primarily focused on extensive as compared with poor metabolizers, with little information known about other metabolizer categories as well as genes involved in the pharmacodynamics of atomoxetine. This review describes the pharmacogenetic associations with atomoxetine pharmacokinetics, treatment response and tolerability with considerations for the clinical utility of this information.

  6. Pharmacokinetics of high-dose intravenous melatonin in humans

    DEFF Research Database (Denmark)

    Andersen, Lars P H; Werner, Mads U; Rosenkilde, Mette Marie

    2016-01-01

    This crossover study investigated the pharmacokinetics and adverse effects of high-dose intravenous melatonin. Volunteers participated in 3 identical study sessions, receiving an intravenous bolus of 10 mg melatonin, 100 mg melatonin, and placebo. Blood samples were collected at baseline and 0, 60......, 120, 180, 240, 300, 360, and 420 minutes after the bolus. Quantitative determination of plasma melatonin concentrations was performed using a radioimmunoassay technique. Pharmacokinetic parameters were estimated by a compartmental pharmacokinetic analysis. Adverse effects included assessments...... of sedation and registration of other symptoms. Sedation, evaluated as simple reaction times, was measured at baseline and 120, 180, 300, and 420 minutes after the bolus. Twelve male volunteers completed the study. Median (IQR) Cmax after the bolus injections of 10 mg and 100 mg of melatonin were 221...

  7. Albendazole nanocrystals with improved pharmacokinetic performance in mice.

    Science.gov (United States)

    Paredes, Alejandro J; Bruni, Sergio Sánchez; Allemandi, Daniel; Lanusse, Carlos; Palma, Santiago D

    2018-02-01

    Albendazole (ABZ) is a broad-spectrum antiparasitic agent with poor aqueous solubility, which leads to poor/erratic bioavailability and therapeutic failures. Here, we aimed to produce a novel formulation of ABZ nanocrystals (ABZNC) and assess its pharmacokinetic performance in mice. Results/methodology: ABZNC were prepared by high-pressure homogenization and spray-drying processes. Redispersion capacity and solid yield were measured in order to obtain an optimized product. The final particle size was 415.69±7.40 nm and the solid yield was 72.32%. The pharmacokinetic parameters obtained in a mice model for ABZNC were enhanced (p < 0.05) with respect to the control formulation. ABZNC with improved pharmacokinetic behavior were produced by a simple, inexpensive and potentially scalable methodology.

  8. Insulin aspart pharmacokinetics

    DEFF Research Database (Denmark)

    Rasmussen, Christian Hove; Roge, Rikke Meldgaard; Ma, Zhulin

    2014-01-01

    Background: Insulin aspart (IAsp) is used by many diabetics as a meal-time insulin to control postprandial glucose levels. As is the case with many other insulin types, the pharmacokinetics (PK), and consequently the pharmacodynamics (PD), is associated with clinical variability, both between...... to investigate and quantify the properties of the subcutaneous depot. Data from Brange et al. (1990) are used to determine the effects of insulin chemistry in subcutis on the absorption rate. Intravenous (i.v.) bolus and infusion PK data for human insulin are used to understand and quantify the systemic...... distribution and elimination (Porksen et al., 1997; Sjostrand et al., 2002). PK and PD profiles for type 1 diabetics from Chen et al. (2005) are analyzed to demonstrate the effects of IAsp antibodies in terms of bound and unbound insulin. PK profiles from Thorisdottir et al. (2009) and Ma et al. (2012b...

  9. Pharmacokinetics of BMEDA after Intravenous Administration in Beagle Dogs

    Directory of Open Access Journals (Sweden)

    Chih-Hsien Chang

    2014-01-01

    Full Text Available The pharmacokinetics of N,N-bis(2-mercapatoethly-N',N'-diethylenediamine (BMEDA, a molecule that can form a chelate with rhenium-188 (188Re to produce the 188Re-BMEDA-liposomes, was studied. In this work, beagles received a single injection of BMEDA, at doses of 1, 2, or 5 mg/kg; the concentration of BMEDA in the beagles’ plasma was then analyzed and determined by liquid chromatography-mass spectrometry/mass spectrometry. Based on the pharmacokinetic parameters of BMEDA, we found that male and female animals shared similar patterns indicating that the pharmacokinetics of BMEDA is independent of gender differences. In addition, the pharmacokinetics of BMEDA was seen to be non-linear because the increase of mean AUC0–t and AUC0–∞ values tend to be greater than dose proportional while the mean Vss and CL values of BMEDA appeared to be dose dependent. The information on the pharmacokinetics of BMEDA generated from this study will serve as a basis to design appropriate pharmacology and toxicology studies for future human use.

  10. Pharmacokinetics of Cannabinoids

    Directory of Open Access Journals (Sweden)

    Iain J McGilveray

    2005-01-01

    Full Text Available Delta-9-tetrahydrocannabinol (Δ-9-THC is the main psychoactive ingredient of cannabis (marijuana. The present review focuses on the pharmacokinetics of THC, but also includes known information for cannabinol and cannabidiol, as well as the synthetic marketed cannabinoids, dronabinol (synthetic THC and nabilone. The variability of THC in plant material (0.3% to 30% leads to variability in tissue THC levels from smoking, which is, in itself, a highly individual process. THC bioavailability averages 30%. With a 3.55% THC cigarette, a peak plasma level of 152±86.3 ng/mL occured approximately 10 min after inhalation. Oral THC, on the other hand, is only 4% to 12% bioavailable and absorption is highly variable. THC is eliminated from plasma in a multiphasic manner, with low amounts detectable for over one week after dosing. A major active 11-hydroxy metabolite is formed after both inhalation and oral dosing (20% and 100% of parent, respectively. THC is widely distributed, particularly to fatty tissues, but less than 1% of an administered dose reaches the brain, while the spleen and body fat are long-term storage sites. The elimination of THC and its many metabolites (from all routes occurs via the feces and urine. Metabolites persist in the urine and feces for severalweeks. Nabilone is well absorbed and the pharmacokinetics, although variable, appear to be linear from oral doses of 1 mg to 4 mg (these doses show a plasma elimination half-life of approximately 2 h. As with THC, there is a high first-pass effect, and the feces to urine ratio of excretion is similar to other cannabinoids. Pharmacokineticpharmacodynamic modelling with plasma THC versus cardiac and psychotropic effects show that after equilibrium is reached, the intensity of effect is proportional to the plasma THC profile. Clinical trials have found that nabilone produces less tachycardia and less euphoria than THC for a similar antiemetic response.

  11. Development of population pharmacokinetics model of icotinib with non-linear absorption characters in healthy Chinese volunteers to assess the CYP2C19 polymorphism and food-intake effect.

    Science.gov (United States)

    Hu, Pei; Chen, Jia; Liu, Dongyang; Zheng, Xin; Zhao, Qian; Jiang, Ji

    2015-07-01

    Icotinib is a potent and selective inhibitor of epidermal growth factor receptors (EGFR) approved to treat non-small cell lung cancer (NSCLC). However, its high variability may impede its application. The objectives of this analysis were to assess plasma pharmacokinetics and identify covariates that may explain variability in icotinib absorption and/or disposition following single dose of icotinib in healthy volunteers. Data from two clinical studies (n = 22) were analyzed. One study was designed as three-period and Latin-squared (six sequence) trial to evaluate dose proportionality, and the other one was designed as two-way crossover trial to evaluate food effect on pharmacokinetics (PK) characters. Icotinib concentrations in plasma were analyzed using non-linear mixed-effects model (NONMEM) method. The model was used to assess influence of food, demographic characteristics, measurements of blood biochemistry, and CYP2C19 genotype on PK characters of icotinib in humans. The final model was diagnosed by goodness-of-fit plots and evaluated by visual predictive check (VPC) and bootstrap methods. A two-compartment model with saturated absorption character was developed to capture icotinib pharmacokinetics. Typical value of clearance, distribution clearance, central volume of distribution, maximum absorption rate were 29.5 L/h, 24.9 L/h, 18.5 L, 122.2 L and 204,245 μg/h, respectively. When icotinib was administrated with food, bioavailability was estimated to be increased by 48%. Inter-occasion variability was identified to affect on maximum absorption rate constant in food-effect study. CL was identified to be significantly influenced by age, albumin concentration (ALB), and CYP2C19 genotype. No obvious bias was found by VPC and bootstrap methods. The developed model can capture icotinib pharmacokinetics well in healthy volunteers. Food intake can increase icotinib exposure. Three covariates, age, albumin concentration, and CYP2C19 genotype, were identified to

  12. Pharmacokinetics of clomipramine during pregnancy

    NARCIS (Netherlands)

    Ter Horst, P G J; Proost, J H; Smit, J P; Vries, M T; de Jong-van den Berg, Lolkje; Wilffert, B

    2015-01-01

    Clomipramine is one of the drugs for depression during pregnancy; however, pharmacokinetic data of clomipramine and its active metabolite desmethylclomipramine in this vulnerable period are lacking. In this study, we describe clomipramine and desmethylclomipramine concentrations including their

  13. Pharmacokinetic interaction between scutellarin and valsartan in rats.

    Science.gov (United States)

    Cui, Ming-Yu; Tian, Chong-Chong; Ju, Ai-Xia; Zhang, Chun-Ting; Li, Qiu-Hong

    2013-04-01

    Scutellarin is the main effective constituent of breviscapine, a flavonoid mixture isolated from the dried whole plant of Erigeron breviscapus (Vant.) Hand-Mazz, and valsartan is used as an antihypertensive drug. These two drugs have already been clinically used together to treat diabetic nephropathy (DN) in China, and the combined medications showed some enhanced protection against DN. The aim of this study is to investigate the potential pharmacokinetic interaction between scutellarin and valsartan in rats. Breviscapine injection (20 mg x kg(-1), i.v.) and valsartan (15 mg x kg-, i.g.), either alone or together were given to 18 male Sprague-Dawley rats. Concentrations of scutellarin and valsartan were quantified by HPLC, and pharmacokinetic parameters were calculated by non-compartmental methods. We found that the pharmacokinetic parameters of scutellarin altered significantly after co-administration of oral valsartan. The plasma clearance (CL(p)) and the bile clearance (CL(b)) of scutellarin were reduced significantly in the presence of valsartan. After oral administration of valsartan with or without intravenous scutellarin, however, the pharmacokinetic parameters of valsartan were comparable. In conclusion, our data suggests that the concurrent use of valsartan reduces the biliary excretion of scutellarin, and this may be due to the inhibitory effect of valsartan on the biliary excretion of scutellarin mediated by Mrp2 (Multidrug resistance-associated protein 2).

  14. Relationship between pharmacokinetics of 5-FU in plasma and in saliva, and toxicity of 5-fluorouracil/folinic acid

    NARCIS (Netherlands)

    Jansman, FGA; Coenen, JLLM; De Graaf, JC; Tobi, H; Sleijfer, DT; Brouwers, JRBJ

    2002-01-01

    Background: Dose adaptation based on pharmacokinetic parameters has been shown to decrease toxicity of some 5-fluorouracil(5-FU)-based continuous infusion regimens. Patients and Methods: In the present study the relationship between 5-FU pharmacokinetics in plasma and in saliva, and toxicity was

  15. Lethal and sublethal effects of cantharidin on the life history traits and population parameters of Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae).

    Science.gov (United States)

    Khan, Rashid A; Rashid, Maryam; Wang, Dun; Zhang, Ya-Lin

    2014-01-01

    The cotton bollworm, Helicoverpa armigera (Hübner), is a serious and cosmopolitan pest of many economic crops. Its control has not been adequate owing to its resistance to many groups of insecticides. Toxicity of cantharidin on armyworm and diamondback moth has already been reported. However, its toxicity on H. armigera has not been investigated previously. In this study, lethal and sublethal effects of cantharidin on H. armigera under laboratory conditions are reported. Results showed gross abnormalities in the population parameters of H. armigera, ranging from larvae to adults. Reduction in larval weight and wing malformation were observed in the cantharidin-treated population cohort, and higher mortality at the larval, pupal and adult stages was observed in cantharidin-treated H. armigera compared with the control. Moreover, almost 5 times less fecundity was recorded in the treated population cohort. Fertility was also severely affected, and reduction in all population parameters was observed. Cantharidin caused larval mortality and other serious abnormalities in H. armigera population parameters, and therefore may have positive implications for pest management decision-making process. More interestingly, the experiment revealed that cantharidin in sublethal dose mimicked insect growth regulator insecticides. Furthermore, cantharidin could be used as a precursor compound for the synthesis of new analogues and compounds to replace ineffective older compounds. © 2013 Society of Chemical Industry.

  16. Pharmacokinetic modeling of therapies for systemic lupus erythematosus

    OpenAIRE

    Yang, Xiaoyan; Sherwin, Catherine MT; Yu, Tian; Yellepeddi, Venkata K; Brunner, Hermine I; Vinks, Alexander A

    2015-01-01

    With the increasing use of different types of therapies in treating autoimmune diseases such as systemic lupus erythematosus (SLE), there is a need to utilize pharmacokinetic (PK) strategies to optimize the clinical outcome of these treatments. Various PK analysis approaches, including population PK modeling and physiologically based PK modeling, have been used to evaluate drug PK characteristics and population variability or to predict drug PK profiles in a mechanistic manner. This review ou...

  17. Parameters in the estimation of the most suitable F2 population size in conventional maize (Zea mays L. breeding programs

    Directory of Open Access Journals (Sweden)

    Delić Nenad

    2010-01-01

    Full Text Available The objective of the present study was to observe differences among four sizes of the F2 populations (100, 200, 300 and 500 plants on the basis of test-crosses for grain yield according to the average values of the populations, genetic and phenotypic variances, genotypic and phenotypic coefficients of variations and broad-sense heritability. The values of genetic variance did not significantly differ over population sizes according to all possible comparisons, including the comparison of values obtained for the phenotypic variance. Furthermore, the values of broadsense heritability (67.8%-69% did not significantly vary over different F2 population sizes. Genetic variability of the observed progenies, as a principal prerequisite of successful selection, was at the satisfactory level in all population sizes.

  18. The pharmacokinetics of cefazolin in patients undergoing elective & semi-elective abdominal aortic aneurysm open repair surgery

    Directory of Open Access Journals (Sweden)

    Roberts Michael S

    2011-02-01

    Full Text Available Abstract Background Surgical site infections are common, so effective antibiotic concentrations at the sites of infection are required. Surgery can lead to physiological changes influencing the pharmacokinetics of antibiotics. The aim of the study is to evaluate contemporary peri-operative prophylactic dosing of cefazolin by determining plasma and subcutaneous interstitial fluid concentrations in patients undergoing elective of semi-elective abdominal aortic aneurysm (AAA open repair surgery. Methods/Design This is an observational pharmacokinetic study of patients undergoing AAA open repair surgery at the Royal Brisbane and Women's Hospital. All patients will be administered 2-g cefazolin by intravenous injection within 30-minutes of the procedure. Participants will have samples from blood and urine, collected at different intervals. Patients will also have a microdialysis catheter inserted into subcutaneous tissue to measure interstitial fluid penetration by cefazolin. Participants will be administered indocyanine green and sodium bromide as well as have cardiac output monitoring performed and tetrapolar bioimpedance to determine physiological changes occurring during surgery. Analysis of samples will be performed using validated liquid chromatography tandem mass-spectrometry. Pharmacokinetic analysis will be performed using non-linear mixed effects modeling to determine individual and population pharmacokinetic parameters and the effect of peri-operative physiological changes on cefazolin disposition. Discussion The study will describe cefazolin levels in plasma and the interstitial fluid of tissues during AAA open repair surgery. The effect of physiological changes to the patient mediated by surgery will also be determined. The results of this study will guide clinicians and pharmacists to effectively dose cefazolin in order to maximize the concentration of antibiotics in the tissues which are the most common site of surgical site infections.

  19. Pharmacokinetic and bioavailability studies of commercially available simvastatin tablets in healthy and moderately hyperlipidaemic human subjects

    International Nuclear Information System (INIS)

    Ahmed, M.; Qamar-uz-Zaman, M.; Madni, A.; Usman, M.; Atif, M.; Akhtar, N.; Murtaza, G.

    2011-01-01

    Simvastatin, an analogue of Lovostatin, is a HMG.CoA reductase inhibitor. It is widely used in the treatment of hyperlipidaemia and coronary heart disease (CHD) with low incidence of myopathy and rhabdomyolysis. As these diseases may alter the pharmacokinetics of drugs, the present study was aimed to elaborate the variation in the pharmacokinetics and bioavailability of simvastatin in local healthy and moderately hyperlipidaemic population. Open, single dose and parallel design was applied to study. A total of 36 male volunteers were used for healthy and moderately hyperlipidaemic groups (n 18 for each) in this study on the basis of screening procedures, body chemistry and physical examination. Simvastatin 40 mg tablets (Saista 40, Bosch, Pakistan) were administered to over-night fasted volunteers. Blood samples were collected before dosing (zero time) and at regular intervals of time. The plasma samples were processed through a liquid-liquid extraction procedure and assayed by using HPLC consisting reversed phase C/sub 18/ column (ZORBAX, 4.6 x 150 mm, 5 mu m), UV detector set at 238 nm. The mobile phase consisted of the mixture of 0.025 M sodium dihydrogen phosphate (pH 4.5): acetonitrile (35: 65, v/v) which was pumped at a flow rate of 1.5 mL.min/sup -1/. The retention time of simvastatin was 7.5 minutes. The plasma drug concentration-time profiles of both groups were found significantly (P 0.05) difference between the values of following pharmacokinetic parameters in healthy and hyperlipidaemic volunteers i.e. C/sub max/, t/sub max/, AUC/sub 0-fi), AUMC/sub 0-enfinity), MRT, t/sub 1/2/, Cl/sub t /and K/sub e/. This study confirmed no significant (P > 0.05) difference in pharmacokinetics and bioavailability parameters after the administration of a single oral dose of 40 mg simvastatin (cholesterol lowering drug) to healthy and moderately hyperlipidaemic volunteers. (author)

  20. Modelling delays in pharmacokinetics

    International Nuclear Information System (INIS)

    Farooqi, Z.H.; Lambrecht, R.M.

    1990-01-01

    Linear system analysis has come to form the backbone of pharmacokinetics. Natural systems usually involve time delays, thus models incorporating them would be an order closer approximation to the real world compared to those that do not. Delays may be modelled in several ways. The approach considered in this study is to have a discrete-time delay dependent rate with the delay respresenting the duration between the entry of a drug into a compartment and its release in some form (may be as a metabolite) from the compartment. Such a delay may be because of one or more of several physiological reasons, like, formation of a reservoir, slow metabolism, or receptor binding. The mathematical structure this gives rise to is a system of delay-differential equations. Examples are given of simple one and two compartment systems with drugs like bumetanide, carbamazepine, and quinolone-caffeine interaction. In these examples generally a good fit is obtained and the suggested models form a good approximation. 21 refs., 6 figs

  1. Pharmacokinetic profile of dextromethorphan hydrobromide in a syrup formulation in children and adolescents.

    Science.gov (United States)

    Guenin, Eric; Armogida, Marianna; Riff, Dennis

    2014-09-01

    Dextromethorphan hydrobromide (DM) is a widely used antitussive. This study determined, for the first time, the basic pharmacokinetic profile of DM and its active metabolite, dextrorphan (DP) in children and adolescents. Thirty-eight male and female subjects at risk for developing an upper respiratory tract infection (URTI), or symptomatic with cough due to URTI, were enrolled in this single-dose, open-label study: ages 2-5 years (Group A, n = 8), 6-11 years (Group B, n = 17), 12-17 years (Group C, n = 13). Subjects were genotyped for cytochrome P450 (CYP) 2D6 polymorphisms and characterized as poor (PM) or non-poor metabolizers (non-PM). Groups A and B were dosed using an age-weight dosing schedule (DM range 7.5-24.75 mg); a 30-mg dose was used for Group C. Average exposures to total DP increased as age group increased, and average exposure to DM was highest in the adolescent group. One subject in that group was a PM. The terminal half-life (t ½) values were longer in the adolescent group due in part to the single PM subject. No relationship between body weight and pharmacokinetic parameters was noted. This is the first evaluation of the pharmacokinetic characteristics of DM in children and adolescents. A single dose of DM in this population was safe, and well tolerated at all doses tested. The data are used to model and compare pediatric DM exposures with those of adults.

  2. Application of the physiological and morphological parameters of the brazilian population sample to the mathematical model of the human respiratory tract

    International Nuclear Information System (INIS)

    Reis, Arlene Alves dos

    2005-01-01

    The Human Respiratory Tract Model proposed by the ICRP Publication 66 accounts for the morphology and physiology of the respiratory tract. The characteristics of air drawn into the lungs and exhaled are greatly influenced by the morphology of the respiratory tract, which causes numerous changes in pressure, flow rate, direction and humidity as air moves into and out of the lungs. Concerning the respiratory physiological parameters the breathing characteristics influence the volume, the inhalation rate of air and the portion that enters through the nose and the mouth. These characteristics are important to determine the fractional deposition. The model uses morphological and physiological parameters from the Caucasian man to establish deposition fractions in the respiratory tract regions. It is known that the morphology and physiology are influenced by environmental, occupational and economic conditions. The ICRP recommends, for a reliable evaluation of the regional deposition, the use of parameters from a local population when information is available. The main purpose of this study is to verify the influence in using the morphology and physiology parameters representative of a sample of the Brazilian population on the deposition model of the ICRP Publication 66. The morphological and physiological data were obtained from the literature. The software EXCEL for Windows (version 2000) was used in order to implement the deposition model and also to allow the changes in parameters of interest. Initially, the implemented model was checked using the parameters defined by the ICRP and the results of the fraction deposition in the respiratory tract compartments were compared. Finally, morphological and physiological parameters from Brazilian adult male were applied and the fractional deposition calculated. The results suggest a significant variation in fractional deposition when Brazilian parameters are applied in the model. (author)

  3. Growth parameters and density variation of a queen conch, Strombus gigas (Neotaenioglossa: Strombidae), population from Xel-Ha park, a marine protected area.

    Science.gov (United States)

    Baqueiro Cárdenas, Erick; Aldana Aranda, Dalila

    2014-03-01

    The queen conch, Strombus gigas, is a gastropod of commercial importance in the Caribbean. Population studies are based on size frequency analysis, using either length or weight parameters for the whole live organism. This contribution used mark-recapture data to estimate the Von Bertalanffy equation parameters and population number variation within a non harvest population from a protected area, to clarify the biometric parameters that better suit for the whole population, or for the juvenile and adult fractions. Conchs from Xel-Ha Park were monthly sampled from November 2001 to August 2005. Every conch found was measured and marked with a numbered tag that identified month and locality; and monthly abundance was estimated with Jolly's method. Length, lip thickness and weight increments were used to estimate the Von Bertalanffy growth equation parameters with Appeldoorn's subroutine of FISAT program. The population number varied through the study, with a minimum of 49 in April 2003 and maximum of 9 848 during June 2005. Conchs make only temporary use of Xel-Ha cove. Shell length gave the best fit for the juvenile fraction: L(infinity)=251, K=0.3, C=0.8 Wp=0.3; and lip thickness for adults: L(infinity)=47.78, K=0.17, C=0.1, Wp=0.86, while, the whole population was better represented by weight: L(infinity)=3850, K=0.36, C=0.8, Wp=0.3. A maximum age of 19 years was estimated from the population. Natural mortality was 0.49/year for juveniles and 0.29/year for adults. There were two pulses of recruitment: fall-winter and summer. It is concluded that population studies from length frequency data, should be analyzed independently in two groups, shell for the juvenile fraction and lip thickness for the adult fraction, or if it is not possible to analyze the population fractions separately, weight should be used to avoid miss calculation of the age structure.

  4. Quantification of nimesulide in human plasma by high-performance liquid chromatography with ultraviolet detector (HPLC-UV): application to pharmacokinetic studies in 28 healthy Korean subjects.

    Science.gov (United States)

    Kim, Mi-Sun; Park, Yoo-Sin; Kim, Shin-Hee; Kim, Sang-Yeon; Lee, Min-Ho; Kim, Youn-Hee; Kim, Do-Wan; Yang, Seok-Chul; Kang, Ju-Seop

    2012-05-01

    Nimesulide is a selective COX-2 inhibitor that is as effective as the classical non-acidic nonsteroidal anti-inflammatory drugs in the relief of various pain and inflammatory conditions, but is better tolerated with lower incidences of adverse effects than other drugs. After oral dose of 100 mg nimesulide to western subjects, a mean maximal concentration (C(max)) of 2.86 ∼ 6.5 µg/mL was reached at 1.22 ∼ 2.75 h and mean t(1/2β) of 1.8 ∼ 4.74 h. This study developed a robust method for quantification of nimesulide for the pharmacokinetics and suitability of its dosage in Korea and compared its suitability with other racial populations. Nimesulide and internal standard were extracted from acidified samples with methyl tert-butyl ether and analyzed by high-performance liquid chromatography with ultraviolet detection (HPLC-UV). The 28 healthy volunteers took 2 tablets of 100 mg nimesulide and blood concentrations were analyzed during the 24 h post dose. Several pharmacokinetic parameters were represented: AUC(0-infinity) = 113.0 mg-h/mL, C(max) = 12.06 mg/mL, time for maximal concentrations (T(max)) = 3.19 h and t(1/2β) = 4.51 h. These were different from those of western populations as follows: AUC was 14.5% and C(max) was 28% that of of Korean subjects and T(max) and t(1/2β) were also different. The validated HPLC-UV method was successfully applied for the pharmacokinetic studies of nimesulide in Korean subjects. Because the pharmacokinetics of nimesulide were different from western populations, its dosage regimen needs to be adjusted for Koreans. © The Author [2012]. Published by Oxford University Press. All rights reserved.

  5. Optimisation of antimicrobial dosing based on pharmacokinetic and pharmacodynamic principles

    Directory of Open Access Journals (Sweden)

    Grace Si Ru Hoo

    2017-01-01

    Full Text Available While suboptimal dosing of antimicrobials has been attributed to poorer clinical outcomes, clinical cure and mortality advantages have been demonstrated when target pharmacokinetic (PK and pharmacodynamic (PD indices for various classes of antimicrobials were achieved to maximise antibiotic activity. Dosing optimisation requires a good knowledge of PK/PD principles. This review serves to provide a foundation in PK/PD principles for the commonly prescribed antibiotics (β-lactams, vancomycin, fluoroquinolones and aminoglycosides, as well as dosing considerations in special populations (critically ill and obese patients. PK principles determine whether an appropriate dose of antimicrobial reaches the intended pathogen(s. It involves the fundamental processes of absorption, distribution, metabolism and elimination, and is affected by the antimicrobial's physicochemical properties. Antimicrobial pharmacodynamics define the relationship between the drug concentration and its observed effect on the pathogen. The major indicator of the effect of the antibiotics is the minimum inhibitory concentration. The quantitative relationship between a PK and microbiological parameter is known as a PK/PD index, which describes the relationship between dose administered and the rate and extent of bacterial killing. Improvements in clinical outcomes have been observed when antimicrobial agents are dosed optimally to achieve their respective PK/PD targets. With the rising rates of antimicrobial resistance and a limited drug development pipeline, PK/PD concepts can foster more rational and individualised dosing regimens, improving outcomes while simultaneously limiting the toxicity of antimicrobials.

  6. Evaluating SGLT2 inhibitors for type 2 diabetes: pharmacokinetic and toxicological considerations.

    Science.gov (United States)

    Scheen, André J

    2014-05-01

    Inhibitors of sodium-glucose cotransporters type 2 (SGLT2), which increase urinary glucose excretion independently of insulin, are proposed as a novel approach for the management of type 2 diabetes mellitus (T2DM). An extensive literature search was performed to analyze the pharmacokinetic characteristics, toxicological issues and safety concerns of SGLT2 inhibitors in humans. This review focuses on three compounds (dapagliflozin, canagliflozin, empagliflozin) with results obtained in healthy volunteers (including drug-drug interactions), patients with T2DM (single dose and multiple doses) and special populations (those with renal or hepatic impairment). The three pharmacological agents share an excellent oral bioavailability, long half-life allowing once-daily administration, low accumulation index and renal clearance, the absence of active metabolites and a limited propensity to drug-drug interactions. No clinically relevant changes in pharmacokinetic parameters were observed in T2DM patients or in patients with mild/moderate renal or hepatic impairment. Adverse events are a slightly increased incidence of mycotic genital and rare benign urinary infections. SGLT2 inhibitors have the potential to reduce several cardiovascular risk factors, and cardiovascular outcome trials are currently ongoing. The best positioning of SGLT2 inhibitors in the armamentarium for treating T2DM is still a matter of debate.

  7. Evaluation of pharmacokinetic model designs for subcutaneous infusion of insulin aspart

    DEFF Research Database (Denmark)

    Mansell, Erin J.; Schmidt, Signe; Docherty, Paul D.

    2017-01-01

    Effective mathematical modelling of continuous subcutaneous infusion pharmacokinetics should aid understanding and control in insulin therapy. Thorough analysis of candidate model performance is important for selecting the appropriate models. Eight candidate models for insulin pharmacokinetics...... included a range of modelled behaviours, parameters and complexity. The models were compared using clinical data from subjects with type 1 diabetes with continuous subcutaneous insulin infusion. Performance of the models was compared through several analyses: R2 for goodness of fit; the Akaike Information...

  8. Characterizing uncertainty and population variability in the toxicokinetics of trichloroethylene and metabolites in mice, rats, and humans using an updated database, physiologically based pharmacokinetic (PBPK) model, and Bayesian approach

    International Nuclear Information System (INIS)

    Chiu, Weihsueh A.; Okino, Miles S.; Evans, Marina V.

    2009-01-01

    We have developed a comprehensive, Bayesian, PBPK model-based analysis of the population toxicokinetics of trichloroethylene (TCE) and its metabolites in mice, rats, and humans, considering a wider range of physiological, chemical, in vitro, and in vivo data than any previously published analysis of TCE. The toxicokinetics of the 'population average,' its population variability, and their uncertainties are characterized in an approach that strives to be maximally transparent and objective. Estimates of experimental variability and uncertainty were also included in this analysis. The experimental database was expanded to include virtually all available in vivo toxicokinetic data, which permitted, in rats and humans, the specification of separate datasets for model calibration and evaluation. The total combination of these approaches and PBPK analysis provides substantial support for the model predictions. In addition, we feel confident that the approach employed also yields an accurate characterization of the uncertainty in metabolic pathways for which available data were sparse or relatively indirect, such as GSH conjugation and respiratory tract metabolism. Key conclusions from the model predictions include the following: (1) as expected, TCE is substantially metabolized, primarily by oxidation at doses below saturation; (2) GSH conjugation and subsequent bioactivation in humans appear to be 10- to 100-fold greater than previously estimated; and (3) mice had the greatest rate of respiratory tract oxidative metabolism as compared to rats and humans. In a situation such as TCE in which there is large database of studies coupled with complex toxicokinetics, the Bayesian approach provides a systematic method of simultaneously estimating model parameters and characterizing their uncertainty and variability. However, care needs to be taken in its implementation to ensure biological consistency, transparency, and objectivity.

  9. Pharmacokinetics of rilmenidine in healthy subjects

    International Nuclear Information System (INIS)

    Genissel, P.; Bromet, N.; Fourtillan, J.B.; Mignot, A.; Albin, H.

    1988-01-01

    Rilmenidine is a novel alpha 2-adrenoceptor agonist, used in the treatment of mild or moderate hypertension at the oral dose of 1 mg once or twice daily. The pharmacokinetic parameters were investigated after single or repeated administration in healthy subjects, using labeled and unlabeled compounds. Rilmenidine was rapidly and extensively absorbed, with an absolute bioavailability factor close to 1 and a maximal plasma concentration achieved within 2 hours. Rilmenidine was not subject to presystemic metabolism. Distribution was independent of the free fraction because rilmenidine was weakly bound to plasma proteins (less than 10%). The volume of distribution was approximately 5 l.kg-1 (315 liters). Elimination was rapid with a total body plasma clearance of approximately 450 ml.min-1 and an elimination half-life of approximately 8 hours. Renal excretion was the major elimination process (two-thirds of the total clearance). Metabolism was very poor, with a renal elimination of rilmenidine as the parent drug (urinary fraction of rilmenidine was about 65% and no metabolite plasma levels were detected). Linear pharmacokinetics were demonstrated for rilmenidine from 0.5 to 2 mg but, at 3 mg, a slight deviation from linearity was observed. In repeated administration, the linear disposition of rilmenidine with dose was confirmed

  10. Population nutrikinetics of green tea extract.

    Science.gov (United States)

    Scholl, Catharina; Lepper, Anna; Lehr, Thorsten; Hanke, Nina; Schneider, Katharina Luise; Brockmöller, Jürgen; Seufferlein, Thomas; Stingl, Julia Carolin

    2018-01-01

    Green tea polyphenols may contribute to the prevention of cancer and other diseases. To learn more about the pharmacokinetics and interindividual variation of green tea polyphenols after oral intake in humans we performed a population nutrikinetic study of standardized green tea extract. 84 healthy participants took green tea extract capsules standardized to 150 mg epigallocatechin-gallate (EGCG) twice a day for 5 days. On day 5 catechin plasma concentrations were analyzed using non-compartmental and population pharmacokinetic methods. A strong between-subject variability in catechin pharmacokinetics was found with maximum plasma concentrations varying more than 6-fold. The AUCs of EGCG, EGC and ECG were 877.9 (360.8-1576.5), 35.1 (8.0-87.4), and 183.6 (55.5-364.6) h*μg/L respectively, and the elimination half lives were 2.6 (1.8-3.8), 3.9 (0.9-10.7) and 1.8 (0.8-2.9) h, respectively. Genetic polymorphisms in genes of the drug transporters MRP2 and OATP1B1 could at least partly explain the high variability in pharmacokinetic parameters. The observed variability in catechin plasma levels might contribute to interindividual variation in benefical and adverse effects of green tea polyphenols. Our data could help to gain a better understanding of the causes of variability of green tea effects and to improve the design of studies on the effects of green tea polyphenols in different health conditions. ClinicalTrials.gov: NCT01360320.

  11. Pharmacokinetics, microbial response, and pulmonary outcomes of multidose intravenous azithromycin in preterm infants at risk for Ureaplasma respiratory colonization.

    Science.gov (United States)

    Merchan, L Marcela; Hassan, Hazem E; Terrin, Michael L; Waites, Ken B; Kaufman, David A; Ambalavanan, Namasivayam; Donohue, Pamela; Dulkerian, Susan J; Schelonka, Robert; Magder, Laurence S; Shukla, Sagar; Eddington, Natalie D; Viscardi, Rose M

    2015-01-01

    The study objectives were to refine the population pharmacokinetics (PK) model, determine microbial clearance, and assess short-term pulmonary outcomes of multiple-dose azithromycin treatment in preterm infants at risk for Ureaplasma respiratory colonization. Fifteen subjects (7 of whom were Ureaplasma positive) received intravenous azithromycin at 20 mg/kg of body weight every 24 h for 3 doses. Azithromycin concentrations were determined in plasma samples obtained up to 168 h post-first dose by using a validated liquid chromatography-tandem mass spectrometry method. Respiratory samples were obtained predose and at three time points post-last dose for Ureaplasma culture, PCR, antibiotic susceptibility testing, and cytokine concentration determinations. Pharmacokinetic data from these 15 subjects as well as 25 additional subjects (who received either a single 10-mg/kg dose [n = 12] or a single 20-mg/kg dose [n = 13]) were analyzed by using a nonlinear mixed-effect population modeling (NONMEM) approach. Pulmonary outcomes were assessed at 36 weeks post-menstrual age and 6 months adjusted age. A 2-compartment model with all PK parameters allometrically scaled on body weight best described the azithromycin pharmacokinetics in preterm neonates. The population pharmacokinetics parameter estimates for clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 0.15 liters/h · kg(0.75), 1.88 liters · kg, 1.79 liters/h · kg(0.75), and 13 liters · kg, respectively. The estimated area under the concentration-time curve over 24 h (AUC24)/MIC90 value was ∼ 4 h. All posttreatment cultures were negative, and there were no drug-related adverse events. One Ureaplasma-positive infant died at 4 months of age, but no survivors were hospitalized for respiratory etiologies during the first 6 months (adjusted age). Thus, a 3-day course of 20 mg/kg/day intravenous azithromycin shows preliminary efficacy in eradicating

  12. An econometric method for estimating population parameters from non-random samples: An application to clinical case finding.

    Science.gov (United States)

    Burger, Rulof P; McLaren, Zoë M

    2017-09-01

    The problem of sample selection complicates the process of drawing inference about populations. Selective sampling arises in many real world situations when agents such as doctors and customs officials search for targets with high values of a characteristic. We propose a new method for estimating population characteristics from these types of selected samples. We develop a model that captures key features of the agent's sampling decision. We use a generalized method of moments with instrumental variables and maximum likelihood to estimate the population prevalence of the characteristic of interest and the agents' accuracy in identifying targets. We apply this method to tuberculosis (TB), which is the leading infectious disease cause of death worldwide. We use a national database of TB test data from South Africa to examine testing for multidrug resistant TB (MDR-TB). Approximately one quarter of MDR-TB cases was undiagnosed between 2004 and 2010. The official estimate of 2.5% is therefore too low, and MDR-TB prevalence is as high as 3.5%. Signal-to-noise ratios are estimated to be between 0.5 and 1. Our approach is widely applicable because of the availability of routinely collected data and abundance of potential instruments. Using routinely collected data to monitor population prevalence can guide evidence-based policy making. Copyright © 2017 John Wiley & Sons, Ltd.

  13. Androgen receptor expression and its relationship with clinicopathological parameters in an Iranian population with invasive breast carcinoma

    Directory of Open Access Journals (Sweden)

    Fereshteh Mohammadizadeh

    2014-01-01

    Conclusions: AR expression was found to be frequently present in breast carcinoma in the studied population. Since half of the ER negative and half of the triple negative tumors were found to be AR positive, AR positive cases may benefit from alternative endocrine therapeutic strategies other than the conventional endocrine-targeted medications.

  14. Effect of gamma-radiation on demographic and morphometric parameters of laboratory population of duckweed Lemna minor

    International Nuclear Information System (INIS)

    Rasskazova, M.M.; Berestina, A.V.

    2015-01-01

    After effect of chronic gamma-exposition on Lemna minor plants, significantly decreases the specific rate of population growth, increases the process of frond's dying-off. The chronic exposition with radiation intensity 5,0 Gy/hour induces roots growth and significantly increased percent of damaged fronds. (authors)

  15. PHARMACOKINETICS AND PHARMACOKINETIC DYNAMIC RELATIONSHIP OF ROCURONIUM BROMIDE IN HUMANS

    NARCIS (Netherlands)

    WIERDA, JMKH; PROOST, JH; SCHIERE, S; HOMMES, FDM

    The existing human pharmacokinetic studies have been reviewed and compared with data derived from animals. The earliest study confirms the similarity of rocuronium to vecuronium with respect to the variables derived from the plasma concentration decay curves and the proportion excreted renally.

  16. Application of physiological parameters of a sample of the Brazilian population in different levels of exercise, on the deposition model of the ICRP Publication 66

    International Nuclear Information System (INIS)

    Reis, Arlene A. dos; Cardoso, Joaquim C.S.; Lourenco, Maria C.

    2005-01-01

    The Human Respiratory Tract Model (HRTM) proposed by the ICRP Publication 66 accounts for the morphology and physiology of the respiratory tract. The characteristics of air drawn into the lungs and exhaled are greatly influenced by the morphology of the respiratory tract, which causes numerous changes in pressure, flow rate, direction and humidity as air moves into and out of the lungs. The model uses morphological and physiological parameters from the Caucasian man to establish deposition fractions in the respiratory tract regions. The ICRP recommends, for a reliable evaluation of the regional deposition, the use of parameters from a local population when information is available. The main purpose of this study is to verify the influence in using the morphology and physiology parameters representative of a sample of the Brazilian population, in different levels of exercise, on the deposition model of the ICRP Publication 66. The deposition model was implemented using software Excel for Windows (version 2000). The results suggest a significant variation in fractional deposition when Brazilian parameters are applied in the model. The variations are not the same for all regions of the respiratory tract and depend on levels of exercise. (author)

  17. An exploratory pilot study into the association between microcirculatory parameters derived by MRI-based pharmacokinetic analysis and glucose utilization estimated by PET-CT imaging in head and neck cancer

    International Nuclear Information System (INIS)

    Bisdas, Sotirios; Ernemann, Ulrike; Seitz, Oliver; Chambron-Pinho, Nicole; Middendorp, Markus; Bisdas, Theodosios; Vogl, Thomas J.; Hammerstingl, Renate; Mack, Martin G.

    2010-01-01

    To examine the feasibility of deriving quantitative microcirculatory parameters and to investigate the relationship between vascular and metabolic characteristics of head and neck tumours in vivo, using dynamic contrast-enhanced (DCE) MRI and fluorodeoxyglucose (FDG) PET imaging. Twenty-seven patients with primary squamous cell carcinoma (SCCA) underwent DCE-MRI and combined PET/CT imaging. DCE-MRI data were post-processed by using commercially available software. Transfer constant (K trans ), extravascular extracellular blood volume (v e ), transfer constant from the extracellular extravascular space to plasma (k ep ) and iAUC (initial area under the signal intensity-time curve) were calculated. 3D static PET data were acquired and standardised uptake values (SUV) calculated. All microcirculatory parameters in tumours were higher than in normal muscle tissue (P ≤ 0.0019). Significant correlations were shown between k ep and K trans (ρ = 0.77), v e and k ep (ρ = -0.7), and iAUC and v e (ρ = 0.53). Significant correlations were observed for SUV mean and v e as well as iAUC (ρ = 0.42 and ρ = 0.66, respectively). SUV max was significantly correlated with iAUC (ρ = 0.69). The demonstrated relationships between vascular and metabolic characteristics of primary SCCA imply a complex interaction between vascular delivery characteristics and tumour metabolism. The lack of correlation between SUV and K trans /k ep suggests that both diagnostic techniques may provide complementary information. (orig.)

  18. Pharmacokinetic-Pharmacodynamic (PKPD) Analysis with Drug Discrimination.

    Science.gov (United States)

    Negus, S Stevens; Banks, Matthew L

    2016-08-30

    Discriminative stimulus and other drug effects are determined by the concentration of drug at its target receptor and by the pharmacodynamic consequences of drug-receptor interaction. For in vivo procedures such as drug discrimination, drug concentration at receptors in a given anatomical location (e.g., the brain) is determined both by the dose of drug administered and by pharmacokinetic processes of absorption, distribution, metabolism, and excretion that deliver drug to and from that anatomical location. Drug discrimination data are often analyzed by strategies of dose-effect analysis to determine parameters such as potency and efficacy. Pharmacokinetic-Pharmacodynamic (PKPD) analysis is an alternative to conventional dose-effect analysis, and it relates drug effects to a measure of drug concentration in a body compartment (e.g., venous blood) rather than to drug dose. PKPD analysis can yield insights on pharmacokinetic and pharmacodynamic determinants of drug action. PKPD analysis can also facilitate translational research by identifying species differences in pharmacokinetics and providing a basis for integrating these differences into interpretation of drug effects. Examples are discussed here to illustrate the application of PKPD analysis to the evaluation of drug effects in rhesus monkeys trained to discriminate cocaine from saline.

  19. Transient population dynamics of mosquitoes during sterile male releases: modelling mating behaviour and perturbations of life history parameters.

    Directory of Open Access Journals (Sweden)

    Christopher M Stone

    Full Text Available The release of genetically-modified or sterile male mosquitoes offers a promising form of mosquito-transmitted pathogen control, but the insights derived from our understanding of male mosquito behaviour have not fully been incorporated into the design of such genetic control or sterile-male release methods. The importance of aspects of male life history and mating behaviour for sterile-male release programmes were investigated by projecting a stage-structured matrix model over time. An elasticity analysis of transient dynamics during sterile-male releases was performed to provide insight on which vector control methods are likely to be most synergistic. The results suggest that high mating competitiveness and mortality costs of released males are required before the sterile-release method becomes ineffective. Additionally, if released males suffer a mortality cost, older males should be released due to their increased mating capacity. If released males are of a homogenous size and size-assortative mating occurs in nature, this can lead to an increase in the abundance of large females and reduce the efficacy of the population-suppression effort. At a high level of size-assortative mating, the disease transmission potential of the vector population increases due to male releases, arguing for the release of a heterogeneously-sized male population. The female population was most sensitive to perturbations of density-dependent components of larval mortality and female survivorship and fecundity. These findings suggest source reduction might be a particularly effective complement to mosquito control based on the sterile insect technique (SIT. In order for SIT to realize its potential as a key component of an integrated vector-management strategy to control mosquito-transmitted pathogens, programme design of sterile-male release programmes must account for the ecology, behaviour and life history of mosquitoes. The model used here takes a step in this

  20. Population dynamics of earthworms in relation to soil physico-chemical parameters in agroforestry systems of Mizoram, India.

    Science.gov (United States)

    Lalthanzara, H; Ramanujam, S N; Jha, L K

    2011-09-01

    Earthworm population dynamics was studied in two agroforestry systems in the tropical hilly terrain of Mizoram, north-east India, over a period of 24 months, from July 2002 to June 2004. Two sites of agroforestry situated at Sakawrtuichhun (SKT) and Pachhunga University College (PUC) campus, Aizawl, having pineapple as the main crop, were selected for detail studies on population dynamics. Five of the total twelve species of earthworm reported from the state were recorded in the study sites. The density of earthworm ranged from 6 to 243 ind.m(-2) and biomass from 3.2 - 677.64 g.m(-2) in SKT. Comparatively the density and biomass in PUC, which is at relatively higher altitude were lowerwith a range of 0 to 176 ind.m(-2) and biomass from 0 - 391.36 g.m(-2) respectively. Population dynamics of earthworm was significantly correlated with rainfall and physical characters of the soil. Earthworm biomass was significantly affected by rainfall and moisture content of the soil. The influence of chemical factors was relatively less.

  1. Using population demographic parameters to assess impacts of two polybrominated diphenyl ethers (BDE-47, BDE-209) on the rotifer Brachionus plicatilis.

    Science.gov (United States)

    Sha, Jingjing; Wang, You; Chen, Hongmei; Wang, Ming; Wang, Hong; Li, Xiaohong; Qi, Lei; Tang, Xuexi

    2015-09-01

    Polybrominated diphenyl ethers (PBDEs) are highly persistent anthropogenic contaminants found in the environment, posing a risk to aquatic ecosystems, whereas there is a lack of data concerning their impacts on marine invertebrates. The objective of this study was to assess the relative lethal and sublethal aquatic toxicity effects of two PBDEs, BDE-47 and BDE-209 congeners, on marine zooplankton rotifer Brachionus plicatilis associated with PBDE concentrations and time of exposure. Gas chromatography-mass spectrometry (GC-MS) analyses were performed to determine actual PBDE concentrations. Rotifer population demographic parameters from life tables, including age-specific survivorship (lx), age-specific fecundity (mx), net reproductive rate (R0), intrinsic rate of increase (rm), finite rate of increase (λ), life expectancy (E0) and generation time (T), were used as measures of treatment effects. Results from this study have revealed increasingly intense negative effects on many of the rotifer demographic parameters with elevated PBDE concentrations. The population growth curves of B. plicatilis showed almost no lag phase and reached peak abundances within 11 days, while B. plicatilis exposed to BDE-209 had a lag phase of about 5 days. In addition, increased PBDE levels reduced the population abundances and peak population densities of B. plicatilis. The two PBDEs have caused the carrying capacity (K) suppressed and the negative influence turned more serious as the concentration rose. Results also revealed that the time to reach growth curve inflection point (Tp) was shortened by PBDEs to different degrees. This study not only indicated that life table demography and population growth curve studies were two important aspects used to evaluate toxicant PBDE effects, but also compared the two PBDE disruptions to the population growth and reproduction of the rotifer. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Plasma and cerebrospinal fluid pharmacokinetics of flurbiprofen in children

    Science.gov (United States)

    Kumpulainen, Elina; Välitalo, Pyry; Kokki, Merja; Lehtonen, Marko; Hooker, Andrew; Ranta, Veli-Pekka; Kokki, Hannu

    2010-01-01

    AIMS This study was designed to characterize paediatric pharmacokinetics and central nervous system exposure of flurbiprofen. METHODS The pharmacokinetics of flurbiprofen were studied in 64 healthy children aged 3 months to 13 years, undergoing surgery with spinal anaesthesia. Children were administered preoperatively a single dose of flurbiprofen intravenously as prodrug (n = 27) or by mouth as syrup (n = 37). A single cerebrospinal fluid (CSF) sample (n = 60) was collected at the induction of anaesthesia, and plasma samples (n = 304) before, during and after the operation (up to 20 h after administration). A population pharmacokinetic model was built using the NONMEM software package. RESULTS Flurbiprofen concentrations in plasma were well described by a three compartment model. The apparent bioavailability of oral flurbiprofen syrup was 81%. The estimated clearance (CL) was 0.96 l h−1 70 kg−1. Age did not affect the clearance after weight had been included as a covariate. The estimated volume of distribution at steady state (Vss) was 8.1 l 70 kg−1. Flurbiprofen permeated into the CSF, reaching concentrations that were seven-fold higher compared with unbound plasma concentrations. CONCLUSIONS Flurbiprofen pharmacokinetics can be described using only weight as a covariate in children above 6 months, while more research is needed in neonates and in younger infants. PMID:20840447

  3. LC30 effects of thiamethoxam and pirimicarb, on population parameters and biological characteristics of Macrolophus pygmaeus (Hemiptera: Miridae

    Directory of Open Access Journals (Sweden)

    Shima Rahmani

    2016-06-01

    Full Text Available Chemical pesticides have important role in integrated pest management strategies. However, they can adversely affect on natural enemies as non-target organisms, even in sublethal concentrations. In this study, sublethal effects of two insecticides, thiamethoxam and pirimicarb, were examined on demographic parameters of an important predator, Macrolophus pygmaeus. Bioassay results indicated that LC30 of thiamethoxam and pirimicarb, applied on the third instar larvae, were 451.6 and 2013.4 mg (ai L-1, respectively. The two insecticides extended the pre-adult duration, significantly. Demographic parameters were analyzed by two-sex life table. The results showed that all of the main demographic traits (r, λ, R0 and T have been changed significantly and there are also some changes in other parameters such as age-specific survival rate (lx and life expectancy (ex. Intrinsic rate of increase in control was 0.15 but it reduced to 0.10 and 0.99 day-1 in thiamethoxam and pirimicarb treatments, respectively. Also, finite rate of increase in control, thiamethoxam and pirimicarb treatments was 1.11, 1.08 and 1.03 day-1 respectively. Reproductive rate in control showed 36.75 offspring/individual but this statistic in thiamethoxam and pirimicarb treatments was 19.62 and 18.24, respectively. Mean generation time was 22.69 days in control but it extended in both treatments and illustrated 27.79 and 31.24 days in thiamethoxam and pirimicarb treatments, respectively. Thus, obtained results in this study showed that although pirimicarb and thiamethoxam are selective insecticides, they have potential to affect on the predator, M. pygmaeus severely, and need to take care in IPM programs.

  4. Influence of various parameters on the calculation of the population exposure due to discharge of radioactive matter into the atmosphere

    International Nuclear Information System (INIS)

    Schmidtlein, P.

    1980-01-01

    The evaluation of the influences of the examined parameters on the calculation of the dose rate shows that a new concept for determination of the radiation exposure in the surroundings of nuclear facilities is required. A computing formalism based on theoretical considerations determines the effective activity absorbed and, after combination with dose rate factors, the effective dose rate per year. It is of great importance to verify the validity of the still incomplete input data for determination of the dose factors of the age groups 'infants' and 'children' and to prepare new data records. (DG) [de

  5. Conceptual parameters of acculturation within the Asian and Pacific Islander American populations: applications for nursing practice and research.

    Science.gov (United States)

    Baker, Dian

    2011-01-01

    Asian and Pacific Islander Americans (A&PIAs) are experiencing health inequities. For example, A&PIA is the only racial/ethnic group in America to experience cancer as their leading cause of death. Several studies within the A&PIA population have pointed to acculturation as a significant variable to explain their health and health-seeking behaviors. Acculturation is a key construct in understanding the health of the A&PIA population. The purpose of this concept analysis is to provide a current conceptual understanding of the relationship between acculturation and health, especially within the A&PIA populations, which will serve as a pragmatic guideline for nursing practice and research. Understanding the contemporary issues surrounding the conceptual application of acculturation will aid in the development of appropriate programs to reduce health inequities. Acculturation was explored using the Morse method of concept analysis. An iterative historical and contemporary literature review across the disciplines of anthropology, sociology, psychology, medicine, and nursing was completed. Analytical questions asked of the resultant data provided the theoretical definition, antecedents, key attributes, outcomes, and implications. The concept analysis resulted in a new theoretical definition that includes multidimensional concepts of acculturation. Dilemmas in the measurement of key attributes of acculturation include unidirectional and bidirectional analysis, psychometric issues, and the appropriateness of proxy measurements. Outcomes of acculturation on health can be positive or negative and depend on an individual's or group's ability to navigate freely with necessary supports. Results of the conceptual analysis resulted in recommendations for nursing practice and future acculturation research. While debate continues about the appropriate use and definition of acculturation, researchers agree that it is an important construct in understanding the health of migrating

  6. [Distribution, abundance and population parameters of Diapterus rhombeus (Pisces: Gerreidae) in Laguna de Términos, Campeche, Mexico].

    Science.gov (United States)

    Ayala-Pérez, L A; Gómez-Montes, B A; Miranda, J R

    2001-06-01

    Diapterus rhombeus dominates the nektonic community of Terminos Lagoon and is associated to zones with submerged vegetation, temperatures between 27 and 33 degrees C and salinity between 25 and 36.5 UPS. A total of 3,024 individuals were collected with a trawl net in 23 sites between September 1997 and September 1998. The length-weight model parameters are a = 0.0098; b = 3.155 with a 96% correlation. The growth parameters are L infinity = 20.4 cm, k = 0.74 and t(o) = -4.207 and the total mortality coefficient is 3.526. Fish length is 2.5-18.0 cm with a mode of 7.5 cm. Recruitment is continuous with a peak from May to August. The species uses several habitats of the lagoon mainly for feeding and growth, reproduction probably occurs in the adjacent continental shelf. Movements between continental shelf and the estuarine system represent a continuous energy flow.

  7. Probabilistic calculations and sensitivity analysis of parameters for a reference biosphere model assessing the potential exposure of a population to radionuclides from a deep geological repository

    Energy Technology Data Exchange (ETDEWEB)

    Staudt, Christian; Kaiser, Jan Christian [Helmholtz Zentrum Muenchen, Institute of Radiation Protection, Munich (Germany); Proehl, Gerhard [International Atomic Energy Agency, Division of Radiation, Transport and Waste Safety, Wagramerstrasse 5, 1400 Vienna (Austria)

    2014-07-01

    Radioecological models are used to assess the exposure of hypothetical populations to radionuclides. Potential radionuclide sources are deep geological repositories for high level radioactive waste. Assessment time frames are long since releases from those repositories are only expected in the far future, and radionuclide migration to the geosphere biosphere interface will take additional time. Due to the long time frames, climate conditions at the repository site will change, leading to changing exposure pathways and model parameters. To identify climate dependent changes in exposure in the far field of a deep geological repository a range of reference biosphere models representing climate analogues for potential future climate states at a German site were developed. In this approach, model scenarios are developed for different contemporary climate states. It is assumed that the exposure pathways and parameters of the contemporary biosphere in the far field of the repository will change to be similar to those at the analogue sites. Since current climate models cannot predict climate developments over the assessment time frame of 1 million years, analogues for a range of realistically possible future climate conditions were selected. These climate states range from steppe to permafrost climate. As model endpoint Biosphere Dose conversion factors (BDCF) are calculated. The radionuclide specific BDCF describe the exposure of a population to radionuclides entering the biosphere in near surface ground water. The BDCF are subject to uncertainties in the exposure pathways and model parameters. In the presented work, probabilistic and sensitivity analysis was used to assess the influence of model parameter uncertainties on the BDCF and the relevance of individual parameters for the model result. This was done for the long half-live radionuclides Cs-135, I-129 and U-238. In addition to this, BDCF distributions for nine climate reference regions and several scenarios were

  8. Association of renal biochemical parameters with left ventricular diastolic dysfunction in a community-based elderly population in China: a cross-sectional study.

    Directory of Open Access Journals (Sweden)

    Jingmin Zhou

    Full Text Available BACKGROUND: Relationship of left ventricular diastolic dysfunction (LVDD with parameters that could provide more information than hemodynamic renal indexes has not been clarified. We aimed to explore the association of comprehensive renal parameters with LVDD in a community-based elderly population. METHODS: 1,166 community residents (aged ≥ 65 years, 694 females participating in the Shanghai Heart Health Study with complete data of renal parameters were investigated. Echocardiography was used to evaluate diastolic function with conventional and tissue Doppler imaging techniques. Serum urea, creatinine, urea-to-creatinine ratio, estimated glomerular filtration rate (eGFR and urinary albumin-to-creatinine ratio (UACR were analyzed on their associations with LVDD. RESULTS: The prevalence of LVDD increased in proportion to increasing serum urea, urea-to-creatinine ratio and UACR. These three renal parameters were found negatively correlated to peak early (E to late (A diastolic velocities ratio (E/A, and positively to left atrial volume index; UACR also positively correlated with E to peak early (E' diastolic mitral annular velocity ratio (E/E'. Serum urea, urea-to-creatinine ratio and UACR correlated