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Sample records for based pharmacokinetic modeling

  1. MEGen: A Physiologically Based Pharmacokinetic Model Generator

    Directory of Open Access Journals (Sweden)

    GeorgeDLoizou

    2011-11-01

    Full Text Available Physiologically based pharmacokinetic models are being used in an increasing number of different areas. These not only include the human safety assessment of pharmaceuticals, pesticides, biocides and environmental chemicals but also for food animal, wild mammal and avian risk assessment. The value of PBPK models is that they are tools for estimating tissue dosimetry by integrating in vitro and in vivo mechanistic, pharmacokinetic and toxicological information through their explicit mathematical description of important anatomical, physiological and biochemical determinants of chemical uptake, disposition and elimination. However, PBPK models are perceived as complex, data hungry, resource intensive and time consuming. In addition, model validation and verification are hindered by the relative complexity of the equations. To begin to address these issues a freely available web application for the rapid construction and documentation of bespoke PBPK models is under development. Here we present an overview of the current capabilities of MEGen, a model equation generator and parameter database and discuss future developments.

  2. Physiologically based pharmacokinetic model for acetone.

    OpenAIRE

    Kumagai, S.; Matsunaga, I

    1995-01-01

    OBJECTIVE--This study aimed to develop a physiologically based pharmacokinetic model for acetone and to predict the kinetic behaviour of acetone in the human body with that model. METHODS--The model consists of eight tissue groups in which acetone can be distributed: the mucous layer of the inhaled air tract, the mucous layer of the exhaled air tract, a compartment for gas exchange (alveolus of the lung), a group of blood vessel rich tissues including the brain and heart, a group of tissues i...

  3. 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

  4. A PC-based graphical simulator for physiological pharmacokinetic models.

    Science.gov (United States)

    Wada, D R; Stanski, D R; Ebling, W F

    1995-04-01

    Since many intravenous anesthetic drugs alter blood flows, physiologically-based pharmacokinetic models describing drug disposition may be time-varying. Using the commercially available programming software MATLAB, a platform to simulate time-varying physiological pharmacokinetic models was developed. The platform is based upon a library of pharmacokinetic blocks which mimic physiological structure. The blocks can be linked together flexibly to form models for different drugs. Because of MATLAB's additional numerical capabilities (e.g. non-linear optimization), the platform provides a complete graphical microcomputer-based tool for physiologic pharmacokinetic modeling. PMID:7656558

  5. Modeling Pharmacokinetics.

    Science.gov (United States)

    Bois, Frederic Y; Brochot, Céline

    2016-01-01

    Pharmacokinetics is the study of the fate of xenobiotics in a living organism. Physiologically based pharmacokinetic (PBPK) models provide realistic descriptions of xenobiotics' absorption, distribution, metabolism, and excretion processes. They model the body as a set of homogeneous compartments representing organs, and their parameters refer to anatomical, physiological, biochemical, and physicochemical entities. They offer a quantitative mechanistic framework to understand and simulate the time-course of the concentration of a substance in various organs and body fluids. These models are well suited for performing extrapolations inherent to toxicology and pharmacology (e.g., between species or doses) and for integrating data obtained from various sources (e.g., in vitro or in vivo experiments, structure-activity models). In this chapter, we describe the practical development and basic use of a PBPK model from model building to model simulations, through implementation with an easily accessible free software. PMID:27311461

  6. Developing a Physiologically-Based Pharmacokinetic Model Knowledgebase in Support of Provisional Model Construction

    Science.gov (United States)

    Developing physiologically-based pharmacokinetic (PBPK) models for chemicals can be resource-intensive, as neither chemical-specific parameters nor in vivo pharmacokinetic data are easily available for model construction. Previously developed, well-parameterized, and thoroughly-v...

  7. Physiologically based pharmacokinetic models for trichloroethylene and its oxidative metabolites.

    OpenAIRE

    Fisher, J W

    2000-01-01

    Trichloroethylene (TCE) pharmacokinetics have been studied in experimental animals and humans for over 30 years. Compartmental and physiologically based pharmacokinetic (PBPK) models have been developed for the uptake, distribution, and metabolism of TCE and the production, distribution, metabolism, and elimination of P450-mediated metabolites of TCE. TCE is readily taken up into systemic circulation by oral and inhalation routes of exposure and is rapidly metabolized by the hepatic P450 syst...

  8. Physiologically-based pharmacokinetic modeling to predict the clinical pharmacokinetics of monoclonal antibodies.

    Science.gov (United States)

    Glassman, Patrick M; Balthasar, Joseph P

    2016-08-01

    Accurate prediction of the clinical pharmacokinetics of new therapeutic entities facilitates decision making during drug discovery, and increases the probability of success for early clinical trials. Standard strategies employed for predicting the pharmacokinetics of small-molecule drugs (e.g., allometric scaling) are often not useful for predicting the disposition monoclonal antibodies (mAbs), as mAbs frequently demonstrate species-specific non-linear pharmacokinetics that is related to mAb-target binding (i.e., target-mediated drug disposition, TMDD). The saturable kinetics of TMDD are known to be influenced by a variety of factors, including the sites of target expression (which determines the accessibility of target to mAb), the extent of target expression, the rate of target turnover, and the fate of mAb-target complexes. In most cases, quantitative information on the determinants of TMDD is not available during early phases of drug discovery, and this has complicated attempts to employ mechanistic mathematical models to predict the clinical pharmacokinetics of mAbs. In this report, we introduce a simple strategy, employing physiologically-based modeling, to predict mAb disposition in humans. The approach employs estimates of inter-antibody variability in rate processes of extravasation in tissues and fluid-phase endocytosis, estimates for target concentrations in tissues derived through use of categorical immunohistochemical scores, and in vitro measures of the turnover of target and target-mAb complexes. Monte Carlo simulations were performed for four mAbs (cetuximab, figitumumab, dalotuzumab, trastuzumab) directed against three targets (epidermal growth factor receptor, insulin-like growth factor receptor 1, human epidermal growth factor receptor 2). The proposed modeling strategy was able to predict well the pharmacokinetics of cetuximab, dalotuzumab, and trastuzumab at a range of doses, but trended towards underprediction of figitumumab concentrations

  9. Developing a Physiologically-Based Pharmacokinetic Model Knowledgebase in Support of Provisional Model Construction - poster

    Science.gov (United States)

    Building new physiologically based pharmacokinetic (PBPK) models requires a lot data, such as the chemical-specific parameters and in vivo pharmacokinetic data. Previously-developed, well-parameterized, and thoroughly-vetted models can be great resource for supporting the constr...

  10. Physiologically Based Pharmacokinetic Modeling in Pediatric Oncology Drug Development.

    Science.gov (United States)

    Rioux, Nathalie; Waters, Nigel J

    2016-07-01

    Childhood cancer represents more than 100 rare and ultra-rare diseases, with an estimated 12,400 new cases diagnosed each year in the United States. As such, this much smaller patient population has led to pediatric oncology drug development lagging behind that for adult cancers. Developing drugs for pediatric malignancies also brings with it a number of unique trial design considerations, including flexible enrollment approaches, age-appropriate formulation, acceptable sampling schedules, and balancing the need for age-stratified dosing regimens, given the smaller patient populations. The regulatory landscape for pediatric pharmacotherapy has evolved with U.S. Food and Drug Administration (FDA) legislation such as the 2012 FDA Safety and Innovation Act. In parallel, regulatory authorities have recommended the application of physiologically based pharmacokinetic (PBPK) modeling, for example, in the recently issued FDA Strategic Plan for Accelerating the Development of Therapies for Pediatric Rare Diseases. PBPK modeling provides a quantitative and systems-based framework that allows the effects of intrinsic and extrinsic factors on drug exposure to be modeled in a mechanistic fashion. The application of PBPK modeling in drug development for pediatric cancers is relatively nascent, with several retrospective analyses of cytotoxic therapies, and latterly for targeted agents such as obatoclax and imatinib. More recently, we have employed PBPK modeling in a prospective manner to inform the first pediatric trials of pinometostat and tazemetostat in genetically defined populations (mixed lineage leukemia-rearranged and integrase interactor-1-deficient sarcomas, respectively). In this review, we evaluate the application of PBPK modeling in pediatric cancer drug development and discuss the important challenges that lie ahead in this field. PMID:26936973

  11. Physiologically based pharmacokinetic modeling of cyclohexane as a tool for integrating animal and human test data

    NARCIS (Netherlands)

    Hissink, A.M.; Kulig, B.M.; Kruse, J.; Freidig, A.P.; Verwei, M.; Muijser, H.; Lammers, J.H.C.M.; Mckee, R.H.; Owen, D.E.; Sweeney, L.M.; Salmon, F.

    2009-01-01

    This report describes a physiologically based pharmacokinetic model for cyclohexane and its use in comparing internal doses in rats and volunteers following inhalation exposures. Parameters describing saturable metabolism of cyclohexane are measured in rats and used along with experimentally determi

  12. Physiologically based pharmacokinetic modeling of POPs in Greenlanders.

    Science.gov (United States)

    Sonne, Christian; Gustavson, Kim; Rigét, Frank F; Dietz, Rune; Krüger, Tanja; Bonefeld-Jørgensen, Eva C

    2014-03-01

    Human exposure to persistent organic pollutants (POPs) and the potential health impact in the Arctic far from the emission sources have been highlighted in numerous studies. As a supplement to human POP biomonitoring studies, a physiologically based pharmacokinetic (PBPK) model was set up to estimate the fate of POPs in Greenlandic Inuit's liver, blood, muscle and adipose tissue following long-term exposure to traditional Greenlandic diet. The PBPK model described metabolism, excretion and POP accumulation on the basis of their physicochemical properties and metabolic rates in the organisms. Basic correlations between chemically analyzed blood POP concentrations and calculated daily POP intake from food questionnaire of 118 middle age (18-35years) Greenlandic Inuits from four cities in West Greenland (Qaanaaq: n=40; Qeqertarsuaq: n=36; Nuuk: n=20; Narsaq: n=22) taken during 2003 to 2006 were analyzed. The dietary items included were polar bear, caribou, musk oxen, several marine species such as whales, seals, bird and fish as well as imported food. The contaminant concentrations of the dietary items as well as their chemical properties, uptake, biotransformation and excretion allowed us to estimate the POP concentration in liver, blood, muscle and adipose tissue following long-term exposure to the traditional Greenlandic diet using the PBPK model. Significant correlations were found between chemically analyzed POP blood concentrations and calculated daily intake of POPs for Qeqertarsuaq, Nuuk and Narsaq Inuit but not for the northernmost settlement Qaanaaq, probably because the highest blood POP level was found in this district which might mask the interview-based POP calculations. Despite the large variation in circulating blood POP concentrations, the PBPK model predicted blood concentrations of a factor 2-3 within the actual measured values. Moreover, the PBPK model showed that estimated blood POP concentration increased significantly after consumption of meals

  13. A comprehensive physiologically based pharmacokinetic knowledgebase and web-based interface for rapid model ranking and querying

    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 pa...

  14. Development of a physiologically based pharmacokinetic model for bisphenol A in pregnant mice

    International Nuclear Information System (INIS)

    Bisphenol A (BPA) is a weakly estrogenic monomer used to produce polymers for food contact and other applications, so there is potential for oral exposure of humans to trace amounts via ingestion. To date, no physiologically based pharmacokinetic (PBPK) model has been located for BPA in pregnant mice with or without fetuses. An estimate by a mathematical model is essential since information on humans is difficult to obtain experimentally. The PBPK model was constructed based on the pharmacokinetic data of our experiment following single oral administration of BPA to pregnant mice. The risk assessment of bisphenol A (BPA) on the development of human offspring is an important issue. There have been limited data on the exposure level of human fetuses to BPA (e.g. BPA concentration in cord blood) and no information is available on the pharmacokinetics of BPA in humans with or without fetuses. In the present study, we developed a physiologically based pharmacokinetic (PBPK) model describing the pharmacokinetics of BPA in a pregnant mouse with the prospect of future extrapolation to humans. The PBPK model was constructed based on the pharmacokinetic data of an experiment we executed on pregnant mice following single oral administration of BPA. The model could describe the rapid transfer of BPA through the placenta to the fetus and the slow disappearance from fetuses. The simulated time courses after three-time repeated oral administrations of BPA by the constructed model fitted well with the experimental data, and the simulation for the 10 times lower dose was also consistent with the experiment. This suggested that the PBPK model for BPA in pregnant mice was successfully verified and is highly promising for extrapolation to humans who are expected to be exposed more chronically to lower doses

  15. Human plasma concentrations of five cytochrome P450 probes extrapolated from pharmacokinetics in dogs and minipigs using physiologically based pharmacokinetic modeling.

    Science.gov (United States)

    Shida, Satomi; Yamazaki, Hiroshi

    2016-09-01

    The pharmacokinetics of cytochrome P450 probes in humans can be extrapolated from corresponding data in cynomolgus monkeys using simplified physiologically based pharmacokinetic (PBPK) modeling. In the current study, despite some species difference in drug clearances, this modeling methodology was adapted to estimate human plasma concentrations of P450 probes based on data from commonly used medium-sized experimental animals, namely dogs and minipigs. Using known species allometric scaling factors and in vitro metabolic clearance data, the observed plasma concentrations of slowly eliminated caffeine and warfarin and rapidly eliminated omeprazole, metoprolol and midazolam in two young dogs were scaled to human oral monitoring equivalents. Using the same approach, the previously reported pharmacokinetics of the five P450 probes in minipigs was also scaled to human monitoring equivalents. The human plasma concentration profiles of the five P450 probes estimated by the simplified human PBPK models based on observed/reported pharmacokinetics in dogs/minipigs were consistent with previously published pharmacokinetic data in humans. These results suggest that dogs and minipigs, in addition to monkeys, could be suitable models for humans during research into new drugs, especially when used in combination with simple PBPK models. PMID:26652678

  16. Pharmacokinetic modeling in aquatic animals. 1. Models and concepts

    Science.gov (United States)

    Barron, M.G.; Stehly, Guy R.; Hayton, W.L.

    1990-01-01

    While clinical and toxicological applications of pharmacokinetics have continued to evolve both conceptually and experimentally, pharmacokinetics modeling in aquatic animals has not progressed accordingly. In this paper we present methods and concepts of pharmacokinetic modeling in aquatic animals using multicompartmental, clearance-based, non-compartmental and physiologically-based pharmacokinetic models. These models should be considered as alternatives to traditional approaches, which assume that the animal acts as a single homogeneous compartment based on apparent monoexponential elimination.

  17. Physiologically based pharmacokinetic modeling of dibromoacetic acid in F344 rats

    OpenAIRE

    Jessica L. Matthews; Schultz, Irvin R.; Easterling, Michael R.; Melnick, Ronald L

    2010-01-01

    A novel physiologically based pharmacokinetic (PBPK) model structure, which includes submodels for the common metabolites (glyoxylate (GXA) and oxalate (OXA)) that may be involved in the toxicity or carcinogenicity of dibromoacetic acid (DBA), has been developed. Particular attention is paid to the representation of hepatic metabolism, which is the primary elimination mechanism. DBA-induced suicide inhibition is modeled by irreversible covalent binding of the intermediate metabolite α-halocar...

  18. Physiologically-based pharmacokinetic model for Fentanyl in support of the development of Provisional Advisory Levels

    International Nuclear Information System (INIS)

    Provisional Advisory Levels (PALs) are tiered exposure limits for toxic chemicals in air and drinking water that are developed to assist in emergency responses. Physiologically-based pharmacokinetic (PBPK) modeling can support this process by enabling extrapolations across doses, and exposure routes, thereby addressing gaps in the available toxicity data. Here, we describe the development of a PBPK model for Fentanyl – a synthetic opioid used clinically for pain management – to support the establishment of PALs. Starting from an existing model for intravenous Fentanyl, we first optimized distribution and clearance parameters using several additional IV datasets. We then calibrated the model using pharmacokinetic data for various formulations, and determined the absorbed fraction, F, and time taken for the absorbed amount to reach 90% of its final value, t90. For aerosolized pulmonary Fentanyl, F = 1 and t90 50 human datasets. • Model predictions are in good agreement with the available pharmacokinetic data. • The model can be used for extrapolating across routes, doses and exposure durations. • We illustrate how the model can be used for developing Provisional Advisory Levels

  19. Improved prediction of tacrolimus concentrations early after kidney transplantation using theory-based pharmacokinetic modelling

    Science.gov (United States)

    Størset, Elisabet; Holford, Nick; Hennig, Stefanie; Bergmann, Troels K; Bergan, Stein; Bremer, Sara; Åsberg, Anders; Midtvedt, Karsten; Staatz, Christine E

    2014-01-01

    Aims The aim was to develop a theory-based population pharmacokinetic model of tacrolimus in adult kidney transplant recipients and to externally evaluate this model and two previous empirical models. Methods Data were obtained from 242 patients with 3100 tacrolimus whole blood concentrations. External evaluation was performed by examining model predictive performance using Bayesian forecasting. Results Pharmacokinetic disposition parameters were estimated based on tacrolimus plasma concentrations, predicted from whole blood concentrations, haematocrit and literature values for tacrolimus binding to red blood cells. Disposition parameters were allometrically scaled to fat free mass. Tacrolimus whole blood clearance/bioavailability standardized to haematocrit of 45% and fat free mass of 60 kg was estimated to be 16.1 l h−1 [95% CI 12.6, 18.0 l h−1]. Tacrolimus clearance was 30% higher (95% CI 13, 46%) and bioavailability 18% lower (95% CI 2, 29%) in CYP3A5 expressers compared with non-expressers. An Emax model described decreasing tacrolimus bioavailability with increasing prednisolone dose. The theory-based model was superior to the empirical models during external evaluation displaying a median prediction error of −1.2% (95% CI −3.0, 0.1%). Based on simulation, Bayesian forecasting led to 65% (95% CI 62, 68%) of patients achieving a tacrolimus average steady-state concentration within a suggested acceptable range. Conclusion A theory-based population pharmacokinetic model was superior to two empirical models for prediction of tacrolimus concentrations and seemed suitable for Bayesian prediction of tacrolimus doses early after kidney transplantation. PMID:25279405

  20. A physiologically based pharmacokinetic model for the oxime TMB-4: simulation of rodent and human data.

    Science.gov (United States)

    Sterner, Teresa R; Ruark, Christopher D; Covington, Tammie R; Yu, Kyung O; Gearhart, Jeffery M

    2013-04-01

    Multiple oximes have been synthesized and evaluated for use as countermeasures against chemical warfare nerve agents. The current U.S. military and civilian oxime countermeasure, 2-[(hydroxyimino)methyl]-1-methylpyridin-1-ium chloride (2-PAM), is under consideration for replacement with a more effective acetylcholinesterase reactivator, 1,1'-methylenebis{4-hydroxyiminomethyl}pyridinium dimethanesulfonate (MMB-4). Kinetic data in the scientific literature for MMB-4 are limited; therefore, a physiologically based pharmacokinetic (PBPK) model was developed for a structurally related oxime, 1,1'-trimethylenebis{4-hydroximinomethyl}pyridinium dibromide. Based on a previous model structure for the organophosphate diisopropylfluorophosphate, the model includes key sites of acetylcholinesterase inhibition (brain and diaphragm), as well as fat, kidney, liver, rapidly perfused tissues and slowly perfused tissues. All tissue compartments are diffusion limited. Model parameters were collected from the literature, predicted using quantitative structure-property relationships or, when necessary, fit to available pharmacokinetic data from the literature. The model was parameterized using rat plasma, tissue and urine time course data from intramuscular administration, as well as human blood and urine data from intravenous and intramuscular administration; sensitivity analyses were performed. The PBPK model successfully simulates rat and human data sets and has been evaluated by predicting intravenous mouse and intramuscular human data not used in the development of the model. Monte Carlo analyses were performed to quantify human population kinetic variability in the human evaluation data set. The model identifies potential pharmacokinetic differences between rodents and humans, indicated by differences in model parameters between species. The PBPK model can be used to optimize the dosing regimen to improve oxime therapeutic efficacy in a human population. PMID:23314320

  1. Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling

    Institute of Scientific and Technical Information of China (English)

    Guo-fu LI; Kun WANG; Rui CHEN; Hao-ru ZHAO; Jin YANG; Qing-shan ZHENG

    2012-01-01

    Aim:To develop and evaluate a whole-body physiologically based pharmacokinetic (WB-PBPK) model of bisoprolol and to simulate its exposure and disposition in healthy adults and patients with renal function impairment.Methods:Bisoprolol dispositions in 14 tissue compartments were described by perfusion-limited compartments.Based the tissue composition equations and drug-specific properties such as log P,permeability,and plasma protein binding published in literatures,the absorption and whole-body distribution of bisoprolol was predicted using the ‘Advanced Compartmental Absorption Transit’ (ACAT)model and the whole-body disposition model,respectively.Renal and hepatic clearances were simulated using empirical scaling methods followed by incorporation into the WB-PBPK model.Model refinements were conducted after a comparison of the simulated concentration-time profiles and pharmacokinetic parameters with the observed data in healthy adults following intravenous and oral administration.Finally,the WB-PBPK model coupled with a Monte Carlo simulation was employed to predict the mean and variability of bisoprolol pharmacokinetics in virtual healthy subjects and patients.Results:The simulated and observed data after both intravenous and oral dosing showed good agreement for all of the dose levels in the reported normal adult population groups.The predicted pharmacokinetic parameters (AUC,Cmax,and Tmax) were reasonably consistent (<1.3-fold error) with the observed values after single oral administration of doses ranging from of 5 to 20 mg using the refined WB-PBPK model.The simulated plasma profiles after multiple oral administration of bisoprolol in healthy adults and patient with renal impairment matched well with the observed profiles.Conclusion:The WB-PBPK model successfully predicts the intravenous and oral pharmacokinetics of bisoprolol across multiple dose levels in diverse normal adult human populations and patients with renal insufficiency.

  2. Physiologically based pharmacokinetic modeling of PLGA nanoparticles with varied mPEG content

    Directory of Open Access Journals (Sweden)

    Avgoustakis K

    2012-03-01

    Full Text Available Mingguang Li1, Zoi Panagi2, Konstantinos Avgoustakis2, Joshua Reineke11Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA; 2Pharmaceutical Technology Laboratory, Department of Pharmacy, University of Patras, Rion, Patras, GreeceAbstract: Biodistribution of nanoparticles is dependent on their physicochemical properties (such as size, surface charge, and surface hydrophilicity. Clear and systematic understanding of nanoparticle properties' effects on their in vivo performance is of fundamental significance in nanoparticle design, development and optimization for medical applications, and toxicity evaluation. In the present study, a physiologically based pharmacokinetic model was utilized to interpret the effects of nanoparticle properties on previously published biodistribution data. Biodistribution data for five poly(lactic-co-glycolic acid (PLGA nanoparticle formulations prepared with varied content of monomethoxypoly (ethyleneglycol (mPEG (PLGA, PLGA-mPEG256, PLGA-mPEG153, PLGA-mPEG51, PLGA-mPEG34 were collected in mice after intravenous injection. A physiologically based pharmacokinetic model was developed and evaluated to simulate the mass-time profiles of nanoparticle distribution in tissues. In anticipation that the biodistribution of new nanoparticle formulations could be predicted from the physiologically based pharmacokinetic model, multivariate regression analysis was performed to build the relationship between nanoparticle properties (size, zeta potential, and number of PEG molecules per unit surface area and biodistribution parameters. Based on these relationships, characterized physicochemical properties of PLGA-mPEG495 nanoparticles (a sixth formulation were used to calculate (predict biodistribution profiles. For all five initial formulations, the developed model adequately simulates the experimental data indicating that the model is suitable for

  3. Physiologically based pharmacokinetic modeling to investigate regional brain distribution kinetics in rats.

    Science.gov (United States)

    Westerhout, Joost; Ploeger, Bart; Smeets, Jean; Danhof, Meindert; de Lange, Elizabeth C M

    2012-09-01

    One of the major challenges in the development of central nervous system (CNS)-targeted drugs is predicting CNS exposure in human from preclinical data. In this study, we present a methodology to investigate brain disposition in rats using a physiologically based modeling approach aiming at improving the prediction of human brain exposure. We specifically focused on quantifying regional diffusion and fluid flow processes within the brain. Acetaminophen was used as a test compound as it is not subjected to active transport processes. Microdialysis probes were implanted in striatum, for sampling brain extracellular fluid (ECF) concentrations, and in lateral ventricle (LV) and cisterna magna (CM), for sampling cerebrospinal fluid (CSF) concentrations. Serial blood samples were taken in parallel. These data, in addition to physiological parameters from literature, were used to develop a physiologically based model to describe the regional brain pharmacokinetics of acetaminophen. The concentration-time profiles of brain ECF, CSF(LV), and CSF(CM) indicate a rapid equilibrium with plasma. However, brain ECF concentrations are on average fourfold higher than CSF concentrations, with average brain-to-plasma AUC(0-240) ratios of 121%, 28%, and 35% for brain ECF, CSF(LV), and CSF(CM), respectively. It is concluded that for acetaminophen, a model compound for passive transport into, within, and out of the brain, differences exist between the brain ECF and the CSF pharmacokinetics. The physiologically based pharmacokinetic modeling approach is important, as it allowed the prediction of human brain ECF exposure on the basis of human CSF concentrations. PMID:22588644

  4. Development of a Human Physiologically Based Pharmacokinetics (PBPK) Model For Dermal Permeability for Lindane

    Science.gov (United States)

    Lindane is a neurotoxicant used for the treatment of lice and scabies present on human skin. Due to its pharmaceutical application, an extensive pharmacokinetic database exists in humans. Mathematical diffusion models allow for calculation of lindane skin permeability coefficient...

  5. Physiologically-based pharmacokinetic modeling of target-mediated drug disposition of bortezomib in mice.

    Science.gov (United States)

    Zhang, Li; Mager, Donald E

    2015-10-01

    Bortezomib is a reversible proteasome inhibitor with potent antineoplastic activity that exhibits dose- and time-dependent pharmacokinetics (PK). Proteasome-mediated bortezomib disposition is proposed as the primary source of its nonlinear and apparent nonstationary PK behavior. Single intravenous (IV) doses of bortezomib (0.25 and 1 mg/kg) were administrated to BALB/c mice, with blood and tissue samples obtained over 144 h, which were analyzed by LC/MS/MS. A physiologically based pharmacokinetic (PBPK) model incorporating tissue drug-target binding was developed to test the hypothesis of proteasome-mediated bortezomib disposition. The final model reasonably captured bortezomib plasma and tissue PK profiles, and parameters were estimated with good precision. The rank-order of model estimated tissue target density correlated well with experimentally measured proteasome concentrations reported in the literature, supporting the hypothesis that binding to proteasome influences bortezomib disposition. The PBPK model was further scaled-up to humans to assess the similarity of bortezomib disposition among species. Human plasma bortezomib PK profiles following multiple IV dosing (1.3 mg/m(2)) on days 1, 4, 8, and 11 were simulated by appropriately scaling estimated mouse parameters. Simulated and observed bortezomib concentrations after multiple dosing were in good agreement, suggesting target-mediated bortezomib disposition is likely for both mice and humans. Furthermore, the model predicts that renal impairment should exert minimal influence on bortezomib exposure in humans, confirming that bortezomib dose adjustment is not necessary for patients with renal impairment. PMID:26391023

  6. Physiologically based pharmacokinetic modeling for assessing the clinical drug-drug interaction of alisporivir.

    Science.gov (United States)

    Xia, Binfeng; Barve, Avantika; Heimbach, Tycho; Zhang, Tao; Gu, Helen; Wang, Lai; Einolf, Heidi; Alexander, Natalya; Hanna, Imad; Ke, June; Mangold, James B; He, Handan; Sunkara, Gangadhar

    2014-10-15

    Alisporivir is a novel cyclophilin-binding molecule with potent anti-hepatitis C virus (HCV) activity. In vitro data from human liver microsomes suggest that alisporivir is a substrate and a time-dependent inhibitor (TDI) of CYP3A4. The aim of the current work was to develop a novel physiologically based pharmacokinetic (PBPK) model to quantitatively assess the magnitude of CYP3A4 mediated drug-drug interactions with alisporivir as the substrate or victim drug. Towards that, a Simcyp PBPK model was developed by integrating in vitro data with in vivo clinical findings to characterize the clinical pharmacokinetics of alisporivir and further assess the magnitude of drug-drug interactions. Incorporated with absorption, distribution, elimination, and TDI data, the model accurately predicted AUC, Cmax, and tmax values after single or multiple doses of alisporivir with a prediction deviation within ± 32%. The model predicted an alisporivir AUC increase by 9.4-fold and a decrease by 86% when alisporivir was co-administrated with ketoconazole (CYP3A4 inhibitor) or rifampin (CYP3A4 inducer), respectively. Predictions were within ± 20% of the observed changes. In conclusion, the PBPK model successfully predicted the alisporivir PK and the magnitude of drug-drug interactions. PMID:25008118

  7. A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR TOLUENE IN THE LONG EVANS RAT: BODY COMPOSITION AND PHYSICAL ACTIVITY.

    Science.gov (United States)

    A physiologically-based pharmacokinetic (PBPK) model for inhaled toluene was developed for Long-Evans rats as a component of an exposure-dose-response (EDR) model for volatile organic compounds. The PBPK model was needed to link airborne toluene exposure to its concentration in b...

  8. Physiologically based modeling of the pharmacokinetics of acetaminophen and its major metabolites in humans using a Bayesian population approach.

    Science.gov (United States)

    Zurlinden, Todd J; Reisfeld, Brad

    2016-06-01

    The principal aim of this study was to develop, validate, and demonstrate a physiologically based pharmacokinetic (PBPK) model to predict and characterize the absorption, distribution, metabolism, and excretion of acetaminophen (APAP) in humans. A PBPK model was created that included pharmacologically and toxicologically relevant tissue compartments and incorporated mechanistic descriptions of the absorption and metabolism of APAP, such as gastric emptying time, cofactor kinetics, and transporter-mediated movement of conjugated metabolites in the liver. Through the use of a hierarchical Bayesian framework, unknown model parameters were estimated using a large training set of data from human pharmacokinetic studies, resulting in parameter distributions that account for data uncertainty and inter-study variability. Predictions from the model showed good agreement to a diverse test set of data across several measures, including plasma concentrations over time, renal clearance, APAP absorption, and pharmacokinetic and exposure metrics. The utility of the model was then demonstrated through predictions of cofactor depletion, dose response of several pharmacokinetic endpoints, and the relationship between APAP biomarker levels in the plasma and those in the liver. The model addressed several limitations in previous PBPK models for APAP, and it is anticipated that it will be useful in predicting the pharmacokinetics of APAP in a number of contexts, such as extrapolating across doses, estimating internal concentrations, quantifying population variability, assessing possible impacts of drug coadministration, and, when coupled with a suitable pharmacodynamic model, predicting toxicity. PMID:25636597

  9. Physiologically-based pharmacokinetic model for Fentanyl in support of the development of Provisional Advisory Levels

    Energy Technology Data Exchange (ETDEWEB)

    Shankaran, Harish, E-mail: harish.shankaran@pnnl.gov [Computational Biology and Bioinformatics Group, Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Adeshina, Femi [National Homeland Security Research Center, United States Environmental Protection Agency, Washington, DC 20460 (United States); Teeguarden, Justin G. [Systems Toxicology Group, Pacific Northwest National Laboratory, Richland, WA 99352 (United States)

    2013-12-15

    Provisional Advisory Levels (PALs) are tiered exposure limits for toxic chemicals in air and drinking water that are developed to assist in emergency responses. Physiologically-based pharmacokinetic (PBPK) modeling can support this process by enabling extrapolations across doses, and exposure routes, thereby addressing gaps in the available toxicity data. Here, we describe the development of a PBPK model for Fentanyl – a synthetic opioid used clinically for pain management – to support the establishment of PALs. Starting from an existing model for intravenous Fentanyl, we first optimized distribution and clearance parameters using several additional IV datasets. We then calibrated the model using pharmacokinetic data for various formulations, and determined the absorbed fraction, F, and time taken for the absorbed amount to reach 90% of its final value, t90. For aerosolized pulmonary Fentanyl, F = 1 and t90 < 1 min indicating complete and rapid absorption. The F value ranged from 0.35 to 0.74 for oral and various transmucosal routes. Oral Fentanyl was absorbed the slowest (t90 ∼ 300 min); the absorption of intranasal Fentanyl was relatively rapid (t90 ∼ 20–40 min); and the various oral transmucosal routes had intermediate absorption rates (t90 ∼ 160–300 min). Based on these results, for inhalation exposures, we assumed that all of the Fentanyl inhaled from the air during each breath directly, and instantaneously enters the arterial circulation. We present model predictions of Fentanyl blood concentrations in oral and inhalation scenarios relevant for PAL development, and provide an analytical expression that can be used to extrapolate between oral and inhalation routes for the derivation of PALs. - Highlights: • We develop a Fentanyl PBPK model for relating external dose to internal levels. • We calibrate the model to oral and inhalation exposures using > 50 human datasets. • Model predictions are in good agreement with the available

  10. Development of a physiologically based pharmacokinetic model for flunixin in cattle (Bos taurus).

    Science.gov (United States)

    Leavens, Teresa L; Tell, Lisa A; Kissell, Lindsey W; Smith, Geoffrey W; Smith, David J; Wagner, Sarah A; Shelver, Weilin L; Wu, Huali; Baynes, Ronald E; Riviere, Jim E

    2014-01-01

    Frequent violation of flunixin residues in tissues from cattle has been attributed to non-compliance with the USFDA-approved route of administration and withdrawal time. However, the effect of administration route and physiological differences among animals on tissue depletion has not been determined. The objective of this work was to develop a physiologically based pharmacokinetic (PBPK) model to predict plasma, liver and milk concentrations of flunixin in cattle following intravenous (i.v.), intramuscular (i.m.) or subcutaneous (s.c.) administration for use as a tool to determine factors that may affect the withdrawal time. The PBPK model included blood flow-limited distribution in all tissues and elimination in the liver, kidney and milk. Regeneration of parent flunixin due to enterohepatic recirculation and hydrolysis of conjugated metabolites was incorporated in the liver compartment. Values for physiological parameters were obtained from the literature, and partition coefficients for all tissues but liver and kidney were derived empirically. Liver and kidney partition coefficients and elimination parameters were estimated for 14 pharmacokinetic studies (including five crossover studies) from the literature or government sources in which flunixin was administered i.v., i.m. or s.c. Model simulations compared well with data for the matrices following all routes of administration. Influential model parameters included those that may be age or disease-dependent, such as clearance and rate of milk production. Based on the model, route of administration would not affect the estimated days to reach the tolerance concentration (0.125 mg kg(-1)) in the liver of treated cattle. The majority of USDA-reported violative residues in liver were below the upper uncertainty predictions based on estimated parameters, which suggests the need to consider variability due to disease and age in establishing withdrawal intervals for drugs used in food animals. The model predicted

  11. A Human Life-Stage Physiologically Based Pharmacokinetic and Pharmacodynamic Model for Chlorpyrifos: Development and Validation

    Energy Technology Data Exchange (ETDEWEB)

    Smith, Jordan N.; Hinderliter, Paul M.; Timchalk, Charles; Bartels, M. J.; Poet, Torka S.

    2014-08-01

    Sensitivity to chemicals in animals and humans are known to vary with age. Age-related changes in sensitivity to chlorpyrifos have been reported in animal models. A life-stage physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed to computationally predict disposition of CPF and its metabolites, chlorpyrifos-oxon (the ultimate toxicant) and 3,5,6-trichloro-2-pyridinol (TCPy), as well as B-esterase inhibition by chlorpyrifos-oxon in humans. In this model, age-dependent body weight was calculated from a generalized Gompertz function, and compartments (liver, brain, fat, blood, diaphragm, rapid, and slow) were scaled based on body weight from polynomial functions on a fractional body weight basis. Blood flows among compartments were calculated as a constant flow per compartment volume. The life-stage PBPK/PD model was calibrated and tested against controlled adult human exposure studies. Model simulations suggest age-dependent pharmacokinetics and response may exist. At oral doses ≥ 0.55 mg/kg of chlorpyrifos (significantly higher than environmental exposure levels), 6 mo old children are predicted to have higher levels of chlorpyrifos-oxon in blood and higher levels of red blood cell cholinesterase inhibition compared to adults from equivalent oral doses of chlorpyrifos. At lower doses that are more relevant to environmental exposures, the model predicts that adults will have slightly higher levels of chlorpyrifos-oxon in blood and greater cholinesterase inhibition. This model provides a computational framework for age-comparative simulations that can be utilized to predict CPF disposition and biological response over various postnatal life-stages.

  12. Predicting drug-drug interactions involving multiple mechanisms using physiologically based pharmacokinetic modeling: a case study with ruxolitinib.

    Science.gov (United States)

    Shi, J G; Fraczkiewicz, G; Williams, W V; Yeleswaram, S

    2015-02-01

    Physiologically based pharmacokinetic modeling was applied to characterize the potential drug-drug interactions for ruxolitinib. A ruxolitinib physiologically based pharmacokinetic model was constructed using all baseline PK data in healthy subjects, and verified by retrospective predictions of observed drug-drug interactions with rifampin (a potent CYP3A4 inducer), ketoconazole (a potent CYP3A4 reversible inhibitor) and erythromycin (a moderate time-dependent inhibitor of CYP3A4). The model prospectively predicts that 100-200 mg daily dose of fluconazole, a dual inhibitor of CYP3A4 and 2C9, would increase ruxolitinib plasma concentration area under the curve by ∼two-fold, and that as a perpetrator, ruxolitinib is highly unlikely to have any discernible effect on digoxin, a sensitive P-glycoprotein substrate. The analysis described here illustrates the capability of physiologically based pharmacokinetic modeling to predict drug-drug interactions involving several commonly encountered interaction mechanisms and makes the case for routine use of model-based prediction for clinical drug-drug interactions. A model verification checklist was explored to harmonize the methodology and use of physiologically based pharmacokinetic modeling. PMID:25670523

  13. Physiologically based pharmacokinetic modeling using microsoft excel and visual basic for applications.

    Science.gov (United States)

    Marino, Dale J

    2005-01-01

    Abstract Physiologically based pharmacokinetic (PBPK) models are mathematical descriptions depicting the relationship between external exposure and internal dose. These models have found great utility for interspecies extrapolation. However, specialized computer software packages, which are not widely distributed, have typically been used for model development and utilization. A few physiological models have been reported using more widely available software packages (e.g., Microsoft Excel), but these tend to include less complex processes and dose metrics. To ascertain the capability of Microsoft Excel and Visual Basis for Applications (VBA) for PBPK modeling, models for styrene, vinyl chloride, and methylene chloride were coded in Advanced Continuous Simulation Language (ACSL), Excel, and VBA, and simulation results were compared. For styrene, differences between ACSL and Excel or VBA compartment concentrations and rates of change were less than +/-7.5E-10 using the same numerical integration technique and time step. Differences using VBA fixed step or ACSL Gear's methods were generally Excel and VBA PBPK model dose metrics differed by no more than -0.013% or -0.23%, respectively, from ACSL results. These differences are likely attributable to different step sizes rather than different numerical integration techniques. These results indicate that Microsoft Excel and VBA can be useful tools for utilizing PBPK models, and given the availability of these software programs, it is hoped that this effort will help facilitate the use and investigation of PBPK modeling. PMID:20021074

  14. Prediction of interindividual variation in drug plasma levels in vivo from individual enzyme kinetic data and physiologically based pharmacokinetic modeling

    NARCIS (Netherlands)

    Bogaards, J.J.P.; Hissink, E.M.; Briggs, M.; Weaver, R.; Jochemsen, R.; Jackson, P.; Bertrand, M.; Bladeren, P. van

    2000-01-01

    A strategy is presented to predict interindividual variation in drug plasma levels in vivo by the use of physiologically based pharmacokinetic modeling and human in vitro metabolic parameters, obtained through the combined use of microsomes containing single cytochrome P450 enzymes and a human liver

  15. PHYSIOLOGICALLY-BASED PHARMACOKINETIC AND PHARMACODYNAMIC (PBPK/PD) MODEL FOR PREDICTING THE DERMAL DOSE AND DISPOSITION OF ORGANOPHOSPHORUS INSECTICIDES

    Science.gov (United States)

    Physiologically-based pharmacokinetic/ pharmacodynamic (PBPK/PD) models are particularly suited for interpretation of cumulative risk via the dermal route for which aggregate exposure must be assessed for chemicals having a common mechanism of toxicity. To this end, a quantita...

  16. Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of the Dopamine D-2 Receptor Occupancy of Olanzapine in Rats

    NARCIS (Netherlands)

    Johnson, Martin; Kozielska, Magdalena; Reddy, Venkatesh Pilla; Vermeulen, An; Li, Cheryl; Grimwood, Sarah; de Greef, Rik; Groothuis, Geny M. M.; Danhof, Meindert; Proost, Johannes H.

    2011-01-01

    A mechanism-based PK-PD model was developed to predict the time course of dopamine D-2 receptor occupancy (D2RO) in rat striatum following administration of olanzapine, an atypical antipsychotic drug. A population approach was utilized to quantify both the pharmacokinetics and pharmacodynamics of ol

  17. Analysing saturable antibody binding based on serum data and pharmacokinetic modelling

    Energy Technology Data Exchange (ETDEWEB)

    Kletting, Peter; Kiryakos, Hady; Reske, Sven N; Glatting, Gerhard, E-mail: gerhard.glatting@uni-ulm.d, E-mail: peter.kletting@uniklinik-ulm.d [Klinik fuer Nuklearmedizin, Universitaet Ulm, D-89070 Ulm (Germany)

    2011-01-07

    In radioimmunotherapy, organ dose calculations are frequently based on pretherapeutic biodistribution measurements, assuming equivalence between pretherapeutic and therapeutic biodistribution. However, when saturation of antibody binding sites is important, this assumption might not be justified. Residual antibody and different amounts of administered antibody may lead to a considerably altered therapeutic biodistribution. In this study we developed a method based on serum activity measurements to investigate this effect in radioimmunotherapy with {sup 90}Y-labelled anti-CD66 antibody. Pretherapeutic and therapeutic serum activity data of ten patients with acute leukaemia were fitted to a set of four parsimonious pharmacokinetic models. All models included the key mechanisms of antibody binding, immunoreactivity and degradation; however, they differed with respect to linear or nonlinear binding and global or individual fitting of the model parameters. The empirically most supported model was chosen according to the corrected Akaike information criterion. The nonlinear models were most supported by the data (sum of probabilities {approx}100%). Using the presented method, we identified relevant saturable binding for radioimmunotherapy with {sup 90}Y-labelled anti-CD66 antibody solely based on serum data. This general method may also be applicable to investigate other systems where saturation of binding sites might be important.

  18. Analysing saturable antibody binding based on serum data and pharmacokinetic modelling

    Science.gov (United States)

    Kletting, Peter; Kiryakos, Hady; Reske, Sven N.; Glatting, Gerhard

    2011-01-01

    In radioimmunotherapy, organ dose calculations are frequently based on pretherapeutic biodistribution measurements, assuming equivalence between pretherapeutic and therapeutic biodistribution. However, when saturation of antibody binding sites is important, this assumption might not be justified. Residual antibody and different amounts of administered antibody may lead to a considerably altered therapeutic biodistribution. In this study we developed a method based on serum activity measurements to investigate this effect in radioimmunotherapy with 90Y-labelled anti-CD66 antibody. Pretherapeutic and therapeutic serum activity data of ten patients with acute leukaemia were fitted to a set of four parsimonious pharmacokinetic models. All models included the key mechanisms of antibody binding, immunoreactivity and degradation; however, they differed with respect to linear or nonlinear binding and global or individual fitting of the model parameters. The empirically most supported model was chosen according to the corrected Akaike information criterion. The nonlinear models were most supported by the data (sum of probabilities ≈100%). Using the presented method, we identified relevant saturable binding for radioimmunotherapy with 90Y-labelled anti-CD66 antibody solely based on serum data. This general method may also be applicable to investigate other systems where saturation of binding sites might be important.

  19. Human-on-a-chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling.

    Science.gov (United States)

    Abaci, Hasan Erbil; Shuler, Michael L

    2015-04-01

    Advances in maintaining multiple human tissues on microfluidic platforms has led to a growing interest in the development of microphysiological systems for drug development studies. Determination of the proper design principles and scaling rules for body-on-a-chip systems is critical for their strategic incorporation into physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) model-aided drug development. While the need for a functional design considering organ-organ interactions has been considered, robust design criteria and steps to build such systems have not yet been defined mathematically. In this paper, we first discuss strategies for incorporating body-on-a-chip technology into the current PBPK modeling-based drug discovery to provide a conceptual model. We propose two types of platforms that can be involved in the different stages of PBPK modeling and drug development; these are μOrgans-on-a-chip and μHuman-on-a-chip. Then we establish the design principles for both types of systems and develop parametric design equations that can be used to determine dimensions and operating conditions. In addition, we discuss the availability of the critical parameters required to satisfy the design criteria, consider possible limitations for estimating such parameter values and propose strategies to address such limitations. This paper is intended to be a useful guide to the researchers focused on the design of microphysiological platforms for PBPK/PD based drug discovery. PMID:25739725

  20. Bayesian population analysis of a washin-washout physiologically based pharmacokinetic model for acetone

    International Nuclear Information System (INIS)

    The aim of this study was to derive improved estimates of population variability and uncertainty of physiologically based pharmacokinetic (PBPK) model parameters, especially of those related to the washin-washout behavior of polar volatile substances. This was done by optimizing a previously published washin-washout PBPK model for acetone in a Bayesian framework using Markov chain Monte Carlo simulation. The sensitivity of the model parameters was investigated by creating four different prior sets, where the uncertainty surrounding the population variability of the physiological model parameters was given values corresponding to coefficients of variation of 1%, 25%, 50%, and 100%, respectively. The PBPK model was calibrated to toxicokinetic data from 2 previous studies where 18 volunteers were exposed to 250-550 ppm of acetone at various levels of workload. The updated PBPK model provided a good description of the concentrations in arterial, venous, and exhaled air. The precision of most of the model parameter estimates was improved. New information was particularly gained on the population distribution of the parameters governing the washin-washout effect. The results presented herein provide a good starting point to estimate the target dose of acetone in the working and general populations for risk assessment purposes.

  1. Metformin and cimetidine: Physiologically based pharmacokinetic modelling to investigate transporter mediated drug-drug interactions.

    Science.gov (United States)

    Burt, H J; Neuhoff, S; Almond, L; Gaohua, L; Harwood, M D; Jamei, M; Rostami-Hodjegan, A; Tucker, G T; Rowland-Yeo, K

    2016-06-10

    Metformin is used as a probe for OCT2 mediated transport when investigating possible DDIs with new chemical entities. The aim of the current study was to investigate the ability of physiologically-based pharmacokinetic (PBPK) models to simulate the effects of OCT and MATE inhibition by cimetidine on metformin kinetics. PBPK models were developed, incorporating mechanistic kidney and liver sub-models for metformin (OCT and MATE substrate) and a mechanistic kidney sub-model for cimetidine. The models were used to simulate inhibition of the MATE1, MATE2-K, OCT1 and OCT2 mediated transport of metformin by cimetidine. Assuming competitive inhibition and using cimetidine Ki values determined in vitro, the predicted metformin AUC ratio was 1.0 compared to an observed value of 1.46. The observed AUC ratio could only be recovered with this model when the cimetidine Ki for OCT2 was decreased 1000-fold or the Ki's for both OCT1 and OCT2 were decreased 500-fold. An alternative description of metformin renal transport by OCT1 and OCT2, incorporating electrochemical modulation of the rate of metformin uptake together with 8-18-fold decreases in cimetidine Ki's for OCTs and MATEs, allowed recovery of the extent of the observed effect of cimetidine on metformin AUC. While the final PBPK model has limitations, it demonstrates the benefit of allowing for the complexities of passive permeability combined with active cellular uptake modulated by an electrochemical gradient and active efflux. PMID:27019345

  2. Meta-analysis of hepatic cytochrome P450 ontogeny to underwrite the prediction of pediatric pharmacokinetics using physiologically based pharmacokinetic modeling.

    Science.gov (United States)

    Upreti, Vijay V; Wahlstrom, Jan L

    2016-03-01

    The accurate prediction of pharmacokinetics (PK) is fundamental to underwriting safety and efficacy in pediatric clinical trials; age-dependent PK may be observed with pediatrics because of the growth and maturation processes that occur during development. Understanding the ontogeny of drug-metabolizing enzymes is a critical enabler for pediatric PK prediction, as enzyme expression or activity may change with age. Although ontogeny functions for the cytochrome P450s (CYPs) have been developed, disconnects between ontogeny functions for the same CYP may exist, depending on whether the functions were derived from in vitro or in vivo data. This report describes the development of ontogeny functions for all the major hepatic CYPs based on in vitro or in vivo data; these ontogeny functions were subsequently incorporated into a physiologically based pharmacokinetic model and evaluated. Pediatric PK predictions based on in vivo-derived ontogeny functions performed markedly better than those developed from in vitro data for intravenous (100% versus 51% within 2-fold, respectively) and oral (98% versus 67%, respectively) dosing. The verified models were then applied to complex pediatric scenarios involving active metabolites, CYP polymorphisms and physiological changes because of critical illness; the models reasonably explained the observed age-dependent changes in pediatric PK. PMID:26139104

  3. Reconstructing Organophosphorus Pesticide Doses Using the Reversed Dosimetry Approach in a Simple Physiologically-Based Pharmacokinetic Model

    Directory of Open Access Journals (Sweden)

    Chensheng Lu

    2012-01-01

    Full Text Available We illustrated the development of a simple pharmacokinetic (SPK model aiming to estimate the absorbed chlorpyrifos doses using urinary biomarker data, 3,5,6-trichlorpyridinol as the model input. The effectiveness of the SPK model in the pesticide risk assessment was evaluated by comparing dose estimates using different urinary composite data. The dose estimates resulting from the first morning voids appeared to be lower than but not significantly different to those using before bedtime, lunch or dinner voids. We found similar trend for dose estimates using three different urinary composite data. However, the dose estimates using the SPK model for individual children were significantly higher than those from the conventional physiologically based pharmacokinetic (PBPK modeling using aggregate environmental measurements of chlorpyrifos as the model inputs. The use of urinary data in the SPK model intuitively provided a plausible alternative to the conventional PBPK model in reconstructing the absorbed chlorpyrifos dose.

  4. A physiologically based pharmacokinetic model for ionic silver and silver nanoparticles

    Directory of Open Access Journals (Sweden)

    Bachler G

    2013-09-01

    Full Text Available Gerald Bachler, Natalie von Goetz, Konrad Hungerbühler ETH Zurich, Institute for Chemical and Bioengineering, Zurich, Switzerland Abstract: Silver is a strong antibiotic that is increasingly incorporated into consumer products as a bulk, salt, or nanosilver, thus potentially causing side-effects related to human exposure. However, the fate and behavior of (nanosilver in the human body is presently not well understood. In order to aggregate the existing experimental information, a physiologically based pharmacokinetic model (PBPK was developed in this study for ionic silver and nanosilver. The structure of the model was established on the basis of toxicokinetic data from intravenous studies. The number of calibrated parameters was minimized in order to enhance the predictive capability of the model. We validated the model structure for both silver forms by reproducing exposure conditions (dermal, oral, and inhalation of in vivo experiments and comparing simulated and experimentally assessed organ concentrations. Therefore, the percutaneous, intestinal, or pulmonary absorption fraction was estimated based on the blood silver concentration of the respective experimental data set. In all of the cases examined, the model could successfully predict the biodistribution of ionic silver and 15–150 nm silver nanoparticles, which were not coated with substances designed to prolong the circulatory time (eg, polyethylene glycol. Furthermore, the results of our model indicate that: (1 within the application domain of our model, the particle size and coating had a minor influence on the biodistribution; (2 in vivo, it is more likely that silver nanoparticles are directly stored as insoluble salt particles than dissolve into Ag+; and (3 compartments of the mononuclear phagocytic system play a minor role in exposure levels that are relevant for human consumers. We also give an example of how the model can be used in exposure and risk assessments based on five

  5. Physiologically based pharmacokinetic modeling of dibromoacetic acid in F344 rats

    International Nuclear Information System (INIS)

    A novel physiologically based pharmacokinetic (PBPK) model structure, which includes submodels for the common metabolites (glyoxylate (GXA) and oxalate (OXA)) that may be involved in the toxicity or carcinogenicity of dibromoacetic acid (DBA), has been developed. Particular attention is paid to the representation of hepatic metabolism, which is the primary elimination mechanism. DBA-induced suicide inhibition is modeled by irreversible covalent binding of the intermediate metabolite α-halocarboxymethylglutathione (αH1) to the glutathione-S-transferase zeta (GSTzeta) enzyme. We also present data illustrating the presence of a secondary non-GSTzeta metabolic pathway for DBA, but not dichloroacetic acid (DCA), that produces GXA. The model is calibrated with plasma and urine concentration data from DBA exposures in female F344 rats through intravenous (IV), oral gavage, and drinking water routes. Sensitivity analysis is performed to confirm identifiability of estimated parameters. Finally, model validation is performed with data sets not used during calibration. Given the structural similarity of dihaloacetates (DHAs), we hypothesize that the PBPK model presented here has the capacity to describe the kinetics of any member or mixture of members of this class in any species with the alteration of chemical-and species-specific parameters.

  6. A Physiologically Based Pharmacokinetic Model to Predict Disposition of CYP2D6 and CYP1A2 Metabolized Drugs in Pregnant Women

    OpenAIRE

    Ke, Alice Ban; Nallani, Srikanth C.; Zhao, Ping; Rostami-Hodjegan, Amin; Isoherranen, Nina; Unadkat, Jashvant D.

    2013-01-01

    Conducting pharmacokinetic (PK) studies in pregnant women is challenging. Therefore, we asked if a physiologically based pharmacokinetic (PBPK) model could be used to evaluate different dosing regimens for pregnant women. We refined and verified our previously published pregnancy PBPK model by incorporating cytochrome P450 CYP1A2 suppression (based on caffeine PK) and CYP2D6 induction (based on metoprolol PK) into the model. This model accounts for gestational age–dependent changes in materna...

  7. Physiologically Based Pharmacokinetic Modeling: Methodology, Applications, and Limitations with a Focus on Its Role in Pediatric Drug Development

    Directory of Open Access Journals (Sweden)

    Feras Khalil

    2011-01-01

    Full Text Available The concept of physiologically based pharmacokinetic (PBPK modeling was introduced years ago, but it has not been practiced significantly. However, interest in and implementation of this modeling technique have grown, as evidenced by the increased number of publications in this field. This paper demonstrates briefly the methodology, applications, and limitations of PBPK modeling with special attention given to discuss the use of PBPK models in pediatric drug development and some examples described in detail. Although PBPK models do have some limitations, the potential benefit from PBPK modeling technique is huge. PBPK models can be applied to investigate drug pharmacokinetics under different physiological and pathological conditions or in different age groups, to support decision-making during drug discovery, to provide, perhaps most important, data that can save time and resources, especially in early drug development phases and in pediatric clinical trials, and potentially to help clinical trials become more “confirmatory” rather than “exploratory”.

  8. A physiologically based pharmacokinetic model for lactational transfer of Na-131I

    Science.gov (United States)

    Turner, Anita Loretta

    The excretion of radionuclides in human breast milk after administration of radiopharmaceuticals is a concern as a radiation risk to nursing infants. It is not uncommon to administer radiopharmaceuticals to lactating patients due to emergency nuclear medicine investigations such as thyroid complications, kidney failure, and pulmonary embolism. There is a need to quantify the amount of radioactivity translocated into breast milk in cases of ingestion by a breast-fed infant. A physiologically based pharmacokinetic model (PBPK) and a modified International Commission on Radiological Protection (ICRP) model have been developed to predict iodine concentrations in breast milk after ingestion of radioiodine by the mother. In the PBPK model, all compartments are interconnected by blood flow and represent real anatomic tissue regions in the body. All parameters involved are measurable values with physiological or physiochemical meaning such as tissue masses, blood flow rates, partition coefficients and cardiac output. However, some of the parameters such as the partition coefficients and metabolic constants are not available for iodine and had to be inferred from other information. The structure of the PBPK model for the mother consists of the following tissue compartments: gastrointestinal tract, blood, kidney, thyroid, milk, and other tissues. With the exception of the milk compartment, the model for the nursing infant is structured similarly to the mother. The ICRP model describing iodine metabolism in a standard 70-kg man was modified to represent iodine metabolism in a lactating woman and nursing infant. The parameters involved in this model are transfer rates and biological half-lives which are based on experimental observations. The results of the PBPK model and the modified ICRP model describing the lactational transfer of iodine were compared. When administering 1 mCi of Na131I to the lactating mother, the concentration reaches a maximum of 0.1 mCi/liter in 24

  9. Quantitative evaluation of dichloroacetic acid kinetics in human--a physiologically based pharmacokinetic modeling investigation.

    Science.gov (United States)

    Li, Ting; Schultz, Irv; Keys, Deborah A; Campbell, Jerry L; Fisher, Jeffrey W

    2008-03-12

    Dichloroacetic acid is a common disinfection by-product in surface waters and is a probable minor metabolite of trichloroethylene. Dichloroacetic acid (DCA) liver carcinogenicity has been demonstrated in rodents but epidemiological evidence in humans is not available. High doses of DCA ( approximately 50mg/kg) are used clinically to treat metabolic acidosis. Biotransformation of DCA by glutathione transferase zeta (GSTzeta) in the liver is the major elimination pathway in humans. GSTzeta is also inactivated by DCA, leading to slower systemic clearance and nonlinear pharmacokinetics after multiple doses. A physiologically based pharmacokinetic (PBPK) model was developed to quantitatively describe DCA biotransformation and kinetics in humans administered DCA by intravenous infusion and oral ingestion. GSTzeta metabolism was described using a Michaelis-Menten equation coupled with rate constants to account for normal GSTzeta synthesis, degradation and irreversible covalent binding and inhibition by the glutathione-bound-DCA intermediate. With some departures between observation and model prediction, the human DCA PBPK model adequately predicted the DCA plasma kinetics over a 20,000-fold range in administered doses. Apparent inhibition of GSTzeta mediated metabolism of DCA was minimal for low doses of DCA (microg/kg day), but was significant for therapeutic doses of DCA. Plasma protein binding of DCA was assumed to be an important factor influencing the kinetics of low doses of DCA (microg/kg day). Polymorphisms of GSTzeta may help explain inter-individual variability in DCA plasma kinetics and warrants evaluation. In conclusion, using a previously published rodent DCA PBPK model (Keys, D.A., Schultz, I.R., Mahle, D.A., Fisher, J.W., 2004. A quantitative description of suicide inhibition of dichloroacetic acid in rats and mice. Toxicol. Sci. 82, 381-393) and this human DCA PBPK model, human equivalent doses (HEDs) were calculated for a 10% increase in mice hepatic

  10. Pharmacokinetic modeling of dynamic MR images using a simulated annealing-based optimization

    Science.gov (United States)

    Sawant, Amit R.; Reece, John H.; Reddick, Wilburn E.

    2000-04-01

    The aim of this work was to use dynamic contrast enhanced MR image (DEMRI) data to generate 'parameter images' which provide functional information about contrast agent access, in bone sarcoma. A simulated annealing based technique was applied to optimize the parameters of a pharmacokinetic model used to describe the kinetics of the tissue response during and after intravenous infusion of a paramagnetic contrast medium, Gd-DTPA. Optimization was performed on a pixel by pixel basis so as to minimize the sum of square deviations of the calculated values from the values obtained experimentally during dynamic contrast enhanced MR imaging. A cost function based on a priori information was introduced during the annealing procedure to ensure that the values obtained were within the expected ranges. The optimized parameters were used in the model to generate parameter images, which reveal functional information that is normally not visible in conventional Gd-DTPA enhanced MR images. This functional information, during and upon completion of pre-operative chemotherapy, is useful in predicting the probability of disease free survival.

  11. Physiologically based pharmacokinetic modeling of inhaled radon to calculate absorbed doses in mice, rats, and humans

    International Nuclear Information System (INIS)

    This is the first report to provide radiation doses, arising from inhalation of radon itself, in mice and rats. To quantify absorbed doses to organs and tissues in mice, rats, and humans, we computed the behavior of inhaled radon in their bodies on the basis of a physiologically based pharmacokinetic (PBPK) model. It was assumed that radon dissolved in blood entering the gas exchange compartment is transported to any tissue by the blood circulation to be instantaneously distributed according to a tissue/blood partition coefficient. The calculated concentrations of radon in the adipose tissue and red bone marrow following its inhalation were much higher than those in the others, because of the higher partition coefficients. Compared with a previous experimental data for rats and model calculation for humans, the present calculation was proved to be valid. Absorbed dose rates to organs and tissues were estimated to be within the range of 0.04-1.4 nGy (Bqm-3)-1 day-1 for all the species. Although the dose rates are not so high, it may be better to pay attention to the dose to the red bone marrow from the perspective of radiation protection. For more accurate dose assessment, it is necessary to update tissue/blood partition coefficients of radon that strongly govern the result of the PBPK modeling. (author)

  12. A physiologically based pharmacokinetic model for 2,4-toluenediamine leached from polyurethane foam-covered breast implants.

    OpenAIRE

    Luu, H M; Hutter, J C; Bushar, H. F.

    1998-01-01

    Physiologically based pharmacokinetic (PBPK) modeling was used to assess the low-dose exposure of patients to the carcinogen 2, 4-toluenediamine (2,4-TDA) released from the degradation of the polyester urethane foam (PU) used in Meme silicone breast implants. The tissues are represented as five compartments: liver, kidney, gastrointestinal tract, slowly perfused tissues (e.g., fat), and richly perfused tissues (e.g., muscle). The PBPK model was fitted to the plasma and urine concentrations of...

  13. IMPROVED TRANSFORMATION OF MORPHOMETRIC MEASUREMENTS FOR A PRIORI PARAMETER ESTIMATION IN A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL OF ETHANOL

    OpenAIRE

    Plawecki, Martin H.; DeCarlo, Ray; Ramchandani, Vijay A.; O’Connor, Sean

    2007-01-01

    Prescription of the brain’s time course of exposure to experimentally administered ethanol can be achieved with intravenous infusion profiles computed from a physiologically-based pharmacokinetic (PBPK) model of alcohol distribution and elimination. Previous parameter estimation employed transformations of an individual’s age, height, weight and gender inferred from the literature, with modeling errors overcome with real-time, intermittent feedback. Current research applications, such as etha...

  14. Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT—Part II: Physiologically Based Pharmacokinetic Modeling and Manganese Risk Assessment

    Directory of Open Access Journals (Sweden)

    Michael D. Taylor

    2012-01-01

    Full Text Available Recently, a variety of physiologically based pharmacokinetic (PBPK models have been developed for the essential element manganese. This paper reviews the development of PBPK models (e.g., adult, pregnant, lactating, and neonatal rats, nonhuman primates, and adult, pregnant, lactating, and neonatal humans and relevant risk assessment applications. Each PBPK model incorporates critical features including dose-dependent saturable tissue capacities and asymmetrical diffusional flux of manganese into brain and other tissues. Varied influx and efflux diffusion rate and binding constants for different brain regions account for the differential increases in regional brain manganese concentrations observed experimentally. We also present novel PBPK simulations to predict manganese tissue concentrations in fetal, neonatal, pregnant, or aged individuals, as well as individuals with liver disease or chronic manganese inhalation. The results of these simulations could help guide risk assessors in the application of uncertainty factors as they establish exposure guidelines for the general public or workers.

  15. Application of a Physiologically Based Pharmacokinetic Model to Study Theophylline Metabolism and Its Interactions With Ciprofloxacin and Caffeine.

    Science.gov (United States)

    Navid, A; Ng, D M; Wong, S E; Lightstone, F C

    2016-02-01

    Theophylline is a commonly used bronchodilator. However, due to its narrow therapeutic range, moderate elevation of serum concentration can result in adverse drug reactions (ADRs). ADRs occur because of interhuman pharmacokinetic variability and interactions with coprescribed medicines. We developed a physiologically based pharmacokinetic (PBPK) model of theophylline, caffeine, and ciprofloxacin metabolisms to: examine theophylline pharmacokinetic variability, and predict population-level outcomes of drug-drug interactions (DDIs). A simulation-based equation for personalized dosing of theophylline was derived. Simulations of DDI show that calculated personalized doses are safe even after cotreatment with large doses of strong inhibitors. Simulations of adult populations indicate that the elderly are most susceptible to ADRs stemming from theophylline-ciprofloxacin and theophylline-caffeine interactions. Females, especially Asians, due to their smaller average size, are more susceptible to DDI-induced ADRs following typical dosing practices. Our simulations also show that the higher adipose and lower muscle fractions in females significantly alter the pharmacokinetics of theophylline or ciprofloxacin. PMID:26933518

  16. Pharmacokinetic Interactions for Drugs with a Long Half-Life-Evidence for the Need of Model-Based Analysis

    OpenAIRE

    Svensson, Elin M.; Acharya, Chayan; Clauson, Björn; Dooley, Kelly E; Karlsson, Mats O

    2016-01-01

    Pharmacokinetic drug-drug interactions (DDIs) can lead to undesired drug exposure, resulting in insufficient efficacy or aggravated toxicity. Accurate quantification of DDIs is therefore crucial but may be difficult when full concentration-time profiles are problematic to obtain. We have compared non-compartmental analysis (NCA) and model-based predictions of DDIs for long half-life drugs by conducting simulation studies and reviewing published trials, using antituberculosis drug bedaquiline ...

  17. Physiologically based pharmacokinetic modeling of zinc oxide nanoparticles and zinc nitrate in mice

    Directory of Open Access Journals (Sweden)

    Chen WY

    2015-10-01

    Full Text Available Wei-Yu Chen,1 Yi-Hsien Cheng,2 Nan-Hung Hsieh,3 Bo-Chun Wu,2 Wei-Chun Chou,4 Chia-Chi Ho,4 Jen-Kun Chen,5 Chung-Min Liao,2,* Pinpin Lin4,* 1Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, 2Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, 3Institute of Labor, Occupational Safety and Health, Ministry of Labor, New Taipei City, 4National Institute of Environmental Health Sciences, 5Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Taiwan *These authors contributed equally to this work Abstract: Zinc oxide nanoparticles (ZnO NPs have been widely used in consumer products, therapeutic agents, and drug delivery systems. However, the fate and behavior of ZnO NPs in living organisms are not well described. The purpose of this study was to develop a physiologically based pharmacokinetic model to describe the dynamic interactions of 65ZnO NPs in mice. We estimated key physicochemical parameters of partition coefficients and excretion or elimination rates, based on our previously published data quantifying the biodistributions of 10 nm and 71 nm 65ZnO NPs and zinc nitrate (65Zn(NO32 in various mice tissues. The time-dependent partition coefficients and excretion or elimination rates were used to construct our physiologically based pharmacokinetic model. In general, tissue partition coefficients of 65ZnO NPs were greater than those of 65Zn(NO32, particularly the lung partition coefficient of 10 nm 65ZnO NPs. Sensitivity analysis revealed that 71 nm 65ZnO NPs and 65Zn(NO32 were sensitive to excretion and elimination rates in the liver and gastrointestinal tract. Although the partition coefficient of the brain was relative low, it increased time-dependently for 65ZnO NPs and 65Zn(NO32. The simulation of 65Zn(NO32 was well fitted with the experimental data. However, replacing partition coefficients of 65ZnO NPs with

  18. Model-based pharmacokinetic analysis of elotuzumab in patients with relapsed/refractory multiple myeloma.

    Science.gov (United States)

    Gibiansky, Leonid; Passey, Chaitali; Roy, Amit; Bello, Akintunde; Gupta, Manish

    2016-06-01

    Elotuzumab is a humanized immunoglobulin G1 monoclonal antibody in development for the treatment of patients with multiple myeloma who have received one or more prior therapies. In this work, 6958 elotuzumab serum concentrations from 375 patients enrolled in four Phase 1 to 3 clinical trials were used to analyze the pharmacokinetics (PK) of elotuzumab. A population PK model with parallel linear and Michaelis-Menten elimination from the central compartment and limited-capacity target-mediated elimination from the peripheral compartment described the elotuzumab concentration-time course. Clearance of elotuzumab increased with increasing body weight and weight-based dosing generated uniform exposures across a range of body weights. Coadministration of lenalidomide/dexamethasone background therapy decreased elotuzumab nonspecific clearance by 35 %. Target-mediated elimination of elotuzumab increased with increasing baseline serum M-protein, resulting in lower exposure in patients with high baseline serum M-protein concentration. Age, race, sex, renal and hepatic function, Eastern Cooperative Oncology Group performance status, lactate dehydrogenase, albumin and β2-microglobulin had less than 20 % effect on model parameters and are unlikely to have clinically meaningful effects. Impact of anti-drug antibodies (ADAs) on the PK of elotuzumab was assessed as an ad hoc analysis. In the majority of ADA-positive patients, immunogenicity started early, was transient and resolved by 2-4 months. Since the majority of patients had ADAs detected early, this resulted in a corresponding transient increase in nonspecific clearance at these time points. Nonspecific clearance appeared to return to baseline at later time points when ADAs were no longer detected. PMID:26993283

  19. Metabolism and physiologically based pharmacokinetic modeling of flumioxazin in pregnant animals

    International Nuclear Information System (INIS)

    A physiologically based pharmacokinetic (PBPK) model was developed to predict the concentration of flumioxazin, in the blood and fetus of pregnant humans during a theoretical accidental intake (1000 mg/kg). The data on flumioxazin concentration in pregnant rats (30 mg/kg po) was used to develop the PBPK model in pregnant rats using physiological parameters and chemical specific parameters. The rat PBPK model developed was extrapolated to a human model. Liver microsomes of female rats and a mixed gender of humans were used for the in vitro metabolism study. To determine the % of flumioxazin absorbed after administration at a dose of 1000 mg/kg assuming maximum accidental intake, the biliary excretion study of [phenyl-U-14C]flumioxazin was conducted in bile duct-cannulated female rats (Crl:CD (SD)) to collect and analyze the bile, urine, feces, gastrointestinal tract, and residual carcass. The % of flumioxazin absorbed at a dose of 1000 mg/kg in rats was low (12.3%) by summing up 14C of the urine, bile, and residual carcass. The pregnant human model that was developed demonstrated that the maximum flumioxazin concentration in the blood and fetus of a pregnant human at a dose of 1000 mg/kg po was 0.86 μg/mL and 0.68 μg/mL, respectively, which is much lower than Km (202.4 μg/mL). Because the metabolism was not saturated and the absorption rate was low at a dose of 1000 mg/kg, the calculated flumioxazin concentration in pregnant humans was thought to be relatively low, considering the flumioxazin concentration in pregnant rats at a dose of 30 mg/kg. For the safety assessment of flumioxazin, these results would be useful for further in vitro toxicology experiments. - Highlights: • A PBPK model of flumioxazin in pregnant humans was developed. • Simulated flumioxazin concentration in pregnant humans was relatively low. • The results would be useful for further in vitro toxicology experiments

  20. Metabolism and physiologically based pharmacokinetic modeling of flumioxazin in pregnant animals

    Energy Technology Data Exchange (ETDEWEB)

    Takaku, Tomoyuki, E-mail: takakut@sc.sumitomo-chem.co.jp; Nagahori, Hirohisa; Sogame, Yoshihisa

    2014-06-15

    A physiologically based pharmacokinetic (PBPK) model was developed to predict the concentration of flumioxazin, in the blood and fetus of pregnant humans during a theoretical accidental intake (1000 mg/kg). The data on flumioxazin concentration in pregnant rats (30 mg/kg po) was used to develop the PBPK model in pregnant rats using physiological parameters and chemical specific parameters. The rat PBPK model developed was extrapolated to a human model. Liver microsomes of female rats and a mixed gender of humans were used for the in vitro metabolism study. To determine the % of flumioxazin absorbed after administration at a dose of 1000 mg/kg assuming maximum accidental intake, the biliary excretion study of [phenyl-U-{sup 14}C]flumioxazin was conducted in bile duct-cannulated female rats (Crl:CD (SD)) to collect and analyze the bile, urine, feces, gastrointestinal tract, and residual carcass. The % of flumioxazin absorbed at a dose of 1000 mg/kg in rats was low (12.3%) by summing up {sup 14}C of the urine, bile, and residual carcass. The pregnant human model that was developed demonstrated that the maximum flumioxazin concentration in the blood and fetus of a pregnant human at a dose of 1000 mg/kg po was 0.86 μg/mL and 0.68 μg/mL, respectively, which is much lower than K{sub m} (202.4 μg/mL). Because the metabolism was not saturated and the absorption rate was low at a dose of 1000 mg/kg, the calculated flumioxazin concentration in pregnant humans was thought to be relatively low, considering the flumioxazin concentration in pregnant rats at a dose of 30 mg/kg. For the safety assessment of flumioxazin, these results would be useful for further in vitro toxicology experiments. - Highlights: • A PBPK model of flumioxazin in pregnant humans was developed. • Simulated flumioxazin concentration in pregnant humans was relatively low. • The results would be useful for further in vitro toxicology experiments.

  1. Model-Based Estimates of the Effects of Efavirenz on Bedaquiline Pharmacokinetics and Suggested Dose Adjustments for Patients Coinfected with HIV and Tuberculosis

    OpenAIRE

    Svensson, Elin M.; Aweeka, Francesca; Park, Jeong-Gun; Marzan, Florence; Dooley, Kelly E; Karlsson, Mats O

    2013-01-01

    Safe, effective concomitant treatment regimens for tuberculosis (TB) and HIV infection are urgently needed. Bedaquiline (BDQ) is a promising new anti-TB drug, and efavirenz (EFV) is a commonly used antiretroviral. Due to EFV's induction of cytochrome P450 3A4, the metabolic enzyme responsible for BDQ biotransformation, the drugs are expected to interact. Based on data from a phase I, single-dose pharmacokinetic study, a nonlinear mixed-effects model characterizing BDQ pharmacokinetics and int...

  2. Development of a physiologically based pharmacokinetic model for a domain antibody in mice using the two-pore theory.

    Science.gov (United States)

    Sepp, Armin; Berges, Alienor; Sanderson, Andrew; Meno-Tetang, Guy

    2015-04-01

    Domain antibodies (dAbs) are the smallest antigen-binding fragments of immunoglobulins. To date, there is limited insight into the pharmacokinetics of dAbs, especially their distribution into tissues and elimination. The objective of this work was to develop a physiologically-based pharmacokinetic model to investigate the biodisposition of a non-specific dAb construct in mice. Following a single IV administration of 10 mg/kg dummy dAb protein to twenty four female mice, frequent blood samples were collected and whole body lateral sections were analyzed by quantitative whole-body autoradiography. The model is based on the two-pore hypothesis of extravasation where organ-specific isogravimetric flow rates (Jorg,ISO) and permeability-surface area products (PSorg) are expressed as linear functions of the lymph flow rate (Jorg) and the kidney compartment is modified to account for glomerular filtration of dAb. As a result, only Jorg, glomerular filtration coefficient and the combined volume of Bowman's capsule, proximal and distal renal tubules and loop of Henle were optimized by fitting simultaneously all blood and organ data to the model. Our model captures the pharmacokinetic profiles of dAb in blood and all organs and shows that extravasation into interstitial space is a predominantly diffusion-driven process. The parameter values were estimated with good precision (%RMSE ≈ 30) and low cross-correlation (R(2) < 0.2). We developed a flexible model with a limited parameter number that may be applied to other biotherapeutics after adapting for size-related effects on extravasation and renal elimination processes. PMID:25577033

  3. Assessing drug distribution in tissues expressing P-glycoprotein through physiologically based pharmacokinetic modeling: model structure and parameters determination

    Directory of Open Access Journals (Sweden)

    Li Jun

    2009-01-01

    Full Text Available Abstract Background The expression and activity of P-glycoproteins due to genetic or environmental factors may have a significant impact on drug disposition, drug effectiveness or drug toxicity. Hence, characterization of drug disposition over a wide range of conditions of these membrane transporters activities is required to better characterize drug pharmacokinetics and pharmacodynamics. This work aims to improve our understanding of the impact of P-gp activity modulation on tissue distribution of P-gp substrate. Methods A PBPK model was developed in order to examine activity and expression of P-gp transporters in mouse brain and heart. Drug distribution in these tissues was first represented by a well-stirred (WS model and then refined by a mechanistic transport-based (MTB model that includes P-gp mediated transport of the drug. To estimate transport-related parameters, we developed an original three-step procedure that allowed extrapolation of in vitro measurements of drug permeability to the in vivo situation. The model simulations were compared to a limited set of data in order to assess the model ability to reproduce the important information of drug distributions in the considered tissues. Results This PBPK model brings insights into the mechanism of drug distribution in non eliminating tissues expressing P-gp. The MTB model accounts for the main transport mechanisms involved in drug distribution in heart and brain. It points out to the protective role of P-gp at the blood-brain barrier and represents thus a noticeable improvement over the WS model. Conclusion Being built prior to in vivo data, this approach brings an interesting alternative to fitting procedures, and could be adapted to different drugs and transporters. The physiological based model is novel and unique and brought effective information on drug transporters.

  4. Physiologically based pharmacokinetic models of small molecules and therapeutic antibodies: a mini-review on fundamental concepts and applications.

    Science.gov (United States)

    Ferl, Gregory Z; Theil, Frank-Peter; Wong, Harvey

    2016-03-01

    The mechanisms of absorption, distribution, metabolism and elimination of small and large molecule therapeutics differ significantly from one another and can be explored within the framework of a physiologically based pharmacokinetic (PBPK) model. This paper briefly reviews fundamental approaches to PBPK modeling, in which drug kinetics within tissues and organs are explicitly represented using physiologically meaningful parameters. The differences in PBPK models applied to small/large molecule drugs are highlighted, thus elucidating differences in absorption, distribution and elimination properties between these two classes of drugs in a systematic manner. The absorption of small and large molecules differs with respect to their common extravascular routes of delivery (oral versus subcutaneous). The role of the lymphatic system in drug distribution, and the involvement of tissues as sites of elimination (through catabolism and target mediated drug disposition) are unique features of antibody distribution and elimination that differ from small molecules, which are commonly distributed into the tissues but are eliminated primarily by liver metabolism. Fundamental differences exist in the ability to predict human pharmacokinetics based upon preclinical data due to differing mechanisms governing small and large molecule disposition. These differences have influence on the evolving utilization of PBPK modeling in the discovery and development of small and large molecule therapeutics. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26461173

  5. Prediction of the pharmacokinetics and tissue distribution of levofloxacin in humans based on an extrapolated PBPK model.

    Science.gov (United States)

    Zhu, Liqin; Zhang, Yuan; Yang, Jianwei; Wang, Yongming; Zhang, Jianlei; Zhao, Yuanyuan; Dong, Weilin

    2016-08-01

    This study developed a physiologically based pharmacokinetic (PBPK) model in intraabdominally infected rats and extrapolated it to humans to predict the levofloxacin pharmacokinetics and penetration into tissues. Twelve male rats with intraabdominal infections induced by Escherichia coli received a single dose of 50 mg/kg body weight of levofloxacin. Blood plasma was collected at 5, 10, 20, 30, 60, 120, 240, 480 and 1440 min after injection, respectively. A PBPK model was developed in rats and extrapolated to humans using GastroPlus software. The predictions were assessed by comparing predictions and observations. In the plasma concentration-versus-time profile of levofloxacin in rats, C max was 23.570 μg/ml at 5 min after intravenous injection, and t1/2 was 2.38 h. The plasma concentration and kinetics in humans were predicted and validated by the observed data. Levofloxacin penetrated and accumulated with high concentrations in the heart, liver, kidney, spleen, muscle and skin tissues in humans. The predicted tissue-to-plasma concentration ratios in abdominal viscera were between 1.9 and 2.3. When rat plasma concentrations were known, extrapolation of a PBPK model was a method to predict the drug pharmacokinetics and penetration in humans. Levofloxacin had good penetration into the liver, kidney and spleen as well as other tissues in humans. This pathological model extrapolation may provide a reference for the study of antiinfective PK/PD. In our study, levofloxacin penetrated well into abdominal organs. Also ADR monitoring should be implemented when using levofloxacin. PMID:25753830

  6. Reproductive performance in East Greenland polar bears (Ursus maritimus) may be affected by organohalogen contaminants as shown by physiologically-based pharmacokinetic (PBPK) modelling

    DEFF Research Database (Denmark)

    Sonne, Christian; Gustavson, Kim; Rigét, Frank F.;

    2009-01-01

    quotient (RQ) evaluation to more quantitatively evaluate the effect risk on reproduction (embryotoxicity and teratogenicity) based on the critical body residue (CBR) concept and using a physiologically-based pharmacokinetic (PBPK) model. We applied modelling approaches to PCBs, p,p′-DDE, dieldrin...

  7. Physiologically-based pharmacokinetic modelling and simulation of oral drug bioavailability: Focus on bariatric surgery patients and mechanism-based inhibition of gut wall metabolism

    OpenAIRE

    Darwich, Adam Saed

    2014-01-01

    AbstractTHE UNIVERSITY OF MANCHESTER,Abstract of thesis submitted by Adam S. Darwich, for the degree of PhD and entitled: "Physiologically-based pharmacokinetic modelling and simulation of oral drug bioavailability: Focus on bariatric surgery patients and mechanism-based inhibition of gut wall metabolism"Month and year of submission: November 2013.Understanding the processes that govern pre-systemic drug absorption and elimination is of high importance in pharmaceutical research and developme...

  8. Moxifloxacin Population Pharmacokinetics and Model-Based Comparison of Efficacy between Moxifloxacin and Ofloxacin in African Patients

    OpenAIRE

    Zvada, Simbarashe P.; Denti, Paolo; Sirgel, Frederick A.; Chigutsa, Emmanuel; Hatherill, Mark; Charalambous, Salome; Mungofa, Stanley; Wiesner, Lubbe; Simonsson, Ulrika S. H.; Jindani, Amina; Harrison, Thomas; McIlleron, Helen M.

    2014-01-01

    Pharmacokinetic exposure and the MIC of fluoroquinolones are important determinants of their efficacy against Mycobacterium tuberculosis. Population modeling was used to describe the steady-state plasma pharmacokinetics of moxifloxacin in 241 tuberculosis (TB) patients in southern Africa. Monte Carlo simulations were applied to obtain the area under the unbound concentration-time curve from 0 to 24 h (fAUC0–24) after daily doses of 400 mg or 800 mg moxifloxacin and 800 mg ofloxacin. The MIC d...

  9. Pharmacokinetic Interactions for Drugs with a Long Half-Life—Evidence for the Need of Model-Based Analysis.

    Science.gov (United States)

    Svensson, Elin M; Acharya, Chayan; Clauson, Björn; Dooley, Kelly E; Karlsson, Mats O

    2016-01-01

    Pharmacokinetic drug-drug interactions (DDIs) can lead to undesired drug exposure, resulting in insufficient efficacy or aggravated toxicity. Accurate quantification of DDIs is therefore crucial but may be difficult when full concentration-time profiles are problematic to obtain. We have compared non-compartmental analysis (NCA) and model-based predictions of DDIs for long half-life drugs by conducting simulation studies and reviewing published trials, using antituberculosis drug bedaquiline (BDQ) as a model compound. Furthermore, different DDI study designs were evaluated. A sequential design mimicking conducted trials and a population pharmacokinetic (PK) model of BDQ and the M2 metabolite were utilized in the simulations where five interaction scenarios from strong inhibition (clearance fivefold decreased) to strong induction (clearance fivefold increased) were evaluated. In trial simulations, NCA systematically under-predicted the DDIs’ impact. The bias in average exposure was 29–96% for BDQ and 20–677% for M2. The model-based analysis generated unbiased predictions, and simultaneous fitting of metabolite data increased precision in DDI predictions. The discrepancy between the methods was also apparent for conducted trials, e.g., lopinavir/ritonavir was predicted to increased BDQ exposure 22% by NCA and 188% by model-based methods. In the design evaluation, studies with parallel designs were considered and shown to generally be inferior to sequential/cross-over designs. However, in the case of low inter-individual variability and no informative metabolite data, a prolonged parallel design could be favored. Model-based analysis for DDI assessments is preferable over NCA for victim drugs with a long half-life and should always be used when incomplete concentration-time profiles are part of the analysis. PMID:26463060

  10. Prediction of drug-drug interactions between various antidepressants and ritonavir using a physiologically based pharmacokinetic model

    Directory of Open Access Journals (Sweden)

    M Siccardi

    2012-11-01

    Full Text Available Depression can impact on the treatment of HIV infection, and effective treatment of depressive conditions can have a beneficial effect improving adherence. However antidepressant treatment requires long-term maintenance, and is prone to pharmacokinetic drug-drug interactions (DDI with antiretrovirals. The aim of this study was to predict the magnitude of DDI between ritonavir (RTV and the most commonly prescribed antidepressants using a physiologically based pharmacokinetic (PBPK model simulating virtual clinical trials. In vitro data describing the physiochemical properties, absorption, metabolism, induction and inhibitory potential of RTV and five antidepressants were obtained from published literature. Interactions between RTV and antidepressants were evaluated using the full PBPK model implemented in the Simcyp Population-based Simulator (Version 11.1, Simcyp Limited, UK and virtual clinical studies were simulated on 50 Caucasian subjects receiving 100mg bid of RTV for 21 days plus sertraline (100mg qd, citalopram (40mg qd, fluoxetine (20mg qd, venlafaxine (25mg qd and then from day 14–21. Simulated pharmacokinetic parameters were compared with observed values available in the literature. The simulated PK parameters of RTV, sertraline, citalopram, fluoxetine, mirtazepine and venlafaxine given alone at standard dosage were similar to reference values obtain from published clinical studies. The effect of simulated RTV co-administration on sertaline, fluoxetine and venlaflaxine was an AUC decrease of 40%, 26% and 6%, respectively and on mirtazepine and citalopram, an AUC increase of 60% and 20% respectively. The magnitude of the simulated DDI between RTV and the antidepressants was overall weak to moderate according to the classification of the FDA. The modest magnitude of these drug-drug interactions could be explained by the fact that antidepressants are substrates of multiple isoforms thus metabolism can still occur through CYPs that are

  11. Human plasma concentrations of tolbutamide and acetaminophen extrapolated from in vivo animal pharmacokinetics using in vitro human hepatic clearances and simple physiologically based pharmacokinetic modeling for radio-labeled microdose clinical studies

    International Nuclear Information System (INIS)

    The aim of the current study was to extrapolate the pharmacokinetics of drug substances orally administered in humans from rat pharmacokinetic data using tolbutamide and acetaminophen as model compounds. Adjusted animal biomonitoring equivalents from rat studies based on reported plasma concentrations were scaled to human biomonitoring equivalents using known species allometric scaling factors. In this extrapolation, in vitro metabolic clearance data were obtained using liver preparations. Rates of tolbutamide elimination were roughly similar in rat and human liver microsome experiments, but acetaminophen elimination by rat liver microsomes and cytosolic preparations showed a tendency to be faster than those in humans. Using a simple physiologically based pharmacokinetic (PBPK) model, estimated human plasma concentrations of tolbutamide and acetaminophen were consistent with reported concentrations. Tolbutamide cleared in a roughly similar manner in humans and rats, but medical-dose levels of acetaminophen cleared (dependent on liver metabolism) more slowly from plasma in humans than it did in rats. The data presented here illustrate how pharmacokinetic data in combination with a simple PBPK model can be used to assist evaluations of the pharmacological/toxicological potential of new drug substances and for estimating human radiation exposures from radio-labeled drugs when planning human studies. (author)

  12. Bayesian inference for generalized linear mixed model based on the multivariate t distribution in population pharmacokinetic study.

    Directory of Open Access Journals (Sweden)

    Fang-Rong Yan

    Full Text Available This article provides a fully bayesian approach for modeling of single-dose and complete pharmacokinetic data in a population pharmacokinetic (PK model. To overcome the impact of outliers and the difficulty of computation, a generalized linear model is chosen with the hypothesis that the errors follow a multivariate Student t distribution which is a heavy-tailed distribution. The aim of this study is to investigate and implement the performance of the multivariate t distribution to analyze population pharmacokinetic data. Bayesian predictive inferences and the Metropolis-Hastings algorithm schemes are used to process the intractable posterior integration. The precision and accuracy of the proposed model are illustrated by the simulating data and a real example of theophylline data.

  13. Estimating Margin of Exposure to Thyroid Peroxidase Inhibitors Using High-Throughput in vitro Data, High-Throughput Exposure Modeling, and Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling.

    Science.gov (United States)

    Leonard, Jeremy A; Tan, Yu-Mei; Gilbert, Mary; Isaacs, Kristin; El-Masri, Hisham

    2016-05-01

    Some pharmaceuticals and environmental chemicals bind the thyroid peroxidase (TPO) enzyme and disrupt thyroid hormone production. The potential for TPO inhibition is a function of both the binding affinity and concentration of the chemical within the thyroid gland. The former can be determined through in vitro assays, and the latter is influenced by pharmacokinetic properties, along with environmental exposure levels. In this study, a physiologically based pharmacokinetic (PBPK) model was integrated with a pharmacodynamic (PD) model to establish internal doses capable of inhibiting TPO in relation to external exposure levels predicted through exposure modeling. The PBPK/PD model was evaluated using published serum or thyroid gland chemical concentrations or circulating thyroxine (T4) and triiodothyronine (T3) hormone levels measured in rats and humans. After evaluation, the model was used to estimate human equivalent intake doses resulting in reduction of T4 and T3 levels by 10% (ED10) for 6 chemicals of varying TPO-inhibiting potencies. These chemicals were methimazole, 6-propylthiouracil, resorcinol, benzophenone-2, 2-mercaptobenzothiazole, and triclosan. Margin of exposure values were estimated for these chemicals using the ED10 and predicted population exposure levels for females of child-bearing age. The modeling approach presented here revealed that examining hazard or exposure alone when prioritizing chemicals for risk assessment may be insufficient, and that consideration of pharmacokinetic properties is warranted. This approach also provides a mechanism for integrating in vitro data, pharmacokinetic properties, and exposure levels predicted through high-throughput means when interpreting adverse outcome pathways based on biological responses. PMID:26865668

  14. An Age-Dependent Physiologically-Based Pharmacokinetic/Pharmacodynamic Model for the Organophosphorus Insecticide Chlorpyrifos in the Preweanling Rat

    Energy Technology Data Exchange (ETDEWEB)

    Timchalk, Chuck; Kousba, Ahmed A.; Poet, Torka S.

    2007-08-01

    Juvenile rats are more susceptible than adults to the acute toxicity of organophosphorus insecticides like chlorpyrifos (CPF). Age- and dose-dependent differences in metabolism may be responsible. Of importance is CYP450 activation and detoxification of CPF to chlorpyrifos-oxon (CPF-oxon) and trichloropyridinol (TCP), as well as B-esterase (cholinesterase; ChE) and A-esterase (PON-1) detoxification of CPF-oxon to TCP. In the current study, a modified physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model incorporating age-dependent changes in CYP450, PON-1, and tissue ChE levels for rats was developed. In this model, age was used as a dependent function to estimate body weight which was then used to allometrically scale both metabolism and tissue ChE levels. Model simulations suggest that preweanling rats are particularly sensitive to CPF toxicity, with levels of CPF-oxon in blood and brain disproportionately increasing, relative to the response in adult rats. This age-dependent non-linear increase in CPF-oxon concentration may potentially result from the depletion of non-target B-esterases, and a lower PON-1 metabolic capacity in younger animals. These results indicate that the PBPK/PD model behaves consistently with the general understanding of CPF toxicity, pharmacokinetics and tissue ChE inhibition in neonatal and adult rats. Hence, this model represents an important starting point for developing a computational model to assess the neurotoxic potential of environmentally relevant organophosphate exposures in infants and children.

  15. Predicting dermal penetration for ToxCast chemicals using in silico estimates for diffusion in combination with physiologically based pharmacokinetic (PBPK) modeling.

    Science.gov (United States)

    Predicting dermal penetration for ToxCast chemicals using in silico estimates for diffusion in combination with physiologically based pharmacokinetic (PBPK) modeling.Evans, M.V., Sawyer, M.E., Isaacs, K.K, and Wambaugh, J.With the development of efficient high-throughput (HT) in ...

  16. Use of novel inhalation kinetic studies to refine physiologically-based-pharmacokinetic models for ethanol in non-pregnant and pregnant rats

    Science.gov (United States)

    Ethanol (EtOH) exposure induces a variety of concentration-dependent neurological and developmental effects in the rat. Physiologically-based pharmacokinetic (PBPK) models have been used to predict the inhalation exposure concentrations necessary to produce blood EtOH concentrat...

  17. Parameter optimization of pharmacokinetics based on artificial immune network

    Institute of Scientific and Technical Information of China (English)

    LIU Li; ZHOU Shao-dan; LU Hong-wen; XIE Fen; XU Wen-bo

    2008-01-01

    A new method for parameter optimization of pharmacokinetics based on an artificial immune network named PKAIN is proposed.To improve local searching ability of the artificial immune network,a partition-based concurrent simplex mutation is developed.By means of evolution of network cells in the PKAIN artificial immune network,an optimal set of parameters of a given pharmacokinetic model is obtained.The Laplace transform is applied to the pharmacokinetic difierential equations of remifentanil and its major metabolite,remifentanil acid.The PKAIN method is used to optimize parameters of the derived compartment models.Experimental results show that the twocompartment model is sufficient for the pharmacokinetic study of remifentanil acid for patients with mild degree of renal impairment.

  18. Providing a theoretical basis for nanotoxicity risk analysis departing from traditional physiologically-based pharmacokinetic (PBPK) modeling

    Science.gov (United States)

    Yamamoto, Dirk P.

    The same novel properties of engineered nanoparticles that make them attractive may also present unique exposure risks. But, the traditional physiologically-based pharmacokinetic (PBPK) modeling assumption of instantaneous equilibration likely does not apply to nanoparticles. This simulation-based research begins with development of a model that includes diffusion, active transport, and carrier mediated transport. An eigenvalue analysis methodology was developed to examine model behavior to focus future research. Simulations using the physico-chemical properties of size, shape, surface coating, and surface charge were performed and an equation was determined which estimates area under the curve for arterial blood concentration, which is a surrogate of nanoparticle dose. Results show that the cellular transport processes modeled in this research greatly affect the biokinetics of nanoparticles. Evidence suggests that the equation used to estimate area under the curve for arterial blood concentration can be written in terms of nanoparticle size only. The new paradigm established by this research leverages traditional in vitro, in vivo, and PBPK modeling, but includes area under the curve to bridge animal testing results to humans. This new paradigm allows toxicologists and policymakers to then assess risk to a given exposure and assist in setting appropriate exposure limits for nanoparticles. This research provides critical understanding of nanoparticle biokinetics and allows estimation of total exposure at any toxicological endpoint in the body. This effort is a significant contribution as it highlights future research needs and demonstrates how modeling can be used as a tool to advance nanoparticle risk assessment.

  19. Semiphysiologically based pharmacokinetic model for midazolam and CYP3A mediated metabolite 1‐OH‐midazolam in morbidly obese and weight loss surgery patients

    OpenAIRE

    Brill, MJE; Välitalo, PAJ; Darwich, AS; van Ramshorst, B.; van Dongen, HPA; Rostami–Hodjegan, A; Danhof, M.; Knibbe, CAJ

    2015-01-01

    This study aimed to describe the pharmacokinetics of midazolam and its cytochrome P450 3A (CYP3A) mediated metabolite 1‐OH‐midazolam in morbidly obese patients receiving oral and i.v. midazolam before (n = 20) and one year after weight loss surgery (n = 18), thereby providing insight into the influence of weight loss surgery on CYP3A activity in the gut wall and liver. In a semiphysiologically based pharmacokinetic (semi‐PBPK) model in which different blood flow scenarios were evaluated, intr...

  20. Prediction of clinical response based on pharmacokinetic/pharmacodynamic models of 5-hydroxytryptamine reuptake inhibitors in mice

    DEFF Research Database (Denmark)

    Kreilgaard, Mads; Smith, D. G.; Brennum, L. T.;

    2008-01-01

    Bridging the gap between preclinical research and clinical trials is vital for drug development. Predicting clinically relevant steady-state drug concentrations (Css) in serum from preclinical animal models may facilitate this transition. Here we used a pharmacokinetic/pharmacodynamic (PK/PD) mod...

  1. A physiologically based pharmacokinetic model for atrazine and its main metabolites in the adult male C57BL/6 mouse

    International Nuclear Information System (INIS)

    Atrazine (ATR) is a chlorotriazine herbicide that is widely used and relatively persistent in the environment. In laboratory rodents, excessive exposure to ATR is detrimental to the reproductive, immune, and nervous systems. To better understand the toxicokinetics of ATR and to fill the need for a mouse model, a physiologically based pharmacokinetic (PBPK) model for ATR and its main chlorotriazine metabolites (Cl-TRIs) desethyl atrazine (DE), desisopropyl atrazine (DIP), and didealkyl atrazine (DACT) was developed for the adult male C57BL/6 mouse. Taking advantage of all relevant and recently made available mouse-specific data, a flow-limited PBPK model was constructed. The ATR and DACT sub-models included blood, brain, liver, kidney, richly and slowly perfused tissue compartments, as well as plasma protein binding and red blood cell binding, whereas the DE and DIP sub-models were constructed as simple five-compartment models. The model adequately simulated plasma levels of ATR and Cl-TRIs and urinary dosimetry of Cl-TRIs at four single oral dose levels (250, 125, 25, and 5 mg/kg). Additionally, the model adequately described the dose dependency of brain and liver ATR and DACT concentrations. Cumulative urinary DACT amounts were accurately predicted across a wide dose range, suggesting the model's potential use for extrapolation to human exposures by performing reverse dosimetry. The model was validated using previously reported data for plasma ATR and DACT in mice and rats. Overall, besides being the first mouse PBPK model for ATR and its Cl-TRIs, this model, by analogy, provides insights into tissue dosimetry for rats. The model could be used in tissue dosimetry prediction and as an aid in the exposure assessment to this widely used herbicide.

  2. Recent Advances in Development and Application of Physiologically-Based Pharmacokinetic (PBPK) Models: a Transition from Academic Curiosity to Regulatory Acceptance

    OpenAIRE

    Jamei, Masoud

    2016-01-01

    There is a renewed surge of interest in applications of physiologically-based pharmacokinetic (PBPK) models by the pharmaceutical industry and regulatory agencies. Developing PBPK models within a systems pharmacology context allows separation of the parameters pertaining to the animal or human body (the system) from that of the drug and the study design which is essential to develop generic drug-independent models used to extrapolate PK/PD properties in various healthy and patient populations...

  3. Physiologically-based pharmacokinetic modelling of distribution, bioaccumulation and excretion of POPs in Greenland sledge dogs (Canis familiaris).

    Science.gov (United States)

    Sonne, Christian; Gustavson, Kim; Letcher, Robert J; Dietz, Rune

    2015-10-01

    We used PBPK (physiologically-based pharmacokinetic) modelling to investigate distribution, bioaccumulation and excretion of the seven POPs (persistent organic pollutants) CB-99, CB-153, HCB, oxychlordane, p,p'-DDE, BDE-47 and BDE-99 in 4 adult captive Greenland sledge dog (Canis familiaris) bitches fed minke whale (Balaenoptera acuterostrata) blubber for 500-635 days. The PBPK modelled POP concentrations in adipose tissue, liver, kidney and plasma were mostly within a factor 2 of actual measured tissue levels even for those at the lower concentration end. The excretion route for oxychlordane and CB-153 was modelled to be via faeces while lung alveolar excretion dominated for BDE-47, BDE-99, HCB, p,p'-DDE and CB-99. Furthermore the model suggested the retained mass of POPs after 500 and 635 days of exposure, respectively, to be relatively low despite these POPs being highly recalcitrant. The retention increased in the following order (% of total intake); p,p'-DDE (1%)tool in risk assessment of POPs in arctic mammals. PMID:26210746

  4. 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...

  5. Prediction of Drug-Drug Interactions with Crizotinib as the CYP3A Substrate Using a Physiologically Based Pharmacokinetic Model.

    Science.gov (United States)

    Yamazaki, Shinji; Johnson, Theodore R; Smith, Bill J

    2015-10-01

    An orally available multiple tyrosine kinase inhibitor, crizotinib (Xalkori), is a CYP3A substrate, moderate time-dependent inhibitor, and weak inducer. The main objectives of the present study were to: 1) develop and refine a physiologically based pharmacokinetic (PBPK) model of crizotinib on the basis of clinical single- and multiple-dose results, 2) verify the crizotinib PBPK model from crizotinib single-dose drug-drug interaction (DDI) results with multiple-dose coadministration of ketoconazole or rifampin, and 3) apply the crizotinib PBPK model to predict crizotinib multiple-dose DDI outcomes. We also focused on gaining insights into the underlying mechanisms mediating crizotinib DDIs using a dynamic PBPK model, the Simcyp population-based simulator. First, PBPK model-predicted crizotinib exposures adequately matched clinically observed results in the single- and multiple-dose studies. Second, the model-predicted crizotinib exposures sufficiently matched clinically observed results in the crizotinib single-dose DDI studies with ketoconazole or rifampin, resulting in the reasonably predicted fold-increases in crizotinib exposures. Finally, the predicted fold-increases in crizotinib exposures in the multiple-dose DDI studies were roughly comparable to those in the single-dose DDI studies, suggesting that the effects of crizotinib CYP3A time-dependent inhibition (net inhibition) on the multiple-dose DDI outcomes would be negligible. Therefore, crizotinib dose-adjustment in the multiple-dose DDI studies could be made on the basis of currently available single-dose results. Overall, we believe that the crizotinib PBPK model developed, refined, and verified in the present study would adequately predict crizotinib oral exposures in other clinical studies, such as DDIs with weak/moderate CYP3A inhibitors/inducers and drug-disease interactions in patients with hepatic or renal impairment. PMID:26180127

  6. Proposed mechanistic description of dose-dependent BDE-47 urinary elimination in mice using a physiologically based pharmacokinetic model

    Energy Technology Data Exchange (ETDEWEB)

    Emond, Claude, E-mail: claude.emond@umontreal.ca [BioSimulation Consulting Inc., Newark, DE (United States); Departments of Environmental and Occupational Health, Medicine Faculty, University of Montreal, Montreal, Quebec (Canada); Sanders, J. Michael, E-mail: sander10@mail.nih.gov [National Cancer Institute, Research Triangle Park, NC (United States); Wikoff, Daniele, E-mail: dwikoff@toxstrategies.com [ToxStrategies, Austin, TX (United States); Birnbaum, Linda S., E-mail: birnbaumls@niehs.nih.gov [National Cancer Institute, Research Triangle Park, NC (United States)

    2013-12-01

    Polybrominated diphenyl ethers (PBDEs) have been used in a wide variety of consumer applications as additive flame retardants. In North America, scientists have noted continuing increases in the levels of PBDE congeners measured in human serum. Some recent studies have found that PBDEs are associated with adverse health effects in humans, in experimental animals, and wildlife. This laboratory previously demonstrated that urinary elimination of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) is saturable at high doses in mice; however, this dose-dependent urinary elimination has not been observed in adult rats or immature mice. Thus, the primary objective of this study was to examine the mechanism of urinary elimination of BDE-47 in adult mice using a physiologically based pharmacokinetic (PBPK) model. To support this objective, additional laboratory data were collected to evaluate the predictions of the PBPK model using novel information from adult multi-drug resistance 1a/b knockout mice. Using the PBPK model, the roles of mouse major urinary protein (a blood protein carrier) and P-glycoprotein (an apical membrane transporter in proximal tubule cells in the kidneys, brain, intestines, and liver) were investigated in BDE-47 elimination. The resulting model and new data supported the major role of m-MUP in excretion of BDE-47 in the urine of adult mice, and a lesser role of P-gp as a transporter of BDE-47 in mice. This work expands the knowledge of BDE-47 kinetics between species and provides information for determining the relevancy of these data for human risk assessment purposes. - Highlights: • We report the first study on PBPK model on flame retardant in mice for BDE-47. • We examine mechanism of urinary elimination of BDE-47 in mice using a PBPK model. • We investigated roles of m-MUP and P-gp as transporters in urinary elimination.

  7. Concomitant use of tamoxifen and endoxifen in postmenopausal early breast cancer: prediction of plasma levels by physiologically-based pharmacokinetic modeling

    OpenAIRE

    Dickschen, Kristin; Eissing, Thomas; Mürdter, Thomas; Schwab, Matthias; Willmann, Stefan; Hempel, Georg

    2014-01-01

    Purpose To overcome cytochrome P450 2D6 (CYP2D6) mediated tamoxifen resistance in postmenopausal early breast cancer, CYP2D6 phenotype-adjusted tamoxifen dosing in patients with impaired CYP2D6 metabolism and/or the application of endoxifen, the most potent tamoxifen metabolite, are alternative treatment options. To elucidate both strategies comprehensively we used a physiologically-based pharmacokinetic (PBPK) modeling approach. Methods Firstly simulation of increasing tamoxifen dosages was ...

  8. Estimation of placental and lactational transfer and tissue distribution of atrazine and its main metabolites in rodent dams, fetuses, and neonates with physiologically based pharmacokinetic modeling

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Zhoumeng [Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602 (United States); Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602 (United States); Fisher, Jeffrey W. [Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079 (United States); Wang, Ran [Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762 (United States); Institute of Food Safety, Jiangsu Academy of Agricultural Sciences, Nanjing 210014 (China); Ross, Matthew K. [Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762 (United States); Filipov, Nikolay M., E-mail: filipov@uga.edu [Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602 (United States); Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602 (United States)

    2013-11-15

    Atrazine (ATR) is a widely used chlorotriazine herbicide, a ubiquitous environmental contaminant, and a potential developmental toxicant. To quantitatively evaluate placental/lactational transfer and fetal/neonatal tissue dosimetry of ATR and its major metabolites, physiologically based pharmacokinetic models were developed for rat dams, fetuses and neonates. These models were calibrated using pharmacokinetic data from rat dams repeatedly exposed (oral gavage; 5 mg/kg) to ATR followed by model evaluation against other available rat data. Model simulations corresponded well to the majority of available experimental data and suggest that: (1) the fetus is exposed to both ATR and its major metabolite didealkylatrazine (DACT) at levels similar to maternal plasma levels, (2) the neonate is exposed mostly to DACT at levels two-thirds lower than maternal plasma or fetal levels, while lactational exposure to ATR is minimal, and (3) gestational carryover of DACT greatly affects its neonatal dosimetry up until mid-lactation. To test the model's cross-species extrapolation capability, a pharmacokinetic study was conducted with pregnant C57BL/6 mice exposed (oral gavage; 5 mg/kg) to ATR from gestational day 12 to 18. By using mouse-specific parameters, the model predictions fitted well with the measured data, including placental ATR/DACT levels. However, fetal concentrations of DACT were overestimated by the model (10-fold). This overestimation suggests that only around 10% of the DACT that reaches the fetus is tissue-bound. These rodent models could be used in fetal/neonatal tissue dosimetry predictions to help design/interpret early life toxicity/pharmacokinetic studies with ATR and as a foundation for scaling to humans. - Highlights: • We developed PBPK models for atrazine in rat dams, fetuses, and neonates. • We conducted pharmacokinetic (PK) study with atrazine in pregnant mice. • Model predictions were in good agreement with experimental rat and mouse PK data

  9. Estimation of placental and lactational transfer and tissue distribution of atrazine and its main metabolites in rodent dams, fetuses, and neonates with physiologically based pharmacokinetic modeling

    International Nuclear Information System (INIS)

    Atrazine (ATR) is a widely used chlorotriazine herbicide, a ubiquitous environmental contaminant, and a potential developmental toxicant. To quantitatively evaluate placental/lactational transfer and fetal/neonatal tissue dosimetry of ATR and its major metabolites, physiologically based pharmacokinetic models were developed for rat dams, fetuses and neonates. These models were calibrated using pharmacokinetic data from rat dams repeatedly exposed (oral gavage; 5 mg/kg) to ATR followed by model evaluation against other available rat data. Model simulations corresponded well to the majority of available experimental data and suggest that: (1) the fetus is exposed to both ATR and its major metabolite didealkylatrazine (DACT) at levels similar to maternal plasma levels, (2) the neonate is exposed mostly to DACT at levels two-thirds lower than maternal plasma or fetal levels, while lactational exposure to ATR is minimal, and (3) gestational carryover of DACT greatly affects its neonatal dosimetry up until mid-lactation. To test the model's cross-species extrapolation capability, a pharmacokinetic study was conducted with pregnant C57BL/6 mice exposed (oral gavage; 5 mg/kg) to ATR from gestational day 12 to 18. By using mouse-specific parameters, the model predictions fitted well with the measured data, including placental ATR/DACT levels. However, fetal concentrations of DACT were overestimated by the model (10-fold). This overestimation suggests that only around 10% of the DACT that reaches the fetus is tissue-bound. These rodent models could be used in fetal/neonatal tissue dosimetry predictions to help design/interpret early life toxicity/pharmacokinetic studies with ATR and as a foundation for scaling to humans. - Highlights: • We developed PBPK models for atrazine in rat dams, fetuses, and neonates. • We conducted pharmacokinetic (PK) study with atrazine in pregnant mice. • Model predictions were in good agreement with experimental rat and mouse PK data.

  10. Life-Stage Physiologically-Based Pharmacokinetic (PBPK) Model Applications to Screen Environmental Hazards.

    Science.gov (United States)

    This presentation discusses methods used to extrapolate from in vitro high-throughput screening (HTS) toxicity data for an endocrine pathway to in vivo for early life stages in humans, and the use of a life stage PBPK model to address rapidly changing physiological parameters. A...

  11. Automated optimal glycaemic control using a physiology based pharmacokinetic, pharmacodynamic model

    OpenAIRE

    Schaller, Stephan

    2015-01-01

    After decades of research, Automated Glucose Control (AGC) is still out of reach for everyday control of blood glucose. The inter- and intra-individual variability of glucose dynamics largely arising from variability in insulin absorption, distribution, and action, and related physiological lag-times remain a core problem in the development of suitable control algorithms. Over the years, model predictive control (MPC) has established itself as the gold standard in AGC systems in research. Mod...

  12. Non-compartment model to compartment model pharmacokinetics transformation meta-analysis – a multivariate nonlinear mixed model

    OpenAIRE

    2010-01-01

    Background To fulfill the model based drug development, the very first step is usually a model establishment from published literatures. Pharmacokinetics model is the central piece of model based drug development. This paper proposed an important approach to transform published non-compartment model pharmacokinetics (PK) parameters into compartment model PK parameters. This meta-analysis was performed with a multivariate nonlinear mixed model. A conditional first-order linearization approach ...

  13. A physiologically based pharmacokinetic model to predict disposition of CYP2D6 and CYP1A2 metabolized drugs in pregnant women.

    Science.gov (United States)

    Ke, Alice Ban; Nallani, Srikanth C; Zhao, Ping; Rostami-Hodjegan, Amin; Isoherranen, Nina; Unadkat, Jashvant D

    2013-04-01

    Conducting pharmacokinetic (PK) studies in pregnant women is challenging. Therefore, we asked if a physiologically based pharmacokinetic (PBPK) model could be used to evaluate different dosing regimens for pregnant women. We refined and verified our previously published pregnancy PBPK model by incorporating cytochrome P450 CYP1A2 suppression (based on caffeine PK) and CYP2D6 induction (based on metoprolol PK) into the model. This model accounts for gestational age-dependent changes in maternal physiology and hepatic CYP3A activity. For verification, the disposition of CYP1A2-metabolized drug theophylline (THEO) and CYP2D6-metabolized drugs paroxetine (PAR), dextromethorphan (DEX), and clonidine (CLO) during pregnancy was predicted. Our PBPK model successfully predicted THEO disposition during the third trimester (T3). Predicted mean postpartum to third trimester (PP:T3) ratios of THEO area under the curve (AUC), maximum plasma concentration, and minimum plasma concentration were 0.76, 0.95, and 0.66 versus observed values 0.75, 0.89, and 0.72, respectively. The predicted mean PAR steady-state plasma concentration (Css) ratio (PP:T3) was 7.1 versus the observed value 3.7. Predicted mean DEX urinary ratio (UR) (PP:T3) was 2.9 versus the observed value 1.9. Predicted mean CLO AUC ratio (PP:T3) was 2.2 versus the observed value 1.7. Sensitivity analysis suggested that a 100% induction of CYP2D6 during T3 was required to recover the observed PP:T3 ratios of PAR Css, DEX UR, and CLO AUC. Based on these data, it is prudent to conclude that the magnitude of hepatic CYP2D6 induction during T3 ranges from 100 to 200%. Our PBPK model can predict the disposition of CYP1A2, 2D6, and 3A drugs during pregnancy. PMID:23355638

  14. Semiphysiologically based pharmacokinetic model for midazolam and CYP3A mediated metabolite 1-OH-midazolam in morbidly obese and weight loss surgery patients.

    Science.gov (United States)

    Brill, M J E; Välitalo, P A J; Darwich, A S; van Ramshorst, B; van Dongen, H P A; Rostami-Hodjegan, A; Danhof, M; Knibbe, C A J

    2016-01-01

    This study aimed to describe the pharmacokinetics of midazolam and its cytochrome P450 3A (CYP3A) mediated metabolite 1-OH-midazolam in morbidly obese patients receiving oral and i.v. midazolam before (n = 20) and one year after weight loss surgery (n = 18), thereby providing insight into the influence of weight loss surgery on CYP3A activity in the gut wall and liver. In a semiphysiologically based pharmacokinetic (semi-PBPK) model in which different blood flow scenarios were evaluated, intrinsic hepatic clearance of midazolam (CLint,H) was 2 (95% CI 1.40-1.64) times higher compared to morbidly obese patients before surgery (P  0.05), with low values for both groups. The results of the semi-PBPK model suggest that, in patients after weight loss surgery, CYP3A hepatic metabolizing capacity seems to recover compared to morbidly obese patients, whereas CYP3A mediated CLint,G was low for both populations and showed large interindividual variability. PMID:26844012

  15. Pharmacokinetic/Pharmacodynamic (PK/PD) Indices of Antibiotics Predicted by a Semimechanistic PKPD Model: a Step toward Model-Based Dose Optimization▿

    OpenAIRE

    Nielsen, Elisabet I.; Cars, Otto; Friberg, Lena E.

    2011-01-01

    A pharmacokinetic-pharmacodynamic (PKPD) model that characterizes the full time course of in vitro time-kill curve experiments of antibacterial drugs was here evaluated in its capacity to predict the previously determined PK/PD indices. Six drugs (benzylpenicillin, cefuroxime, erythromycin, gentamicin, moxifloxacin, and vancomycin), representing a broad selection of mechanisms of action and PK and PD characteristics, were investigated. For each drug, a dose fractionation study was simulated, ...

  16. Reconstructing Exposures from Biomarkers using Exposure-Pharmacokinetic Modeling - A Case Study with Carbaryl

    Science.gov (United States)

    Sources of uncertainty involved in exposure reconstruction for a short half-life chemical, carbaryl, were characterized using the Cumulative and Aggregate Risk Evaluation System (CARES), an exposure model, and a human physiologically based pharmacokinetic (PBPK) model. CARES was...

  17. A detailed physiologically-based model to simulate the pharmacokinetics and hormonal pharmacodynamics of enalapril on the circulating endocrine renin-angiotensin-aldosterone system

    Directory of Open Access Journals (Sweden)

    MichaelBlock

    2013-02-01

    Full Text Available The renin-angiotensin-aldosterone system (RAAS plays a key role in the pathogenesis of cardiovascular disorders including hypertension and is one of the most important targets for drugs. A whole body physiologically-based pharmacokinetic (wb PBPK model integrating this hormone circulation system and its inhibition can be used to explore the influence of drugs that interfere with this system, and thus to improve the understanding of interactions between drugs and the target system. In this study, we describe the development of a mechanistic RAAS model and exemplify drug action by a simulation of enalapril administration. Enalapril and its metabolite enalaprilat are potent inhibitors of the angiotensin-converting enzyme (ACE. To this end, a coupled dynamic parent-metabolite PBPK model was developed and linked with the RAAS model that consists of seven coupled PBPK models for aldosterone, ACE , angiotensin 1, angiotensin 2, angiotensin 2 receptor type 1, renin and prorenin. The results indicate that the model represents the interactions in the RAAS in response to the pharmacokinetics (PK and pharmacodynamics (PD of enalapril and enalaprilat in an accurate manner. The full set of RAAS hormone profiles and interactions are consistently described at pre- and post-administration steady state as well as during their dynamic transition and show a good agreement to literature data. The model allows a simultaneous representation of the parent-metabolite conversion to the active form as well as the effect of the drug on the hormone levels, offering a detailed mechanistic insight into the hormone cascade and its inhibition. This model constitutes a first major step to establish a PBPK-PD model including the PK and the mode of action (MoA of a drug acting on a dynamic RAAS that can be further used to link to clinical endpoints such as blood pressure.

  18. Metabolite Kinetics: The Segregated Flow Model for Intestinal and Whole Body Physiologically Based Pharmacokinetic Modeling to Describe Intestinal and Hepatic Glucuronidation of Morphine in Rats In Vivo.

    Science.gov (United States)

    Yang, Qi Joy; Fan, Jianghong; Chen, Shu; Liu, Lutan; Sun, Huadong; Pang, K Sandy

    2016-07-01

    We used the intestinal segregated flow model (SFM) versus the traditional model (TM), nested within physiologically based pharmacokinetic (PBPK) models, to describe the biliary and urinary excretion of morphine 3β-glucuronide (MG) after intravenous and intraduodenal dosing of morphine in rats in vivo. The SFM model describes a partial (5%-30%) intestinal blood flow perfusing the transporter- and enzyme-rich enterocyte region, whereas the TM describes 100% flow perfusing the intestine as a whole. For the SFM, drugs entering from the circulation are expected to be metabolized to lesser extents by the intestine due to the segregated flow, reflecting the phenomenon of shunting and route-dependent intestinal metabolism. The poor permeability of MG crossing the liver or intestinal basolateral membranes mandates that most of MG that is excreted into bile is hepatically formed, whereas MG that is excreted into urine originates from both intestine and liver metabolism, since MG is effluxed back to blood. The ratio of MG amounts in urine/bile [Formula: see text] for intraduodenal/intravenous dosing is expected to exceed unity for the SFM but approximates unity for the TM. Compartmental analysis of morphine and MG data, without consideration of the permeability of MG and where MG is formed, suggests the ratio to be 1 and failed to describe the kinetics of MG. The observed intraduodenal/intravenous ratio of [Formula: see text] (2.55 at 4 hours) was better predicted by the SFM-PBPK (2.59 at 4 hours) and not the TM-PBPK (1.0), supporting the view that the SFM is superior for the description of intestinal-liver metabolism of morphine to MG. The SFM-PBPK model predicts an appreciable contribution of the intestine to first pass M metabolism. PMID:27098743

  19. A model to resolve organochlorine pharmacokinetics in migrating humpback whales.

    Science.gov (United States)

    Cropp, Roger; Nash, Susan Bengtson; Hawker, Darryl

    2014-07-01

    Humpback whales are iconic mammals at the top of the Antarctic food chain. Their large reserves of lipid-rich tissues such as blubber predispose them to accumulation of lipophilic contaminants throughout their lifetime. Changes in the volume and distribution of lipids in humpback whales, particularly during migration, could play an important role in the pharmacokinetics of lipophilic contaminants such as the organochlorine pesticide hexachlorobenzene (HCB). Previous models have examined constant feeding and nonmigratory scenarios. In the present study, the authors develop a novel heuristic model to investigate HCB dynamics in a humpback whale and its environment by coupling an ecosystem nutrient-phytoplankton-zooplankton-detritus (NPZD) model, a dynamic energy budget (DEB) model, and a physiologically based pharmacokinetic (PBPK) model. The model takes into account the seasonal feeding pattern of whales, their energy requirements, and fluctuating contaminant burdens in the supporting plankton food chain. It is applied to a male whale from weaning to maturity, spanning 20 migration and feeding cycles. The model is initialized with environmental HCB burdens similar to those measured in the Southern Ocean and predicts blubber HCB concentrations consistent with empirical concentrations observed in a southern hemisphere population of male, migrating humpback whales. Results show for the first time some important details of the relationship between energy budgets and organochlorine pharmacokinetics. PMID:24733631

  20. 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.

  1. The calculation of human toxicity thresholds of 2,3,7,8-TCDD; A Physiologically Based Pharmacokinetic modeling approach

    NARCIS (Netherlands)

    Zeilmaker MJ; van Eijkeren JCH; LBO

    1998-01-01

    Dit rapport beschrijft de toepassing van een 'Physiologically Based PharmacoKinetic' model (PBPK model) bij het berekenen van de verwachte 'No Adverse Effect Level' van 2,3,7,8-TetraChloroDibenzo-p-Dioxine (TCDD) bij de mens. Het model houdt rekening met variabiliteit en onzeker

  2. Pharmacokinetics local model and Its application in nuclear medicine

    Institute of Scientific and Technical Information of China (English)

    曹国宪; 李卫一; 等

    1996-01-01

    The Pharmacokinetics local model for studying kinetic action of pharmaceuticals in the specific part of the body is established on the basis of the compartment model.A series of formulae is deduced,and with them the pharmacokinetic equation and several important parameters can be obtained.The local model successfully expanded the area of pharmacokinetics from the compartment model ,which is mainly dealing with kinetic action of pharmaceuticals in blood,to the local model,which can study kinetic action of pharmaceuticals in any organ,tissue or fluid.

  3. Associations of Perfluoroalkyl Substances (PFAS) with Lower Birth Weight: An Evaluation of Potential Confounding by Glomerular Filtration Rate Using a Physiologically Based Pharmacokinetic Model (PBPK)

    Science.gov (United States)

    Loccisano, Anne E.; Morken, Nils-Halvdan; Yoon, Miyoung; Wu, Huali; McDougall, Robin; Maisonet, Mildred; Marcus, Michele; Kishi, Reiko; Miyashita, Chihiro; Chen, Mei-Huei; Hsieh, Wu-Shiun; Andersen, Melvin E.; Clewell, Harvey J.; Longnecker, Matthew P.

    2015-01-01

    Background Prenatal exposure to perfluoroalkyl substances (PFAS) has been associated with lower birth weight in epidemiologic studies. This association could be attributable to glomerular filtration rate (GFR), which is related to PFAS concentration and birth weight. Objectives We used a physiologically based pharmacokinetic (PBPK) model of pregnancy to assess how much of the PFAS–birth weight association observed in epidemiologic studies might be attributable to GFR. Methods We modified a PBPK model to reflect the association of GFR with birth weight (estimated from three studies of GFR and birth weight) and used it to simulate PFAS concentrations in maternal and cord plasma. The model was run 250,000 times, with variation in parameters, to simulate a population. Simulated data were analyzed to evaluate the association between PFAS levels and birth weight due to GFR. We compared simulated estimates with those from a meta-analysis of epidemiologic data. Results The reduction in birth weight for each 1-ng/mL increase in simulated cord plasma for perfluorooctane sulfonate (PFOS) was 2.72 g (95% CI: –3.40, –2.04), and for perfluorooctanoic acid (PFOA) was 7.13 g (95% CI: –8.46, –5.80); results based on maternal plasma at term were similar. Results were sensitive to variations in PFAS level distributions and the strength of the GFR–birth weight association. In comparison, our meta-analysis of epidemiologic studies suggested that each 1-ng/mL increase in prenatal PFOS and PFOA levels was associated with 5.00 g (95% CI: –21.66, –7.78) and 14.72 g (95% CI: –8.92, –1.09) reductions in birth weight, respectively. Conclusion Results of our simulations suggest that a substantial proportion of the association between prenatal PFAS and birth weight may be attributable to confounding by GFR and that confounding by GFR may be more important in studies with sample collection later in pregnancy. Citation Verner MA, Loccisano AE, Morken NH, Yoon M, Wu H, Mc

  4. Optimization of drug-drug interaction study design: comparison of minimal physiologically based pharmacokinetic models on prediction of CYP3A inhibition by ketoconazole.

    Science.gov (United States)

    Han, Bing; Mao, Jialin; Chien, Jenny Y; Hall, Stephen D

    2013-07-01

    Ketoconazole is a potent CYP3A inhibitor used to assess the contribution of CYP3A to drug clearance and quantify the increase in drug exposure due to a strong inhibitor. Physiologically based pharmacokinetic (PBPK) models have been used to evaluate treatment regimens resulting in maximal CYP3A inhibition by ketoconazole but have reached different conclusions. We compare two PBPK models of the ketoconazole-midazolam interaction, model 1 (Chien et al., 2006) and model 2 implemented in Simcyp (version 11), to predict 16 published treatment regimens. With use of model 2, 41% of the study point estimates of area under the curve (AUC) ratio and 71% of the 90% confidence intervals were predicted within 1.5-fold of the observed, but these increased to 82 and 100%, respectively, with model 1. For midazolam, model 2 predicted a maximal midazolam AUC ratio of 8 and a hepatic fraction metabolized by CYP3A (f(m)) of 0.97, whereas model 1 predicted 17 and 0.90, respectively, which are more consistent with observed data. On the basis of model 1, ketoconazole (400 mg QD) for at least 3 days and substrate administration within 2 hours is required for maximal CYP3A inhibition. Ketoconazole treatment regimens that use 200 mg BID underestimate the systemic fraction metabolized by CYP3A (0.86 versus 0.90) for midazolam. The systematic underprediction also applies to CYP3A substrates with high bioavailability and long half-lives. The superior predictive performance of model 1 reflects the need for accumulation of ketoconazole at enzyme site and protracted inhibition. Model 2 is not recommended for inferring optimal study design and estimation of fraction metabolized by CYP3A. PMID:23584886

  5. Incorporation of Therapeutic Interventions in Physiologically Based Pharmacokinetic Modeling of Human Clinical Case Reports of Accidental or Intentional Overdosing with Ethylene Glycol

    Energy Technology Data Exchange (ETDEWEB)

    Corley, Rick A.; McMartin, K. E.

    2005-05-16

    Ethylene glycol is a high production volume chemical used in the manufacture of resins and fibers, antifreeze, deicing fluids, heat transfer and hydraulic fluids. Although occupational uses of ethylene glycol have not been associated with adverse effects, there are case reports where humans have either intentionally or accidentally ingested large quantities of ethylene glycol, primarily from antifreeze. The acute toxicity of ethylene glycol in humans and animals and can proceed through three stages, each associated with a different metabolite: central nervous system depression (ethylene glycol), cardiopulmonary effects associated with metabolic acidosis (glycolic acid) and ultimately renal toxicity (oxalic acid), depending upon the total amounts consumed and effectiveness of therapeutic interventions. A physiologically based pharmacokinetic (PBPK) model developed in a companion paper (Corley et al., 2004) was refined in this study to include clinically relevant treatment regimens for ethylene glycol poisoning such as hemodialysis or metabolic inhibition with either ethanol or fomepizole. Such modifications enabled the model to describe several human case reports which included analysis of ethylene glycol and/or glycolic acid. Such data and model simulations provide important confirmation that the PBPK model developed previously can adequately describe the pharmacokinetics of ethylene glycol in humans following low, occupational or environmentally relevant inhalation exposures, as well as massive oral doses even under conditions where treatments have been employed that markedly affect the disposition of ethylene glycol and glycolic acid. By integrating the case report data sets with controlled studies in this PBPK model, it was demonstrated that fomepizole, if administered early enough in a clinical situation, can be more effective than ethanol or hemodialysis in preventing the metabolism of ethylene glycol to more toxic metabolites. Hemodialysis remains an

  6. A Mechanistic Pharmacokinetic Model for Liver Transporter Substrates Under Liver Cirrhosis Conditions.

    Science.gov (United States)

    Li, R; Barton, H A; Maurer, T S

    2015-06-01

    Liver cirrhosis is a disease characterized by the loss of functional liver mass. Physiologically based pharmacokinetic (PBPK) modeling was applied to interpret and predict how the interplay among physiological changes in cirrhosis affects pharmacokinetics. However, previous PBPK models under cirrhotic conditions were developed for permeable cytochrome P450 substrates and do not directly apply to substrates of liver transporters. This study characterizes a PBPK model for liver transporter substrates in relation to the severity of liver cirrhosis. A published PBPK model structure for liver transporter substrates under healthy conditions and the physiological changes for cirrhosis are combined to simulate pharmacokinetics of liver transporter substrates in patients with mild and moderate cirrhosis. The simulated pharmacokinetics under liver cirrhosis reasonably approximate observations. This analysis includes meta-analysis to obtain system-dependent parameters in cirrhosis patients and a top-down approach to improve understanding of the effect of cirrhosis on transporter-mediated drug disposition under cirrhotic conditions. PMID:26225262

  7. Pharmacokinetic analysis program based on tank-in-series model, MULTI(TIS), for evaluation of capacity-limited local disposition.

    Science.gov (United States)

    Fukumura, K; Yamaoka, K; Higashimori, M; Nakagawa, T

    1998-12-01

    A pharmacokinetic analysis program based on a tank-in-series model, MULTI(TIS), was developed for the evaluation of dose-dependency in the local disposition of a drug. The program written in FORTRAN was constructed by expanding MULTI(RUNGE). The reliability of MULTI(TIS) was verified by analyzing the experimental data based on linear and nonlinear tank-in-series models. Linear one- and two-compartment tank-in-series models were adopted to analyze outflow time profiles in single-pass hepatic perfusion following a pulse input of 5'-deoxy-5-fluorouridine (DFUR). The estimated parameters agreed well with those by MULTI(FILT) which is widely used for linear kinetic analysis. The nonlinear models adopted were one-compartment model with Michaelis-Menten elimination and two-compartment models with Michaelis-Menten elimination from central and peripheral compartments. Oxacillin was used as a model drug, because time courses of oxacillin show a capacity-limited hepatic disposition following a pulse input in high doses to the liver (300, 1000, 3000 and 5000 microg). The hepatic recovery ratio (F(H)) of oxacillin increased with dose, whereas the mean transit time (tH) was almost constant. The maximum elimination rate constant (Vmax) and Michaelis constant (Km) of oxacillin were estimated to be 1980 microg/ml/min and 54.1 microg/ml, respectively. Thus, the reliability of MULTI(TIS) was demonstrated for the analysis of nonlinear local disposition, especially, capacity-limited elimination in the liver. PMID:9881650

  8. Physiologically Based Pharmacokinetics of Matrine in the Rat after Oral Administration of Pure Chemical and ACAPHA

    OpenAIRE

    Gao, Guanghua; Law, Francis C. P.

    2009-01-01

    ACAPHA, a botanical drug for the treatment of human esophageal cancer in China, is under investigation as a lung cancer chemoprevention agent at the BC Cancer Agency (Vancouver, BC, Canada). Little or no information is available on the pharmacokinetics of ACAPHA in animals. The objectives of this study were as follows: to examine the disposition kinetics of matrine, a bioactive marker of ACAPHA in the rat; to develop a physiologically based pharmacokinetic (PBPK) model...

  9. Application of pharmacokinetics local model to evaluate renal function

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    The pharmacokinetics local model was used to evaluate renal function.Some typical kinds of renal function cases, normal or disorder, were selected to be imaged with SPECT and those data measured were treated by the pharmacokinetics local model computer program (PLM).The results indicated that parameters, including peak value, peak time, inflexion time, half-excretion time, and kinetic equation played and importantrole in judging renal function.The fact confirms that local model isvery useful in evaluating renal function.

  10. Use of a physiologically-based pharmacokinetic model to simulate artemether dose adjustment for overcoming the drug-drug interaction with efavirenz

    OpenAIRE

    Siccardi, Marco; Olagunju, Adeniyi; Seden, Kay; Ebrahimjee, Farid; Rannard, Steve; Back, David; Owen, Andrew

    2013-01-01

    Purpose To treat malaria, HIV-infected patients normally receive artemether (80 mg twice daily) concurrently with antiretroviral therapy and drug-drug interactions can potentially occur. Artemether is a substrate of CYP3A4 and CYP2B6, antiretrovirals such as efavirenz induce these enzymes and have the potential to reduce artemether pharmacokinetic exposure. The aim of this study was to develop an in vitro in vivo extrapolation (IVIVE) approach to model the interaction between efavirenz and ar...

  11. Feasibility of Using Limited-Population-Based Arterial Input Function for Pharmacokinetic Modeling of Osteosarcoma Dynamic Contrast-Enhanced MRI Data

    OpenAIRE

    Wang, YA; Huang, Wei; Panicek, David M.; Schwartz, Lawrence H.; Koutcher, Jason A

    2008-01-01

    For clinical dynamic contrast-enhanced (DCE) MRI studies, it is often not possible to obtain reliable arterial input function (AIF) in each measurement. Thus, it is important to find a representative AIF for pharmacokinetic modeling of DCE-MRI data when individual AIF (Ind-AIF) measurements are not available. A total of 16 patients with osteosarcomas in the lower extremity (knee region) underwent multislice DCE-MRI. Reliable Ind-AIFs were obtained in five patients with a contrast injection ra...

  12. Using Physiologically-Based Pharmacokinetic Models to Incorporate Chemical and Non-Chemical Stressors into Cumulative Risk Assessment: A Case Study of Pesticide Exposures

    Directory of Open Access Journals (Sweden)

    Jonathan I. Levy

    2012-05-01

    Full Text Available Cumulative risk assessment has been proposed as an approach to evaluate the health risks associated with simultaneous exposure to multiple chemical and non-chemical stressors. Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD models can allow for the inclusion and evaluation of multiple stressors, including non-chemical stressors, but studies have not leveraged PBPK/PD models to jointly consider these disparate exposures in a cumulative risk context. In this study, we focused on exposures to organophosphate (OP pesticides for children in urban low-income environments, where these children would be simultaneously exposed to other pesticides (including pyrethroids and non-chemical stressors that may modify the effects of these exposures (including diet. We developed a methodological framework to evaluate chemical and non-chemical stressor impacts on OPs, utilizing an existing PBPK/PD model for chlorpyrifos. We evaluated population-specific stressors that would influence OP doses or acetylcholinesterase (AChE inhibition, the relevant PD outcome. We incorporated the impact of simultaneous exposure to pyrethroids and dietary factors on OP dose through the compartments of metabolism and PD outcome within the PBPK model, and simulated combinations of stressors across multiple exposure ranges and potential body weights. Our analyses demonstrated that both chemical and non-chemical stressors can influence the health implications of OP exposures, with up to 5-fold variability in AChE inhibition across combinations of stressor values for a given OP dose. We demonstrate an approach for modeling OP risks in the presence of other population-specific environmental stressors, providing insight about co-exposures and variability factors that most impact OP health risks and contribute to children’s cumulative health risk from pesticides. More generally, this framework can be used to inform cumulative risk assessment for any compound impacted by

  13. Dynamically simulating the interaction of midazolam and the CYP3A4 inhibitor itraconazole using individual coupled whole-body physiologically-based pharmacokinetic (WB-PBPK models

    Directory of Open Access Journals (Sweden)

    Jang In-Jin

    2007-03-01

    Full Text Available Abstract Background Drug-drug interactions resulting from the inhibition of an enzymatic process can have serious implications for clinical drug therapy. Quantification of the drugs internal exposure increase upon administration with an inhibitor requires understanding to avoid the drug reaching toxic thresholds. In this study, we aim to predict the effect of the CYP3A4 inhibitors, itraconazole (ITZ and its primary metabolite, hydroxyitraconazole (OH-ITZ on the pharmacokinetics of the anesthetic, midazolam (MDZ and its metabolites, 1' hydroxymidazolam (1OH-MDZ and 1' hydroxymidazolam glucuronide (1OH-MDZ-Glu using mechanistic whole body physiologically-based pharmacokinetic simulation models. The model is build on MDZ, 1OH-MDZ and 1OH-MDZ-Glu plasma concentration time data experimentally determined in 19 CYP3A5 genotyped adult male individuals, who received MDZ intravenously in a basal state. The model is then used to predict MDZ, 1OH-MDZ and 1OH-MDZ-Glu concentrations in an CYP3A-inhibited state following ITZ administration. Results For the basal state model, three linked WB-PBPK models (MDZ, 1OH-MDZ, 1OH-MDZ-Glu for each individual were elimination optimized that resulted in MDZ and metabolite plasma concentration time curves that matched individual observed clinical data. In vivo Km and Vmax optimized values for MDZ hydroxylation were similar to literature based in vitro measures. With the addition of the ITZ/OH-ITZ model to each individual coupled MDZ + metabolite model, the plasma concentration time curves were predicted to greatly increase the exposure of MDZ as well as to both increase exposure and significantly alter the plasma concentration time curves of the MDZ metabolites in comparison to the basal state curves. As compared to the observed clinical data, the inhibited state curves were generally well described although the simulated concentrations tended to exceed the experimental data between approximately 6 to 12 hours following

  14. Determination of a suitable voriconazole pharmacokinetic model for personalised dosing.

    Science.gov (United States)

    McDougall, David A J; Martin, Jennifer; Playford, E Geoffrey; Green, Bruce

    2016-04-01

    Model based personalised dosing (MBPD) is a sophisticated form of individualised therapy, where a population pharmacokinetic (PK) or pharmacodynamic model is utilised to estimate the dose required to reach a target exposure or effect. The choice of which model to implement in MBPD is a subjective decision. By choosing one model, information from the remaining models is ignored, as well as the rest of the literature base. This manuscript describes a methodology to develop a 'hybrid' model for voriconazole that incorporated information from prior models in a biologically plausible manner. Voriconazole is a triazole antifungal with difficult to predict PK, although it does have a defined exposure-response relationship. Nine population PK models of voriconazole were identified from the literature. The models differed significantly in structural components. The hybrid model contained a two-compartment disposition model with mixed linear and nonlinear time-dependent clearance. The parameters for the hybrid model were determined using simulation techniques. Validation of the hybrid model was assessed via visual predictive checks, which indicated the majority of the variability in the literature models was captured by the hybrid model. The predictive performance was assessed using four different sampling strategies of limited concentrations from ten richly PK sampled subjects to predict future concentrations. Overall, the hybrid model predicted future concentrations with good precision. Further prospective and retrospective validation of the hybrid model is required before it could be used in clinical practice. PMID:26676909

  15. Using publicly available data, a physiologically-based pharmacokinetic model and Bayesian simulation to improve arsenic non-cancer dose-response.

    Science.gov (United States)

    Dong, Zhaomin; Liu, CuiXia; Liu, Yanju; Yan, Kaihong; Semple, Kirk T; Naidu, Ravi

    2016-01-01

    Publicly available data can potentially examine the relationship between environmental exposure and public health, however, it has not yet been widely applied. Arsenic is of environmental concern, and previous studies mathematically parameterized exposure duration to create a link between duration of exposure and increase in risk. However, since the dose metric emerging from exposure duration is not a linear or explicit variable, it is difficult to address the effects of exposure duration simply by using mathematical functions. To relate cumulative dose metric to public health requires a lifetime physiologically-based pharmacokinetic (PBPK) model, yet this model is not available at a population level. In this study, the data from the U.S. total diet study (TDS, 2006-2011) was employed to assess exposure: daily dietary intakes for total arsenic (tAs) and inorganic arsenic (iAs) were estimated to be 0.15 and 0.028μg/kg/day, respectively. Meanwhile, using National Health and Nutrition Examination Survey (NHANES, 2011-2012) data, the fraction of urinary As(III) levels (geometric mean: 0.31μg/L) in tAs (geometric mean: 7.75μg/L) was firstly reported to be approximately 4%. Together with Bayesian technique, the assessed exposure and urinary As(III) concentration were input to successfully optimize a lifetime population PBPK model. Finally, this optimized PBPK model was used to derive an oral reference dose (Rfd) of 0.8μg/kg/day for iAs exposure. Our study also suggests the previous approach (by using mathematical functions to account for exposure duration) may result in a conservative Rfd estimation. PMID:27107229

  16. Physiologically-based pharmacokinetic modeling of tamoxifen and its metabolites in women of different CYP2D6 phenotypes provides new insight into the tamoxifen mass balance

    Directory of Open Access Journals (Sweden)

    Kristin eDickschen

    2012-05-01

    Full Text Available Tamoxifen is a first-line endocrine agent in the mechanism-based treatment of estrogen receptor positive (ER+ mammary carcinoma and applied to breast cancer patients all over the world. Endoxifen is a secondary and highly active metabolite of tamoxifen that is formed among others by the polymorphic cytochrome P450 2D6 (CYP2D6. It is widely accepted that CYP2D6 poor metabolizers (PM exert a pronounced decrease in endoxifen steady-state plasma concentrations compared to CYP2D6 extensive metabolizers (EM. Nevertheless, an in-depth understanding of the chain of cause and effect between CYP2D6 genotype, endoxifen steady-state plasma concentration, and subsequent tamoxifen treatment benefit still remains to be evolved.In this context, physiologically-based pharmacokinetic (PBPK-modeling provides a useful tool to mechanistically investigate the impact of CYP2D6 phenotype on endoxifen formation in female breast cancer patients undergoing tamoxifen therapy.It has long been thought that only a minor percentage of endoxifen is formed via 4-hydroxytamoxifen. However, the current investigation supports very recently published data that postulates a contribution of 4-hydroxytamoxifen above 20 % to total endoxifen formation. The developed PBPK-model describes tamoxifen PK in rats and humans. Moreover, tamoxifen metabolism in dependence of CYP2D6 phenotype in populations of European female individuals is well described, thus providing a good basis to further investigate the linkage of PK, mode of action, and treatment outcome in dependence of factors such as phenotype, ethnicity or co-treatment with CYP2D6 inhibitors.

  17. Modeling in biopharmaceutics, pharmacokinetics and pharmacodynamics homogeneous and heterogeneous approaches

    CERN Document Server

    Macheras, Panos

    2016-01-01

    The state of the art in Biopharmaceutics, Pharmacokinetics, and Pharmacodynamics Modeling is presented in this new second edition book. It shows how advanced physical and mathematical methods can expand classical models in order to cover heterogeneous drug-biological processes and therapeutic effects in the body. The book is divided into four parts; the first deals with the fundamental principles of fractals, diffusion and nonlinear dynamics; the second with drug dissolution, release, and absorption; the third with epirical, compartmental, and stochastic pharmacokinetic models, with two new chapters, one on fractional pharmacokinetics and one on bioequivalence; and the fourth mainly with classical and nonclassical aspects of pharmacodynamics. The classical models that have relevance and application to these sciences are also considered throughout. This second edition has new information on reaction limited models of dissolution, non binary biopharmaceutic classification system, time varying models, and interf...

  18. The In Vivo Quantitation of Diazinon, chlorpyrifos, and Their Major Metabolites in Rat Blood for the Refinement of a Physiologically-Based Pharmacokinetic/Pharmacodynamic Models

    Energy Technology Data Exchange (ETDEWEB)

    Busby, A.; Kousba, A.; Timchalk, C.

    2004-01-01

    Chlorpyrifos (CPF)(O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl]-phosphorothioate, CAS 2921-88-2), and diazinon (DZN)(O,O-diethyl-O-2-isopropyl-4-methyl-6-pyrimidyl thiophosphate, CAS 333-41-5) are commonly encountered organophosphorus insecticides whose oxon metabolites (CPF-oxon and DZN-oxon) have the ability to strongly inhibit acetylcholinesterase, an enzyme responsible for the breakdown of acetylcholine at nerve synapses. Chlorpyrifos-oxon and DZN-oxon are highly unstable compounds that degrade via hepatic, peripheral blood, and intestinal metabolism to the more stable metabolites, TCP (3,5,6-trichloro-2-pyridinol, CAS not assigned) and IMHP (2-isopropyl-6-methyl-4-pyrimidinol, CAS 2814-20-2), respectively. Studies have been performed to understand and model the chronic and acute toxic effects of CPF and DZN individually but little is known about their combined effects. The purpose of this study was to improve physiologically based pharmacokinetic/ pharmacodynamic (PBPK/PD) computational models by quantifying concentrations of CPF and DZN and their metabolites TCP and IMHP in whole rat blood, following exposure to the chemicals individually or as a mixture. Male Sprague-Dawley rats were orally dosed with 60 mg/kg of CPF, DZN, or a mixture of these two pesticides. When administered individually DZN and CPF were seen to reach their maximum concentration at ~3 hours post-dosing. When given as a mixture, both DZN and CPF peak blood concentrations were not achieved until ~6 hours post-dosing and the calculated blood area under the curve (AUC) for both chemicals exceeded those calculated following the single dose. Blood concentrations of IMHP and TCP correlated with these findings. It is proposed that the higher AUC obtained for both CPF and DZN as a mixture resulted from competition for the same metabolic enzyme systems.

  19. Use of a simulated annealing algorithm to fit compartmental models with an application to fractal pharmacokinetics.

    Science.gov (United States)

    Marsh, Rebeccah E; Riauka, Terence A; McQuarrie, Steve A

    2007-01-01

    Increasingly, fractals are being incorporated into pharmacokinetic models to describe transport and chemical kinetic processes occurring in confined and heterogeneous spaces. However, fractal compartmental models lead to differential equations with power-law time-dependent kinetic rate coefficients that currently are not accommodated by common commercial software programs. This paper describes a parameter optimization method for fitting individual pharmacokinetic curves based on a simulated annealing (SA) algorithm, which always converged towards the global minimum and was independent of the initial parameter values and parameter bounds. In a comparison using a classical compartmental model, similar fits by the Gauss-Newton and Nelder-Mead simplex algorithms required stringent initial estimates and ranges for the model parameters. The SA algorithm is ideal for fitting a wide variety of pharmacokinetic models to clinical data, especially those for which there is weak prior knowledge of the parameter values, such as the fractal models. PMID:17706176

  20. Computational toxicology: Physiologically based pharmacokinetic models (PBPK) for lifetime exposure and bioaccumulation of polybrominated diphenyl ethers (PBDEs) in marine mammals

    International Nuclear Information System (INIS)

    Due to migration of harbour porpoises towards more polluted areas like the North Sea and their sensitivity towards pollution, there is a need for proper conservation measures for this species. As a consequence, knowledge about the pollutant’s kinetics is required. The present study is the first to investigate the kinetics of PBDEs in marine mammals using PBPK modeling as a non-destructive tool for describing the chemical’s kinetics in a protected animal species. The models were developed and parameterized using data from the literature and Black Sea harbour porpoises through computer optimization. The predictability of these models in time was assessed by reverse dosimetry modeling using data from North Sea porpoises (1990–2008). From these predictions, PBDE 99 levels were found to decrease the fastest, followed by PBDE 153, 47 and 100. Results show that the PBPK models can be applied for harbour porpoises from different regions and also simulate time trends. - Highlights: ► PBPK modeling is a non-invasive and non-destructive tool for risk assessment. ► PBPK modeling was used to study the kinetics of several PBDEs in harbour porpoises. ► Harbour porpoises are sensitive to pollution and therefore ideal model organisms. ► Black Sea data were used for model parameterization. ► North Sea data were used for assessing temporal trends (1990–2008). - PBPK models as a non-invasive tool for describing the kinetics of relevant chemicals in organisms can be used for harbour porpoises from different regions and time periods.

  1. Integration of in vitro binding mechanism into the semiphysiologically based pharmacokinetic interaction model between ketoconazole and midazolam.

    Science.gov (United States)

    Quinney, Sara K; Knopp, Shawn; Chang, Chien; Hall, Stephen D; Li, Lang

    2013-01-01

    In vitro screening for drug-drug interactions is an integral component of drug development, with larger emphasis now placed on the use of in vitro parameters to predict clinical inhibition. However, large variability exists in Ki reported for ketoconazole with midazolam, a model inhibitor-substrate pair for CYP3A. We reviewed the literature and extracted Ki for ketoconazole as measured by the inhibition of hydroxymidazolam formation in human liver microsomes. The superset of data collected was analyzed for the impact of microsomal binding, using Langmuir and phase equilibrium binding models, and fitted to various inhibition models: competitive, noncompetitive, and mixed. A mixed inhibition model with binding corrected by an independent binding model was best able to fit the data (Kic = 19.2 nmol/l and Kin = 39.8 nmol/l) and to predict clinical effect of ketoconazole on midazolam area under the concentration-time curve. The variability of reported Ki may partially be explained by microsomal binding and choice of inhibition model. PMID:24448021

  2. Integration of In Vitro Binding Mechanism Into the Semiphysiologically Based Pharmacokinetic Interaction Model Between Ketoconazole and Midazolam

    OpenAIRE

    Quinney, Sara K.; Knopp, Shawn; Chang, Chien; Hall, Stephen D.; Li, Lang

    2013-01-01

    In vitro screening for drug–drug interactions is an integral component of drug development, with larger emphasis now placed on the use of in vitro parameters to predict clinical inhibition. However, large variability exists in K i reported for ketoconazole with midazolam, a model inhibitor–substrate pair for CYP3A. We reviewed the literature and extracted K i for ketoconazole as measured by the inhibition of hydroxymidazolam formation in human liver microsomes. The superset of data collected ...

  3. Albumin-deficient mouse models for studying metabolism of human albumin and pharmacokinetics of albumin-based drugs

    OpenAIRE

    Roopenian, Derry C.; Low, Benjamin E.; Christianson, Gregory J.; Proetzel, Gabriele; Sproule, Thomas J.; Wiles, Michael V.

    2015-01-01

    Serum albumin is the major determinant of blood colloidal osmotic pressure acting as a depot and distributor of compounds including drugs. In humans, serum albumin exhibits an unusually long half-life mainly due to protection from catabolism by neonatal Fc receptor (FcRn)-mediated recycling. These properties make albumin an attractive courier of therapeutically-active compounds. However, pharmaceutical research and development of albumin-based therapeutics has been hampered by the lack of app...

  4. 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…

  5. Assessment of cytochrome P450-mediated drug-drug interaction potential of orteronel and exposure changes in patients with renal impairment using physiologically based pharmacokinetic modeling and simulation.

    Science.gov (United States)

    Lu, Chuang; Suri, Ajit; Shyu, Wen Chyi; Prakash, Shimoga

    2014-12-01

    Orteronel is a nonsteroidal, selective inhibitor of 17,20-lyase that was recently in phase 3 clinical development as a treatment for castration-resistant prostate cancer. In humans, the primary clearance route for orteronel is renal excretion. Human liver microsomal studies indicated that orteronel weakly inhibits CYP1A2, 2C8, 2C9 and 2C19, with IC50 values of 17.8, 27.7, 30.8 and 38.8 µm, respectively, whereas orteronel does not inhibit CYP2B6, 2D6 or 3A4/5 (IC50  > 100 µm). Orteronel also does not exhibit time-dependent inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5. The results of a static model indicated an [I]/Ki ratio >0.1 for CYP1A2, 2C8, 2C9 and 2C19. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to assess the potential for drug-drug interactions (DDIs) between orteronel and theophylline, repaglinide, (S)-warfarin and omeprazole, which are sensitive substrates of CYP1A2, 2C8, 2C9 and 2C19, respectively. Simulation of the area under the plasma concentration-time curve (AUC) of these four CYP substrates in the presence and absence of orteronel revealed geometric mean AUC ratios <1.25. Therefore, in accordance with the 2012 US FDA Draft Guidance on DDIs, orteronel can be labeled a 'non-inhibitor' and further clinical DDI evaluation is not required. In PBPK models of moderate and severe renal impairment, the AUC of orteronel was predicted to increase by 52% and 83%, respectively. These results are in agreement with those of a clinical trial in which AUC increases of 38% and 87% were observed in patients with moderate and severe renal impairment, respectively. PMID:25264242

  6. Development and evaluation of a harmonized physiologically based pharmacokinetic (PBPK) model for perchloroethylene toxicokinetics in mice, rats, and humans

    International Nuclear Information System (INIS)

    This article reports on the development of a 'harmonized' PBPK model for the toxicokinetics of perchloroethylene (tetrachloroethylene or perc) in mice, rats, and humans that includes both oxidation and glutathione (GSH) conjugation of perc, the internal kinetics of the oxidative metabolite trichloroacetic acid (TCA), and the urinary excretion kinetics of the GSH conjugation metabolites N-Acetylated trichlorovinyl cysteine and dichloroacetic acid. The model utilizes a wider range of in vitro and in vivo data than any previous analysis alone, with in vitro data used for initial, or 'baseline,' parameter estimates, and in vivo datasets separated into those used for 'calibration' and those used for 'evaluation.' Parameter calibration utilizes a limited Bayesian analysis involving flat priors and making inferences only using posterior modes obtained via Markov chain Monte Carlo (MCMC). As expected, the major route of elimination of absorbed perc is predicted to be exhalation as parent compound, with metabolism accounting for less than 20% of intake except in the case of mice exposed orally, in which metabolism is predicted to be slightly over 50% at lower exposures. In all three species, the concentration of perc in blood, the extent of perc oxidation, and the amount of TCA production is well-estimated, with residual uncertainties of ∼ 2-fold. However, the resulting range of estimates for the amount of GSH conjugation is quite wide in humans (∼ 3000-fold) and mice ( 60-fold). While even high-end estimates of GSH conjugation in mice are lower than estimates of oxidation, in humans the estimated rates range from much lower to much higher than rates for perc oxidation. It is unclear to what extent this range reflects uncertainty, variability, or a combination. Importantly, by separating total perc metabolism into separate oxidative and conjugative pathways, an approach also recommended in a recent National Research Council review, this analysis reconciles the disparity

  7. PKreport: report generation for checking population pharmacokinetic model assumptions

    Directory of Open Access Journals (Sweden)

    Li Jun

    2011-05-01

    Full Text Available Abstract Background Graphics play an important and unique role in population pharmacokinetic (PopPK model building by exploring hidden structure among data before modeling, evaluating model fit, and validating results after modeling. Results The work described in this paper is about a new R package called PKreport, which is able to generate a collection of plots and statistics for testing model assumptions, visualizing data and diagnosing models. The metric system is utilized as the currency for communicating between data sets and the package to generate special-purpose plots. It provides ways to match output from diverse software such as NONMEM, Monolix, R nlme package, etc. The package is implemented with S4 class hierarchy, and offers an efficient way to access the output from NONMEM 7. The final reports take advantage of the web browser as user interface to manage and visualize plots. Conclusions PKreport provides 1 a flexible and efficient R class to store and retrieve NONMEM 7 output, 2 automate plots for users to visualize data and models, 3 automatically generated R scripts that are used to create the plots; 4 an archive-oriented management tool for users to store, retrieve and modify figures, 5 high-quality graphs based on the R packages, lattice and ggplot2. The general architecture, running environment and statistical methods can be readily extended with R class hierarchy. PKreport is free to download at http://cran.r-project.org/web/packages/PKreport/index.html.

  8. Pharmacokinetic Modeling of Intranasal Scopolamine in Plasma Saliva and Urine

    Science.gov (United States)

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

    2015-01-01

    An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS). The bioavailability and pharmacokinetics (PK) were evaluated under IND (Investigational New Drug) guidelines. The aim of the project was to develop a PK model that can predict the relationships among plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trial protocol with INSCOP. Twelve healthy human subjects were administered at three dose levels (0.1, 0.2 and 0.4 mg) of INSCOP. Serial blood, saliva and urine samples were collected between 5 min to 24 h after dosing and scopolamine concentrations were measured by using a validated LC-MS-MS assay. PK compartmental models, using actual dosing and sampling time, were established using Phoenix (version 1.2). Model selection was based on a likelihood ratio test on the difference of criteria (-2LL (i.e. log-likelihood ratio test)) and comparison of the quality of fit plots. The results: Predictable correlations among scopolamine concentrations in compartments of plasma, saliva and urine were established, and for the first time the model satisfactorily predicted the population and individual PK of INSCOP in plasma, saliva and urine. The model can be utilized to predict the INSCOP plasma concentration by saliva and urine data, and it will be useful for monitoring the PK of scopolamine in space and other remote environments using non-invasive sampling of saliva and/or urine.

  9. Modeling in biopharmaceutics, pharmacokinetics, and pharmacodynamics homogeneous and heterogeneous approaches

    CERN Document Server

    Macheras, Panos

    2006-01-01

    The state of the art in Biopharmaceutics, Pharmacokinetics, and Pharmacodynamics Modeling is presented in this book. It shows how advanced physical and mathematical methods can expand classical models in order to cover heterogeneous drug-biological processes and therapeutic effects in the body. The book is divided into four parts; the first deals with the fundamental principles of fractals, diffusion and nonlinear dynamics; the second with drug dissolution, release, and absorption; the third with empirical, compartmental, and stochastic pharmacokinetic models, and the fourth mainly with nonclassical aspects of pharmacodynamics. The classical models that have relevance and application to these sciences are also considered throughout. Many examples are used to illustrate the intrinsic complexity of drug administration related phenomena in the human, justifying the use of advanced modeling methods. This timely and useful book will appeal to graduate students and researchers in pharmacology, pharmaceutical scienc...

  10. Semimechanistic cell-cycle type-based pharmacokinetic/pharmacodynamic model of chemotherapy-induced neutropenic effects of diflomotecan under different dosing schedules.

    Science.gov (United States)

    Mangas-Sanjuan, Víctor; Buil-Bruna, Núria; Garrido, María J; Soto, Elena; Trocóniz, Iñaki F

    2015-07-01

    The current work integrates cell-cycle dynamics occurring in the bone marrow compartment as a key element in the structure of a semimechanistic pharmacokinetic/pharmacodynamic model for neutropenic effects, aiming to describe, with the same set of system- and drug-related parameters, longitudinal data of neutropenia gathered after the administration of the anticancer drug diflomotecan (9,10-difluoro-homocamptothecin) under different dosing schedules to patients (n = 111) with advanced solid tumors. To achieve such an objective, the general framework of the neutropenia models was expanded, including one additional physiologic process resembling cell cycle dynamics. The main assumptions of the proposed model are as follows: within the stem cell compartment, proliferative and quiescent cells coexist, and only cells in the proliferative condition are sensitive to drug effects and capable of following the maturation chain. Cell cycle dynamics were characterized by two new parameters, FProl (the fraction of proliferative [Prol] cells that enters into the maturation chain) and kcycle (first-order rate constant governing cell cycle dynamics within the stem cell compartment). Both model parameters were identifiable as indicated by the results from a bootstrap analysis, and their estimates were supported by date from the literature. The estimates of FProl and kcycle were 0.58 and 1.94 day(-1), respectively. The new model could properly describe the neutropenic effects of diflomotecan after very different dosing scenarios, and can be used to explore the potential impact of dosing schedule dependencies on neutropenia prediction. PMID:25948593

  11. Development of a Rat Plasma and Brain Extracellular Fluid Pharmacokinetic Model for Bupropion and Hydroxybupropion Based on Microdialysis Sampling, and Application to Predict Human Brain Concentrations.

    Science.gov (United States)

    Cremers, Thomas I F H; Flik, Gunnar; Folgering, Joost H A; Rollema, Hans; Stratford, Robert E

    2016-05-01

    Administration of bupropion [(±)-2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one] and its preformed active metabolite, hydroxybupropion [(±)-1-(3-chlorophenyl)-2-[(1-hydroxy-2-methyl-2-propanyl)amino]-1-propanone], to rats with measurement of unbound concentrations by quantitative microdialysis sampling of plasma and brain extracellular fluid was used to develop a compartmental pharmacokinetics model to describe the blood-brain barrier transport of both substances. The population model revealed rapid equilibration of both entities across the blood-brain barrier, with resultant steady-state brain extracellular fluid/plasma unbound concentration ratio estimates of 1.9 and 1.7 for bupropion and hydroxybupropion, respectively, which is thus indicative of a net uptake asymmetry. An overshoot of the brain extracellular fluid/plasma unbound concentration ratio at early time points was observed with bupropion; this was modeled as a time-dependent uptake clearance of the drug across the blood-brain barrier. Translation of the model was used to predict bupropion and hydroxybupropion exposure in human brain extracellular fluid after twice-daily administration of 150 mg bupropion. Predicted concentrations indicate that preferential inhibition of the dopamine and norepinephrine transporters by the metabolite, with little to no contribution by bupropion, would be expected at this therapeutic dose. Therefore, these results extend nuclear imaging studies on dopamine transporter occupancy and suggest that inhibition of both transporters contributes significantly to bupropion's therapeutic efficacy. PMID:26916207

  12. Gender-based effects on methylprednisolone pharmacokinetics and pharmacodynamics

    Science.gov (United States)

    Lew, Kim H.; Ludwig, Elizabeth A.; Milad, Mark A.; Donovan, Kathleen; Middleton, Elliott; Ferry, James J.; Jusko, William J.

    2014-01-01

    The pharmacokinetics and selected pharmacodynamic responses to methylprednisolone were investigated in six men and six premenopausal women after a dose of 0.6 mg/kg ideal body weight. Women (luteal phase) exhibited a greater methylprednisolone clearance (0.45 versus 0.29 L/hr/kg) and shorter elimination half-life (1.7 versus 2.6 hours) than men. The volume of distribution of methylprednisolone was similar when normalized for ideal body weight. Pharmacodynamic models were used to examine the methylprednisolone suppressive effects on cortisol secretion and basophil and helper T lymphocyte trafficking. A significantly smaller 50% inhibitory concentration (IC50) value (0.1 versus 1.7 ng/ml) was seen in the women for suppression of cortisol secretion, indicating increased sensitivity. However, the area under the concentration-time curve of effect was similar for both groups. The IC50 values for effects of methylprednisolone on basophil trafficking related to estradiol concentrations in a log-linear fashion in women, with increased sensitivity found at higher estradiol concentrations. Men displayed a greater 24-hour net suppression in blood basophil numbers, but no difference was observed in net cortisol and helper T lymphocyte suppression between the sexes. These findings suggest that methylprednisolone dosages should be based on ideal body weight. Although women are more sensitive to methylprednisolone as measured by cortisol suppression, they eliminate the drug more quickly, generally producing a similar net response. PMID:8222483

  13. Pharmacokinetic modeling and dosage adaptation of biapenem in Japanese patients during continuous venovenous hemodiafiltration.

    Science.gov (United States)

    Ikawa, Kazuro; Morikawa, Norifumi; Ikeda, Kayo; Suyama, Hidemichi

    2008-02-01

    The present study examined the pharmacokinetics of biapenem during continuous venovenous hemodiafiltration (CVVHDF) and assessed the pharmacodynamic exposure, based on a pharmacokinetic model, to consider biapenem dosage adaptation in CVVHDF. Biapenem (300 mg) was administered by 2-h infusion to seven critically ill patients receiving CVVHDF. The flow rates were 60 ml/min for blood, 800 ml/h for filtrate, and 600 ml/h for dialysate. The drug concentrations in plasma and filtrate-dialysate were determined by high-performance liquid chromatography and analyzed pharmacokinetically. The sieving coefficient was 0.92 +/- 0.06 (mean +/- SD). The simulation curves, using a multicompartment model, were well fitted to the measurements in plasma and filtrate-dialysate. The clearance by CVVHDF and the clearance by non-CVVHDF routes were 1.29 +/- 0.08 and 6.14 +/- 1.89 l/h, respectively. The multicompartment model was used to assess the pharmacodynamic exposure (time above the minimum inhibitory concentration of 4 microg/ml) in plasma. When the total daily dose was 600 mg, the duration of time was greater at 300 mg every 12 h than at 600 mg every 24 h. The minimum dosages needed to achieve more than 30% of the dosing interval at filtrate-dialysate flow rates of 1.4, 2.8, and 5.6 l/h were 300 mg every 12 h, 600 mg every 12 h, and 600 mg every 12 h, respectively. These results suggested that low doses or increased dosing intervals should be avoided in patients receiving this renal replacement technique. Information on pharmacodynamic exposure obtained from this model may help us to determine the appropriate biapenem dosage for CVVHDF. Moreover, our pharmacokinetic model may be useful for further pharmacokinetic studies of biapenem. PMID:18297447

  14. A Population Pharmacokinetic/Pharmacodynamic Model Predicts Favorable HDL Cholesterol Changes Over the First 5 Years in Children Treated With Current Efavirenz-Based Regimens.

    Science.gov (United States)

    Homkham, Nontiya; Cressey, Tim R; Ingsrisawang, Lily; Bouazza, Naïm; Ngampiyaskul, Chaiwat; Hongsiriwon, Suchat; Srirojana, Sakulrat; Kanjanavanit, Suparat; Bhakeecheep, Sorakij; Coeur, Sophie Le; Salvadori, Nicolas; Treluyer, Jean Marc; Jourdain, Gonzague; Urien, Saik

    2016-09-01

    Efavirenz use is associated with changes in cholesterol concentrations, but it is unclear whether this effect is related to drug concentrations. Using efavirenz and cholesterol plasma concentrations measured in 87 antiretroviral-naive children in Thailand, we assessed indirect response models to describe the evolution of high- and low-density lipoprotein (HDL, LDL) cholesterol concentrations in relation to efavirenz plasma concentrations over time where efavirenz was assumed to either stimulate cholesterol production or inhibit its elimination. Simulations of cholesterol evolution for children with different average efavirenz concentrations (Cav ) according to their assumed status of "fast" or "slow" metabolizers of efavirenz were performed. At treatment initiation, children's median (interquartile range, IQR) age was 8 years (5 to 10), body mass index z-score 0.01 (-1.05 to 1.44), HDL 31 mg/dL (24 to 44), and LDL 83 mg/dL (69 to 100). Median (IQR) efavirenz Cav was 1.7 mg/L (1.3 to 2.1) during the period of observation. The best model describing the evolution of HDL and LDL cholesterol concentrations over time assumed that efavirenz inhibited their elimination. HDL concentrations increase over 5 years, whereas LDL concentrations increased only during the first 4 months and then returned to baseline levels afterward. Simulations predicted that, after 3 years, HDL would increase to 63 mg/dL in "fast" metabolizers and 97 mg/dL in "slow" metabolizers of efavirenz. The population pharmacokinetic-pharmacodynamic (PK-PD) model shows that favorable HDL cholesterol changes can be expected in children with current efavirenz dosing guidelines over 5 years of treatment. PMID:26749102

  15. A nonlinear mixed effects modelling analysis of topiramate pharmacokinetics in patients with epilepsy.

    Science.gov (United States)

    Vovk, Tomaz; Jakovljević, Mihajlo B; Kos, Mojca Kerec; Janković, Slobodan M; Mrhar, Ales; Grabnar, Iztok

    2010-01-01

    Topiramate pharmacokinetics is influenced by individual factors such as patient age, renal function and co-treatment. The aim of this study was to develop a population pharmacokinetic model of topiramate to assist dosage adjustments in individual patients. Steady-state topiramate plasma concentrations in patients with epilepsy were determined by HPLC using fluorescent labelling. Demographic, biochemical data and dosing history including concomitant drug therapy were collected from patients' charts. Nonlinear mixed effects modelling was used to fit a one-compartment pharmacokinetic model. The influence of patient weight and gender, body surface area, age, creatinine clearance, serum transaminases, topiramate daily dose and co-treatment with carbamazepine, valproic acid, benzodiazepines, and risperidone on topiramate pharmacokinetics was evaluated. Additionally, the relationship between topiramate plasma concentration and clinical response was investigated. Volume of distribution of topiramate was 0.518 l/kg. For a typical patient oral clearance was estimated at 1.47 l/h, with interindividual variability of 39.2%. Clearance was 70% higher in patients co-treated with carbamazepine and was found to increase with patient age. Somnolence was the most frequently observed adverse event. Incidence of headache was associated with topiramate plasma concentration. Somnolence, ataxia, tremor, speech disorders and fatigue were associated with adjunctive therapy with carbamazepine, valproic acid, benzodiazepines, risperidone, and clozapine. No association of topiramate plasma concentration with frequency of seizures or patient quality of life was observed. The developed model can be used for Bayesian estimation of pharmacokinetic parameters based on sparse plasma samples and for selection of optimum dosing in routine patient care. PMID:20606310

  16. Toxicokinetics and Pharmacokinetic Modeling of Arsenic

    Science.gov (United States)

    This chapter provides an overview of arsenic toxicokinetics and physiologically-basedpharmacokinetic (PBPK) modeling with particular emphasis on key 'actors needed fordevelopment of a model useful for dose-response analysis, applications of arsenicmodels, as well research needs.U...

  17. Comparison of the Efficacy and Safety of a Pharmacokinetic Model-Based Dosing Scheme Versus a Conventional Fentanyl Dosing Regimen For Patient-Controlled Analgesia Immediately Following Robot-Assisted Laparoscopic Prostatectomy: A Randomized Clinical Trial.

    Science.gov (United States)

    Jin, Seok-Joon; Lim, Hyeong-Seok; Kwon, Youn-Ju; Park, Se-Ung; Yi, Jung-Min; Chin, Ji-Hyun; Hwang, Jai-Hyun; Kim, Young-Kug

    2016-01-01

    Conventional, intravenous, patient-controlled analgesia, which is only administered by demand bolus without basal continuous infusion, is closely associated with inappropriate analgesia. Pharmacokinetic model-based dosing schemes can quantitatively describe the time course of drug effects and achieve optimal drug therapy. We compared the efficacy and safety of a conventional dosing regimen for intravenous patient-controlled analgesia that was administered by demand bolus without basal continuous infusion (group A) versus a pharmacokinetic model-based dosing scheme performed by decreasing the dosage of basal continuous infusion according to the model-based simulation used to achieve a targeted concentration (group B) following robot-assisted laparoscopic prostatectomy.In total, 70 patients were analyzed: 34 patients in group A and 36 patients in group B. The postoperative opioid requirements, pain scores assessed by the visual analog scale, and adverse events (eg, nausea, vomiting, pruritis, respiratory depression, desaturation, sedation, confusion, and urinary retention) were compared on admission to the postanesthesia care unit and at 0.5, 1, 4, 24, and 48 h after surgery between the 2 groups. All patients were kept for close observation in the postanesthesia care unit for 1 h, and then transferred to the general ward.The fentanyl requirements in the postanesthesia care unit for groups A and B were 110.0 ± 46.4 μg and 77.5 ± 35.3 μg, respectively. The pain scores assessed by visual analog scale at 0.5, 1, 4, and 24 h after surgery in group B were significantly lower than in group A (all P comparison with conventional dosing regimen. PMID:26765479

  18. Review of pharmacokinetic models for target controlled infusions in anesthesia

    Directory of Open Access Journals (Sweden)

    Subash Kennedy Sivasubramaniam

    2014-06-01

    Full Text Available Intravenous injection of anesthetic drugs dates back to the 17th Century when opium and chloral hydrate have been injected intravenously. It was not until the 1930s intravenous anesthesia became popular with the invention of barbiturates.Early intravenous anesthetic agents such as barbiturates were ideal for induction of anesthesia, but not suitable for maintenance of anesthesia. Most of these drugs accumulated significantly with increasing durations of infusion and also resulted in cardiorespiratory depression. The invention of propofol and shorter acting opioid analgesics such as remifentanil and alfentanil have revolutionized intravenous anesthesia. The rapid onset and offset of these drugs lends itself to being suitable agents for maintenance of anesthesia over prolonged periods of time. Detailed understanding of the pharmacokinetics of propofol and remifentanil, combined with technological advances in intravenous pumps capable of accurate delivery of drugs have resulted in great development of the field of total intravenous anesthesia and target controlled infusions. I would like to discuss, in this article, the pharmacokinetics and pharmacokinetic models behind these intravenous infusion pumps. [Int J Basic Clin Pharmacol 2014; 3(3.000: 417-423

  19. Selection between Michaelis–Menten and target-mediated drug disposition pharmacokinetic models

    OpenAIRE

    Yan, Xiaoyu; Mager, Donald E.; Krzyzanski, Wojciech

    2009-01-01

    Target-mediated drug disposition (TMDD) models have been applied to describe the pharmacokinetics of drugs whose distribution and/or clearance are affected by its target due to high binding affinity and limited capacity. The Michaelis–Menten (M–M) model has also been frequently used to describe the pharmacokinetics of such drugs. The purpose of this study is to investigate conditions for equivalence between M–M and TMDD pharmacokinetic models and provide guidelines for selection between these...

  20. 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; Savic, Rada; Yan, Shirley; Bartelink, Imke; Musick, Lisa; French, Deborah; Law, Jason; Horn, Biljana; Cowan, Morton J.; Dvorak, Christopher C.

    2014-01-01

    Background Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared to conventional dosing. 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, Css) and implement a simple, model-based tool for the initial dosing of busulfan in children undergoing HCT. Patients and Methods Model development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone HCT with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the non-linear 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. Results Modeling of busulfan time-concentration data indicates busulfan CL displays non-linearity in children, decreasing up to approximately 20% between the concentrations of 250–2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan CL were actual body weight and age. The percentage of individuals achieving a therapeutic Css was significantly higher in subjects receiving initial doses based on the population PK model (81%) versus historical controls dosed on conventional guidelines (52%) (p = 0.02). Conclusion When compared to the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults. PMID:25162216

  1. EXPOSURE RELATED DOSE ESTIMATING MODEL ( ERDEM ) A PHYSIOLOGICALLY-BASED PHARMACOKINETIC AND PHARMACODYNAMIC ( PBPK/PD ) MODEL FOR ASSESSING HUMAN EXPOSURE AND RISK

    Science.gov (United States)

    The Exposure Related Dose Estimating Model (ERDEM) is a PBPK/PD modeling system that was developed by EPA's National Exposure Research Laboratory (NERL). The ERDEM framework provides the flexibility either to use existing models and to build new PBPK and PBPK/PD models to address...

  2. Dose Reconstruction of Di(2-ethylhexyl) Phthalate Using a Simple Pharmacokinetic Model

    OpenAIRE

    Lorber, Matthew; Calafat, Antonia M.

    2012-01-01

    Background: Di(2-ethylhexyl) phthalate (DEHP), used primarily as a plasticizer for polyvinyl chloride, is found in a variety of products. Previous studies have quantified human exposure by back calculating intakes based on DEHP metabolite concentrations in urine and by determining concentrations of DEHP in exposure media (e.g., air, food, dust). Objectives: To better understand the timing and extent of DEHP exposure, we used a simple pharmacokinetic model to “reconstruct” the DEHP dose respon...

  3. A Simple Pharmacokinetic Model of Prenatal and Postnatal Exposure to Perfluoroalkyl Substances (PFASs).

    Science.gov (United States)

    Verner, Marc-André; Ngueta, Gérard; Jensen, Elizabeth T; Fromme, Hermann; Völkel, Wolfgang; Nygaard, Unni Cecilie; Granum, Berit; Longnecker, Matthew P

    2016-01-19

    Most children are exposed to perfluoroalkyl substances (PFASs) through placental transfer, breastfeeding, and other environmental sources. To date, there are no validated tools to estimate exposure and body burden during infancy and childhood. In this study, we aimed to (i) develop a two-generation pharmacokinetic model of prenatal and postnatal exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonate (PFOS), and perfluorohexanesulfonate (PFHxS); and to (ii) evaluate it against measured children's levels in two studies. We developed a pharmacokinetic model consisting of a maternal and a child compartment to simulate lifetime exposure in women and transfer to the child across the placenta and through breastfeeding. To evaluate the model, we performed simulations for each mother-child dyad from two studies in which maternal PFAS levels at delivery and children's PFAS levels were available. Model predictions based on maternal PFAS levels, sex of child, body weight, and duration of breastfeeding explained between 52% and 60% of the variability in measured children's levels at 6 months of age and between 52% and 62% at 36 months. Monte Carlo simulations showed that the daily intake through breastfeeding and resulting internal PFAS levels can be much higher in nursing infants than in mothers. This pharmacokinetic model shows potential for postnatal exposure assessment in the context of epidemiological studies and risk assessment. PMID:26691063

  4. Nonparametric Bayes approach for a semi-mechanistic pharmacokinetic and pharmacodynamic model

    Science.gov (United States)

    Dong, Yan

    Both frequentist and Bayesian approaches have been used to characterize population pharmacokinetics and pharmacodynamics(PK/PD) models. These methods focus on estimating the population parameters and assessing the association between the characteristics of PK/PD and the subject covariates. In this work, we propose a Dirichlet process mixture model to classify the patients based on their individualized pharmacokinetic and pharmacodynamic profiles. Then we can predict the new patients' dose-response curves given their concentration-time profiles. Additionally, we implement a modern Markov Chain Monte Carlo algorithm for sampling inference of parameters. The detailed sampling procedures as well as the results are discussed in a simulation data and a real data example. We also evaluate an approximate solution of a system of nonlinear differential equations from Euler's method and compare the results with a general numerical solver, ode from R package, deSolve.

  5. An Evaluation of Using Population Pharmacokinetic Models to Estimate Pharmacodynamic Parameters for Propofol and Bispectral Index in Children

    NARCIS (Netherlands)

    Coppens, Marc J.; Eleveld, Douglas J.; Proost, Johannes H.; Marks, Luc A. M.; Van Bocxlaer, Jan F. P.; Vereecke, Hugo; Absalom, Anthony R.; Struys, Michel M. R. F.

    2011-01-01

    Background: To study propofol pharmacodynamics in a clinical setting a pharmacokinetic model must be used to predict drug plasma concentrations. Some investigators use a population pharmacokinetic model from existing literature and minimize the pharmacodynamic objective function. The purpose of the

  6. Pharmacokinetic properties and in silico ADME modeling in drug discovery.

    Science.gov (United States)

    Honório, Kathia M; Moda, Tiago L; Andricopulo, Adriano D

    2013-03-01

    The discovery and development of a new drug are time-consuming, difficult and expensive. This complex process has evolved from classical methods into an integration of modern technologies and innovative strategies addressed to the design of new chemical entities to treat a variety of diseases. The development of new drug candidates is often limited by initial compounds lacking reasonable chemical and biological properties for further lead optimization. Huge libraries of compounds are frequently selected for biological screening using a variety of techniques and standard models to assess potency, affinity and selectivity. In this context, it is very important to study the pharmacokinetic profile of the compounds under investigation. Recent advances have been made in the collection of data and the development of models to assess and predict pharmacokinetic properties (ADME--absorption, distribution, metabolism and excretion) of bioactive compounds in the early stages of drug discovery projects. This paper provides a brief perspective on the evolution of in silico ADME tools, addressing challenges, limitations, and opportunities in medicinal chemistry. PMID:23016542

  7. Impact of Sample Size on the Performance of Multiple-Model Pharmacokinetic Simulations▿

    OpenAIRE

    Tam, Vincent H.; Kabbara, Samer; Yeh, Rosa F.; Leary, Robert H.

    2006-01-01

    Monte Carlo simulations are increasingly used to predict pharmacokinetic variability of antimicrobials in a population. We investigated the sample size necessary to provide robust pharmacokinetic predictions. To obtain reasonably robust predictions, a nonparametric model derived from a sample population size of ≥50 appears to be necessary as the input information.

  8. Ocular and systemic pharmacokinetic models for drug discovery and development

    OpenAIRE

    del Amo Páez, Eva María

    2015-01-01

    Drug discovery and development is a long process: it takes usually 12 to 15 years before a drug candidate reaches the market. The pharmacokinetics of the drug is an important aspect of drug discovery and development, because the drug must reach its target site and exert the therapeutic response. The pharmacokinetic parameters of new compounds should be investigated early in drug discovery. Pharmacokinetic predictions can be made with Quantitative Structure-Property Relationships (QSPR) which ...

  9. Pharmacokinetic-Pharmacodynamic Modeling to Study the Antipyretic Effect of Qingkailing Injection on Pyrexia Model Rats

    Directory of Open Access Journals (Sweden)

    Zhixin Zhang

    2016-03-01

    Full Text Available Qingkailing injection (QKLI is a modern Chinese medicine preparation derived from a well-known classical formulation, An-Gong-Niu-Huang Wan. Although the clinical efficacy of QKLI has been well defined, its severe adverse drug reactions (ADRs were extensively increased. Through thorough attempts to reduce ADR rates, it was realized that the effect-based rational use plays the key role in clinical practices. Hence, the pharmacokinetic-pharmacodynamic (PK-PD model was introduced in the present study, aiming to link the pharmacokinetic profiles with the therapeutic outcomes of QKLI, and subsequently to provide valuable guidelines for the rational use of QKLI in clinical settings. The PK properties of the six dominant ingredients in QKLI were compared between the normal treated group (NTG and the pyrexia model group (MTG. Rectal temperatures were measured in parallel with blood sampling for NTG, MTG, model control group (MCG, and normal control group (NCG. Baicalin and geniposide exhibited appropriate PK parameters, and were selected as the PK markers to map the antipyretic effect of QKLI. Then, a PK-PD model was constructed upon the bacalin and geniposide plasma concentrations vs. the rectal temperature variation values, by a two-compartment PK model with a Sigmoid Emax PD model to explain the time delay between the drug plasma concentration of PK markers and the antipyretic effect after a single dose administration of QKLI. The findings obtained would provide fundamental information to propose a more reasonable dosage regimen and improve the level of individualized drug therapy in clinical settings.

  10. Selection between Michaelis-Menten and target-mediated drug disposition pharmacokinetic models.

    Science.gov (United States)

    Yan, Xiaoyu; Mager, Donald E; Krzyzanski, Wojciech

    2010-02-01

    Target-mediated drug disposition (TMDD) models have been applied to describe the pharmacokinetics of drugs whose distribution and/or clearance are affected by its target due to high binding affinity and limited capacity. The Michaelis-Menten (M-M) model has also been frequently used to describe the pharmacokinetics of such drugs. The purpose of this study is to investigate conditions for equivalence between M-M and TMDD pharmacokinetic models and provide guidelines for selection between these two approaches. Theoretical derivations were used to determine conditions under which M-M and TMDD pharmacokinetic models are equivalent. Computer simulations and model fitting were conducted to demonstrate these conditions. Typical M-M and TMDD profiles were simulated based on literature data for an anti-CD4 monoclonal antibody (TRX1) and phenytoin administered intravenously. Both models were fitted to data and goodness of fit criteria were evaluated for model selection. A case study of recombinant human erythropoietin was conducted to qualify results. A rapid binding TMDD model is equivalent to the M-M model if total target density R ( tot ) is constant, and R ( tot ) K ( D ) /(K ( D ) + C) ( 2 ) < 1 where K ( D ) represents the dissociation constant and C is the free drug concentration. Under these conditions, M-M parameters are defined as: V ( max ) = k ( int ) R ( tot ) V ( c ) and K ( m ) = K ( D ) where k ( int ) represents an internalization rate constant, and V ( c ) is the volume of the central compartment. R ( tot ) is constant if and only if k ( int ) = k ( deg,) where k ( deg ) is a degradation rate constant. If the TMDD model predictions are not sensitive to k ( int ) or k ( deg ) parameters, the condition of R ( tot ) K ( D ) /(K ( D ) + C) ( 2 ) < 1 alone can preserve the equivalence between rapid binding TMDD and M-M models. The model selection process for drugs that exhibit TMDD should involve a full mechanistic model as well as reduced models. The best model

  11. Mathematical modeling and simulation in animal health. Part I: Moving beyond pharmacokinetics.

    Science.gov (United States)

    Riviere, J E; Gabrielsson, J; Fink, M; Mochel, J

    2016-06-01

    The application of mathematical modeling to problems in animal health has a rich history in the form of pharmacokinetic modeling applied to problems in veterinary medicine. Advances in modeling and simulation beyond pharmacokinetics have the potential to streamline and speed-up drug research and development programs. To foster these goals, a series of manuscripts will be published with the following goals: (i) expand the application of modeling and simulation to issues in veterinary pharmacology; (ii) bridge the gap between the level of modeling and simulation practiced in human and veterinary pharmacology; (iii) explore how modeling and simulation concepts can be used to improve our understanding of common issues not readily addressed in human pharmacology (e.g. breed differences, tissue residue depletion, vast weight ranges among adults within a single species, interspecies differences, small animal species research where data collection is limited to sparse sampling, availability of different sampling matrices); and (iv) describe how quantitative pharmacology approaches could help understanding key pharmacokinetic and pharmacodynamic characteristics of a drug candidate, with the goal of providing explicit, reproducible, and predictive evidence for optimizing drug development plans, enabling critical decision making, and eventually bringing safe and effective medicines to patients. This study introduces these concepts and introduces new approaches to modeling and simulation as well as clearly articulate basic assumptions and good practices. The driving force behind these activities is to create predictive models that are based on solid physiological and pharmacological principles as well as adhering to the limitations that are fundamental to applying mathematical and statistical models to biological systems. PMID:26592724

  12. Model-Based Meta-Analysis of Population Pharmacokinetic Models for Paclitaxel in Humans, Rats and Mice%紫杉醇种属间药动学相关性的荟萃分析

    Institute of Scientific and Technical Information of China (English)

    张澍; 任宇鹏; 尚德为; 孙谊; 周田彦; 卢炜

    2013-01-01

    nonlinear mixed-effects model (NONMEM) was developed to describe the paclitaxel PK profiles for mice, rats and humans. A two-compartment pharmacokinetic model fitted the data well, and consistent with the reported results. The models were evaluated by NDPE, the final model was accurate and reliable. The allometric scaling of CL and Vtotal among three different species for paclitaxel was r2= 0. 997 4 and r2 = 0. 937 2, respectively. CONCLUSION Take paclitaxel for example, established the model-based meta-analysis, successfully, and evaluated the correlation on the PK parameters of paclitaxel among different species quantitatively.

  13. Development of a Human Physiologically Based Pharmacokinetic (PBPK Toolkit for Environmental Pollutants

    Directory of Open Access Journals (Sweden)

    Patricia Ruiz

    2011-10-01

    Full Text Available Physiologically Based Pharmacokinetic (PBPK models can be used to determine the internal dose and strengthen exposure assessment. Many PBPK models are available, but they are not easily accessible for field use. The Agency for Toxic Substances and Disease Registry (ATSDR has conducted translational research to develop a human PBPK model toolkit by recoding published PBPK models. This toolkit, when fully developed, will provide a platform that consists of a series of priority PBPK models of environmental pollutants. Presented here is work on recoded PBPK models for volatile organic compounds (VOCs and metals. Good agreement was generally obtained between the original and the recoded models. This toolkit will be available for ATSDR scientists and public health assessors to perform simulations of exposures from contaminated environmental media at sites of concern and to help interpret biomonitoring data. It can be used as screening tools that can provide useful information for the protection of the public.

  14. A simple pharmacokinetics subroutine for modeling double peak phenomenon.

    Science.gov (United States)

    Mirfazaelian, Ahmad; Mahmoudian, Massoud

    2006-04-01

    Double peak absorption has been described with several orally administered drugs. Numerous reasons have been implicated in causing the double peak. DRUG-KNT--a pharmacokinetic software developed previously for fitting one and two compartment kinetics using the iterative curve stripping method--was modified and a revised subroutine was incorporated to solve double-peak models. This subroutine considers the double peak as two hypothetical doses administered with a time gap. The fitting capability of the presented model was verified using four sets of data showing double peak profiles extracted from the literature (piroxicam, ranitidine, phenazopyridine and talinolol). Visual inspection and statistical diagnostics showed that the present algorithm provided adequate curve fit disregarding the mechanism involved in the emergence of the secondary peaks. Statistical diagnostic parameters (RSS, AIC and R2) generally showed good fitness in the plasma profile prediction by this model. It was concluded that the algorithm presented herein provides adequate predicted curves in cases of the double peak phenomenon. PMID:16400712

  15. Pharmacokinetic-pharmacodynamic modeling of dopamine D2 receptor occupancy in humans using Bayesian modeling tools

    NARCIS (Netherlands)

    Johnson, Martin; Mafirakureva, Nyashadzaishe; Kozielska, Magdalena; Pilla Reddy, Venkatesh; Vermeulen, An; Liu, Jing; de Greef, Rik; Groothuis, Genoveva; Danhof, Meindert; Proost, Johannes

    2011-01-01

    Objectives: Blockade of dopamine-2 receptors is the key pharmacological component to the antipsychotic efficacy of both the typical and atypical antipsychotics (1). A pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to describe the relationship between the plasma concentration of a

  16. Using physiologically based pharmacokinetic modeling to address nonlinear kinetics and changes in rodent physiology and metabolism due to aging and adaptation in deriving reference values for propylene glycol methyl ether and propylene glycol methyl ether acetate.

    Energy Technology Data Exchange (ETDEWEB)

    Kirman, C R.; Sweeney, Lisa M.; Corley, Rick A.; Gargas, M L.

    2005-04-01

    Reference values, including an oral reference dose (RfD) and an inhalation reference concentration (RfC), were derived for propylene glycol methyl ether (PGME), and an oral RfD was derived for its acetate (PGMEA). These values were based upon transient sedation observed in F344 rats and B6C3F1 mice during a two-year inhalation study. The dose-response relationship for sedation was characterized using internal dose measures as predicted by a physiologically based pharmacokinetic (PBPK) model for PGME and its acetate. PBPK modeling was used to account for changes in rodent physiology and metabolism due to aging and adaptation, based on data collected during weeks 1, 2, 26, 52, and 78 of a chronic inhalation study. The peak concentration of PGME in richly perfused tissues was selected as the most appropriate internal dose measure based upon a consideration of the mode of action for sedation and similarities in tissue partitioning between brain and other richly perfused tissues. Internal doses (peak tissue concentrations of PGME) were designated as either no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs) based upon the presence or absence of sedation at each time-point, species, and sex in the two year study. Distributions of the NOAEL and LOAEL values expressed in terms of internal dose were characterized using an arithmetic mean and standard deviation, with the mean internal NOAEL serving as the basis for the reference values, which was then divided by appropriate uncertainty factors. Where data were permitting, chemical-specific adjustment factors were derived to replace default uncertainty factor values of ten. Nonlinear kinetics are were predicted by the model in all species at PGME concentrations exceeding 100 ppm, which complicates interspecies and low-dose extrapolations. To address this complication, reference values were derived using two approaches which differ with respect to the order in which these extrapolations

  17. 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.

  18. TopFit: a PC-based pharmacokinetic/pharmacodynamic data analysis program.

    Science.gov (United States)

    Tanswell, P; Koup, J

    1993-10-01

    The program TopFit was developed and validated within the European pharmaceutical industry. It provides both pharmacokinetic data analysis support for international regulatory submissions of new drugs, and sophisticated techniques for model-based kinetic/dynamic evaluation during drug development. TopFit features are: (1) non-compartmental methods; (2) standard compartment models assembled from input and disposition modules; (3) a potentially unlimited number of linear user-defined models that accommodate metabolites, effects, and absorption profiles; (4) a library of 24 non-linear models. No user programming is required. A well-defined file structure allows ready exchange of data with other programs such as SAS. TopFit version 2.0 is now commercially available, with comprehensive documentation, in the form of an MS-DOS application for the PC. PMID:8262691

  19. A nonlinear mixed effects modelling analysis of topiramate pharmacokinetics in patients with epilepsy

    OpenAIRE

    Janković, Slobodan; Jakovljević, Mihajlo; Kerec Kos, Mojca; Vovk, Tomaž; Mrhar, Aleš; Grabnar, Iztok

    2015-01-01

    Topiramate pharmacokinetics is influenced by individual factors such as patient age, renal function and co-treatment. The aim of this study was to develop a population pharmacokinetic model of topiramate to assist dosage adjustments in individual patients. Steady-state topiramate plasma concentrations in patients with epilepsy were determined by HPLC using fluorescent labelling. Demographic, biochemical data and dosing history including concomitant drug therapy were collected from patientsć c...

  20. Improving Predictive Modeling in Pediatric Drug Development: Pharmacokinetics, Pharmacodynamics, and Mechanistic Modeling

    Energy Technology Data Exchange (ETDEWEB)

    Slikker, William; Young, John F.; Corley, Rick A.; Dorman, David C.; Conolly, Rory B.; Knudsen, Thomas; Erstad, Brian L.; Luecke, Richard H.; Faustman, Elaine M.; Timchalk, Chuck; Mattison, Donald R.

    2005-07-26

    A workshop was conducted on November 18?19, 2004, to address the issue of improving predictive models for drug delivery to developing humans. Although considerable progress has been made for adult humans, large gaps remain for predicting pharmacokinetic/pharmacodynamic (PK/PD) outcome in children because most adult models have not been tested during development. The goals of the meeting included a description of when, during development, infants/children become adultlike in handling drugs. The issue of incorporating the most recent advances into the predictive models was also addressed: both the use of imaging approaches and genomic information were considered. Disease state, as exemplified by obesity, was addressed as a modifier of drug pharmacokinetics and pharmacodynamics during development. Issues addressed in this workshop should be considered in the development of new predictive and mechanistic models of drug kinetics and dynamics in the developing human.

  1. Elucidation of Arctigenin Pharmacokinetics After Intravenous and Oral Administrations in Rats: Integration of In Vitro and In Vivo Findings via Semi-mechanistic Pharmacokinetic Modeling

    OpenAIRE

    Gao, Qiong; Zhang, Yufeng; Wo, Siukwan; Zuo, Zhong

    2014-01-01

    Although arctigenin (AR) has attracted substantial research interests due to its promising and diverse therapeutic effects, studies regarding its biotransformation were limited. The current study aims to provide information regarding the pharmacokinetic properties of AR via various in vitro and in vivo experiments as well as semi-mechanistic pharmacokinetic modeling. Our in vitro rat microsome incubation studies revealed that glucuronidation was the main intestinal and liver metabolic pathway...

  2. Analysis of the impact of controlled release formulations on oral drug absorption, gut wall metabolism and relative bioavailability of CYP3A substrates using a physiologically-based pharmacokinetic model.

    Science.gov (United States)

    Olivares-Morales, Andrés; Kamiyama, Yoshiteru; Darwich, Adam S; Aarons, Leon; Rostami-Hodjegan, Amin

    2015-01-25

    Controlled release (CR) formulations are usually designed to achieve similar exposure (AUC) levels as the marketed immediate release (IR) formulation. However, the AUC is often lower following CR compared to IR formulations. There are a few exceptions when the CR formulations have shown higher AUC. This study investigated the impact of CR formulations on oral drug absorption and CYP3A4-mediated gut wall metabolism. A review of the current literature on relative bioavailability (Frel) between CR and IR formulations of CYP3A substrates was conducted. This was followed by a systematic analysis to assess the impact of the release characteristics and the drug-specific factors (including metabolism and permeability) on oral bioavailability employing a physiologically-based pharmacokinetic (PBPK) modelling and simulation approach. From the literature review, only three CYP3A4 substrates showed higher Frel when formulated as CR. Several scenarios were investigated using the PBPK approach; in most of them, the oral absorption of CR formulations was lower as compared to the IR formulations. However, for highly permeable compounds that were CYP3A4 substrates the reduction in absorption was compensated by an increase in the fraction that escapes from first pass metabolism in the gut wall (FG), where the magnitude was dependent on CYP3A4 affinity. The systematic simulations of various interplays between different parameters demonstrated that BCS class 1 highly-cleared CYP3A4 substrates can display up to 220% higher relative bioavailability when formulated as CR compared to IR, in agreement with the observed data collected from the literature. The results and methodology of this study can be employed during the formulation development process in order to optimize drug absorption, especially for CYP3A4 substrates. PMID:25444842

  3. Application of Physiologically-Based Pharmacokinetic Modeling to Explore the Role of Kidney Transporters in Renal Reabsorption of Perfluorooctanoic Acid in the Rat

    Science.gov (United States)

    Worley, Rachel Rogers; Fisher, Jeffrey

    2015-01-01

    Renal elimination and the resulting clearance of perfluorooctanoic acid (PFOA) from the serum exhibit pronounced sex differences in the adult rat. The literature suggests that this is largely due to hormonally regulated expression of organic anion transporters (OATs) on the apical and basolateral membranes of the proximal tubule cells that facilitate excretion and reabsorption of PFOA from the filtrate into the blood. Previously developed PBPK models of PFOA exposure in the rat have not been parameterized to specifically account for transporter-mediated renal elimination. We developed a PBPK model for PFOA in the male and female rat to explore the role of Oat1, Oat3, and Oatp1a1 in sex-specific renal reabsorption and excretion of PFOA. Descriptions of the kinetic behavior of these transporters were extrapolated from in vitro studies and the model was used to simulate time-course serum, liver, and urine data for intravenous (IV) and oral exposures in both sexes. Model predicted concentrations of PFOA in the liver, serum, and urine showed good agreement with experimental data for both the male and female rat indicating that in vitro derived physiological descriptions of transporter-mediated renal reabsorption can successfully predict sex-dependent excretion of PFOA in the rat. This study supports the hypothesis that sex-specific serum half-lives for PFOA are largely driven by expression of transporters in the kidney and contributes to the development of PBPK modeling as a tool for evaluating the role of transporters in renal clearance. PMID:26522833

  4. Improving Pharmacokinetic-Pharmacodynamic Modeling to Investigate Anti-Infective Chemotherapy with Application to the Current Generation of Antimalarial Drugs

    OpenAIRE

    Katherine Kay; Hastings, Ian M.

    2013-01-01

    Mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) modelling is the standard computational technique for simulating drug treatment of infectious diseases with the potential to enhance our understanding of drug treatment outcomes, drug deployment strategies, and dosing regimens. Standard methodologies assume only a single drug is used, it acts only in its unconverted form, and that oral drugs are instantaneously absorbed across the gut wall to their site of action. For drugs with short ha...

  5. Application of Physiologically-Based Pharmacokinetic Modeling to Explore the Role of Kidney Transporters in Renal Reabsorption of Perfluorooctanoic Acid in the Rat

    OpenAIRE

    Worley, Rachel Rogers; Fisher, Jeffrey

    2015-01-01

    Renal elimination and the resulting clearance of perfluorooctanoic acid (PFOA) from the serum exhibit pronounced sex differences in the adult rat. The literature suggests that this is largely due to hormonally regulated expression of organic anion transporters (OATs) on the apical and basolateral membranes of the proximal tubule cells that facilitate excretion and reabsorption of PFOA from the filtrate into the blood. Previously developed PBPK models of PFOA exposure in the rat have not been ...

  6. Using physiologically-based pharmacokinetic modeling to address nonlinear kinetics and changes in rodent physiology and metabolism due to aging and adaptation in deriving reference values for propylene glycol methyl ether and propylene glycol methyl ether acetate.

    Science.gov (United States)

    Kirman, C R; Sweeney, L M; Corley, R; Gargas, M L

    2005-04-01

    Reference values, including an oral reference dose (RfD) and an inhalation reference concentration (RfC), were derived for propylene glycol methyl ether (PGME), and an oral RfD was derived for its acetate (PGMEA). These values were based on transient sedation observed in F344 rats and B6C3F1 mice during a two-year inhalation study. The dose-response relationship for sedation was characterized using internal dose measures as predicted by a physiologically-based pharmacokinetic (PBPK) model for PGME and its acetate. PBPK modeling was used to account for changes in rodent physiology and metabolism due to aging and adaptation, based on data collected during Weeks 1, 2, 26, 52, and 78 of a chronic inhalation study. The peak concentration of PGME in richly perfused tissues (i.e., brain) was selected as the most appropriate internal dose measure based on a consideration of the mode of action for sedation and similarities in tissue partitioning between brain and other richly perfused tissues. Internal doses (peak tissue concentrations of PGME) were designated as either no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs) based on the presence or the absence of sedation at each time point, species, and sex in the two-year study. Distributions of the NOAEL and LOAEL values expressed in terms of internal dose were characterized using an arithmetic mean and standard deviation, with the mean internal NOAEL serving as the basis for the reference values, which was then divided by appropriate uncertainty factors. Where data were permitting, chemical-specific adjustment factors were derived to replace default uncertainty factor values of 10. Nonlinear kinetics, which was predicted by the model in all species at PGME concentrations exceeding 100 ppm, complicate interspecies, and low-dose extrapolations. To address this complication, reference values were derived using two approaches that differ with respect to the order in which these

  7. 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.

  8. Physiological modeling and extrapolation of pharmacokinetic interactions from binary to more complex chemical mixtures.

    Science.gov (United States)

    Krishnan, Kannan; Haddad, Sami; Béliveau, Martin; Tardif, Robert

    2002-12-01

    The available data on binary interactions are yet to be considered within the context of mixture risk assessment because of our inability to predict the effect of a third or a fourth chemical in the mixture on the interacting binary pairs. Physiologically based pharmacokinetic (PBPK) models represent a potentially useful framework for predicting the consequences of interactions in mixtures of increasing complexity. This article highlights the conceptual basis and validity of PBPK models for extrapolating the occurrence and magnitude of interactions from binary to more complex chemical mixtures. The methodology involves the development of PBPK models for all mixture components and interconnecting them at the level of the tissue where the interaction is occurring. Once all component models are interconnected at the binary level, the PBPK framework simulates the kinetics of all mixture components, accounting for the interactions occurring at various levels in more complex mixtures. This aspect was validated by comparing the simulations of a binary interaction-based PBPK model with experimental data on the inhalation kinetics of m-xylene, toluene, ethyl benzene, dichloromethane, and benzene in mixtures of varying composition and complexity. The ability to predict the kinetics of chemicals in complex mixtures by accounting for binary interactions alone within a PBPK model is a significant step toward the development of interaction-based risk assessment for chemical mixtures. PMID:12634130

  9. Pharmacokinetic/Pharmacodynamic Relationship of Gabapentin in a CFA-induced Inflammatory Hyperalgesia Rat Model

    DEFF Research Database (Denmark)

    Larsen, Malte Selch; Keizer, Ron; Munro, Gordon;

    2016-01-01

    provides further knowledge into the understanding of gabapentin's non-linear pharmacokinetics and the link between plasma/brain disposition and anti-hyperalgesic effects. The model suggests that intestinal absorption is the primary source of non-linearity and that the investigated rat model provides...

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

    Directory of Open Access Journals (Sweden)

    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

  11. Convex-Optimization-Based Compartmental Pharmacokinetic Analysis for Prostate Tumor Characterization Using DCE-MRI.

    Science.gov (United States)

    Ambikapathi, ArulMurugan; Chan, Tsung-Han; Lin, Chia-Hsiang; Yang, Fei-Shih; Chi, Chong-Yung; Wang, Yue

    2016-04-01

    Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a powerful imaging modality to study the pharmacokinetics in a suspected cancer/tumor tissue. The pharmacokinetic (PK) analysis of prostate cancer includes the estimation of time activity curves (TACs), and thereby, the corresponding kinetic parameters (KPs), and plays a pivotal role in diagnosis and prognosis of prostate cancer. In this paper, we endeavor to develop a blind source separation algorithm, namely convex-optimization-based KPs estimation (COKE) algorithm for PK analysis based on compartmental modeling of DCE-MRI data, for effective prostate tumor detection and its quantification. The COKE algorithm first identifies the best three representative pixels in the DCE-MRI data, corresponding to the plasma, fast-flow, and slow-flow TACs, respectively. The estimation accuracy of the flux rate constants (FRCs) of the fast-flow and slow-flow TACs directly affects the estimation accuracy of the KPs that provide the cancer and normal tissue distribution maps in the prostate region. The COKE algorithm wisely exploits the matrix structure (Toeplitz, lower triangular, and exponential decay) of the original nonconvex FRCs estimation problem, and reformulates it into two convex optimization problems that can reliably estimate the FRCs. After estimation of the FRCs, the KPs can be effectively estimated by solving a pixel-wise constrained curve-fitting (convex) problem. Simulation results demonstrate the efficacy of the proposed COKE algorithm. The COKE algorithm is also evaluated with DCE-MRI data of four different patients with prostate cancer and the obtained results are consistent with clinical observations. PMID:26292336

  12. BioDMET: a physiologically based pharmacokinetic simulation tool for assessing proposed solutions to complex biological problems.

    Science.gov (United States)

    Graf, John F; Scholz, Bernhard J; Zavodszky, Maria I

    2012-02-01

    We developed a detailed, whole-body physiologically based pharmacokinetic (PBPK) modeling tool for calculating the distribution of pharmaceutical agents in the various tissues and organs of a human or animal as a function of time. Ordinary differential equations (ODEs) represent the circulation of body fluids through organs and tissues at the macroscopic level, and the biological transport mechanisms and biotransformations within cells and their organelles at the molecular scale. Each major organ in the body is modeled as composed of one or more tissues. Tissues are made up of cells and fluid spaces. The model accounts for the circulation of arterial and venous blood as well as lymph. Since its development was fueled by the need to accurately predict the pharmacokinetic properties of imaging agents, BioDMET is more complex than most PBPK models. The anatomical details of the model are important for the imaging simulation endpoints. Model complexity has also been crucial for quickly adapting the tool to different problems without the need to generate a new model for every problem. When simpler models are preferred, the non-critical compartments can be dynamically collapsed to reduce unnecessary complexity. BioDMET has been used for imaging feasibility calculations in oncology, neurology, cardiology, and diabetes. For this purpose, the time concentration data generated by the model is inputted into a physics-based image simulator to establish imageability criteria. These are then used to define agent and physiology property ranges required for successful imaging. BioDMET has lately been adapted to aid the development of antimicrobial therapeutics. Given a range of built-in features and its inherent flexibility to customization, the model can be used to study a variety of pharmacokinetic and pharmacodynamic problems such as the effects of inter-individual differences and disease-states on drug pharmacokinetics and pharmacodynamics, dosing optimization, and inter

  13. An overview of the pharmacokinetics of polymer-based nanoassemblies and nanoparticles.

    Science.gov (United States)

    Zhao, Qing-He; Qiu, Li-Yan

    2013-10-01

    Advancements in the design and synthesis of polymer-based nanoassemblies and nanoparticles, combined with achievements in nanotechnology and medicine, have resulted in remarkable applications of polymer nanosystems in the areas of nanomedicine and pharmaceutical sciences. However, a complete understanding of the absorption, distribution, metabolism, and elimination (ADME) processes of such polymer nanosystems in living systems has not been achieved. The influences of the pharmacokinetic parameters of polymer nanomaterials on the ADME processes are reviewed in this article, with discussions of the absorption and transportation of polymer nanoparticles across biological barriers, the factors affecting the bodily distribution of polymer nanocarriers, the transformation of polymer nanomaterials in vivo, the elimination pathway of polymer nanoparticles from biological systems, and perspectives of future pharmacokinetics and safety investigations of polymer-based nanoassemblies. A full and better understanding of the pharmacokinetic parameters of polymer-based nanomaterials is of vital importance in developing polymer nanosystems with optimal pharmacokinetics and biological safety for applications in nanomedicine and the pharmaceutical industry. PMID:24016113

  14. Modeling In Vivo Pharmacokinetics and Pharmacodynamics of Moxifloxacin Therapy for Mycobacterium tuberculosis Infection by Using a Novel Cartridge System

    OpenAIRE

    Ginsburg, Amy Sarah; Lee, Jin; Woolwine, Samuel C.; Jacques H Grosset; Hamzeh, Fayez M.; Bishai, William R.

    2005-01-01

    To study the efficacy of moxifloxacin treatment for tuberculosis, we utilized a novel cartridge system to simulate in vivo pharmacokinetics. We found this system to be a robust method for modeling in vivo pharmacokinetics and present data supporting the utility of intermittent moxifloxacin treatment as a component of antituberculosis chemotherapy.

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

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel

    2005-01-01

    The present thesis deals with different aspects of population pharmacokinetic/ pharmacodynamic (PK/PD) modelling of the male hypothalamic-pituitary-go-nadal (HPG) axis. The thesis consists of a summary report and five scientific research papers. An overview of the main topics covered in the thesis...

  16. Mixed-Effects Modeling of the Influence of Midazolam on Propofol Pharmacokinetics

    NARCIS (Netherlands)

    Vuyk, Jaap; Lichtenbelt, Bart Jan; Olofsen, Erik; van Kleef, Jack W.; Dahan, Albert

    2009-01-01

    BACKGROUND: The combined administration of anesthetics has been associated with pharmacokinetic interactions that induce concentration changes of up to 30%. Midazolam is often used as a preoperative sedative in advance of a propofol-based anesthetic. In this study, we identified the influence of mid

  17. Computational Analysis of Pharmacokinetic Behavior of Ampicillin

    Directory of Open Access Journals (Sweden)

    Mária Ďurišová

    2016-07-01

    Full Text Available orrespondence: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, 841 04 Bratislava, Slovak Republic. Phone + 42-1254775928; Fax +421254775928; E-mail: maria.durisova@savba.sk 84 RESEARCH ARTICLE The objective of this study was to perform a computational analysis of the pharmacokinetic behavior of ampicillin, using data from the literature. A method based on the theory of dynamic systems was used for modeling purposes. The method used has been introduced to pharmacokinetics with the aim to contribute to the knowledge base in pharmacokinetics by including the modeling method which enables researchers to develop mathematical models of various pharmacokinetic processes in an identical way, using identical model structures. A few examples of a successful use of the modeling method considered here in pharmacokinetics can be found in full texts articles available free of charge at the website of the author, and in the example given in the this study. The modeling method employed in this study can be used to develop a mathematical model of the pharmacokinetic behavior of any drug, under the condition that the pharmacokinetic behavior of the drug under study can be at least partially approximated using linear models.

  18. Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

    Institute of Scientific and Technical Information of China (English)

    Jing ZHANG; Pei LI; Hai-fang GUO; Li LIU; Xiao-dong LIU

    2012-01-01

    Aim:To characterize pharmacokinetic-pharmacodynamic modeling of diclofenac in Freund's complete adjuvant (FCA)-induced arthritic rats using prostaglandin E2 (PGE2) as a biomarker.Methods:The pharmacokinetics of diclofenac was investigated using 20-day-old arthritic rats.PGE2 level in the rats was measured using an enzyme immunoassay.A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to illustrate the relationship between the plasma concentration of diclofenac and the inhibition of PGE2 production.The inhibition of diclofenac on lipopolysaccharide (LPS)-induced PGE2 production in blood cells was investigated in vitro.Results:Similar pharmacokinetic behavior of diclofenac was found both in normal and FCA-induced arthritic rats.Diclofenac significantly decreased the plasma levels of PGE2 in both normal and arthritic rats.The inhibitory effect on PGE2 levels in the plasma was in proportion to the plasma concentration of diclofenac.No delay in the onset of inhibition was observed,suggesting that the effect compartment was located in the central compartment.An inhibitory effect sigmoid/max model was selected to characterize the relationship between the plasma concentration of diclofenac and the inhibition of PGE2 production in vivo.The /max model was also used to illustrate the inhibition of diclofenac on LPS-induced PGE2 production in blood cells in vitro.Conclusion:Arthritis induced by FCA does not alter the pharmacokinetic behaviors of diclofenac in rats,but the pharmacodynamics of diclofenac is slightly affected.A PK-PD model characterizing an inhibitory effect sigmoid /max can be used to fit the relationship between the plasma PGE2 and diclofenac levels in both normal rats and FCA-induced arthritic rats.

  19. Serum albumin 'camouflage' of plant virus based nanoparticles prevents their antibody recognition and enhances pharmacokinetics.

    Science.gov (United States)

    Pitek, Andrzej S; Jameson, Slater A; Veliz, Frank A; Shukla, Sourabh; Steinmetz, Nicole F

    2016-05-01

    Plant virus-based nanoparticles (VNPs) are a novel class of nanocarriers with unique potential for biomedical applications. VNPs have many advantageous properties such as ease of manufacture and high degree of quality control. Their biocompatibility and biodegradability make them an attractive alternative to synthetic nanoparticles (NPs). Nevertheless, as with synthetic NPs, to be successful in drug delivery or imaging, the carriers need to overcome several biological barriers including innate immune recognition. Plasma opsonization can tag (V)NPs for clearance by the mononuclear phagocyte system (MPS), resulting in shortened circulation half lives and non-specific sequestration in non-targeted organs. PEG coatings have been traditionally used to 'shield' nanocarriers from immune surveillance. However, due to broad use of PEG in cosmetics and other industries, the prevalence of anti-PEG antibodies has been reported, which may limit the utility of PEGylation in nanomedicine. Alternative strategies are needed to tailor the in vivo properties of (plant virus-based) nanocarriers. We demonstrate the use of serum albumin (SA) as a viable alternative. SA conjugation to tobacco mosaic virus (TMV)-based nanocarriers results in a 'camouflage' effect more effective than PEG coatings. SA-'camouflaged' TMV particles exhibit decreased antibody recognition, as well as enhanced pharmacokinetics in a Balb/C mouse model. Therefore, SA-coatings may provide an alternative and improved coating technique to yield (plant virus-based) NPs with improved in vivo properties enhancing drug delivery and molecular imaging. PMID:26950168

  20. Fractional model for pharmacokinetics of high dose methotrexate in children with acute lymphoblastic leukaemia

    Science.gov (United States)

    Popović, Jovan K.; Spasić, Dragan T.; Tošić, Jela; Kolarović, Jovanka L.; Malti, Rachid; Mitić, Igor M.; Pilipović, Stevan; Atanacković, Teodor M.

    2015-05-01

    The aim of this study is to promote a model based on the fractional differential calculus related to the pharmacokinetic individualization of high dose methotrexate treatment in children with acute lymphoblastic leukaemia, especially in high risk patients. We applied two-compartment fractional model on 8 selected cases with the largest number (4-19) of measured concentrations, among 43 pediatric patients received 24-h methotrexate 2-5 g/m2 infusions. The plasma concentrations were determined by fluorescence polarization immunoassay. Our mathematical procedure, designed by combining Post's and Newton's method, was coded in Mathematica 8.0 and performed on Fujicu Celsius M470-2 PC. Experimental data show that most of the measured values of methotrexate were in decreasing order. However, in certain treatments local maximums were detected. On the other hand, integer order compartmental models do not give values which fit well with the observed data. By the use of our model, we obtained better results, since it gives more accurate behavior of the transmission, as well as the local maximums which were recognized in methotrexate monitoring. It follows from our method that an additional test with a small methotrexate dose can be suggested for the fractional system parameter identification and the prediction of a possible pattern with a full dose in the case of high risk patients. A special feature of the fractional model is that it can also recognize and better fit an observed non-monotonic behavior. A new parameter determination procedure can be successfully used.

  1. Assessment of pharmacokinetic interaction of spirulina with glitazone in a type 2 diabetes rat model.

    Science.gov (United States)

    Gupta, Annu; Nair, Anroop; Kumria, Rachna; Al-Dhubiab, Bandar-E; Chattopadhyaya, Ipshita; Gupta, Sumeet

    2013-12-01

    The objective of the current study was to assess the possible pharmacokinetic interactions of spirulina with glitazones in an insulin resistance rat model. Wistar male albino rats were equally divided into five groups: insulin resistant rats+spirulina (500 mg/kg)+pioglitazone (10 mg/kg), insulin resistant rats+pioglitazone (10 mg/kg), insulin resistant rats+spirulina (500 mg/kg)+rosiglitazone (10 mg/kg), insulin resistant rats+rosiglitazone (10 mg/kg), and insulin resistant rats+spirulina (500 mg/kg). Described doses of pioglitazone, rosiglitazone, or spirulina were per orally administered and the plasma drug concentrations were determined. The pharmacokinetic parameters such as Tmax, Cmax, AUC(0-α), t1/2, and Kel were determined by plotting the drug concentration as a function of time. The data observed in this acute study indicated that there was no statistically significant difference in any of the pharmacokinetic parameters (Tmax, Cmax, AUC(0-α), t1/2, and Kel) of glitazones (pioglitazone, rosiglitazone) or spirulina, when they were coadministered. Given the promising results, this study concludes that the coadministration of spirulina does not influence the pharmacokinetics of glitazones in a type 2 diabetes rat model. Further chronic in vivo studies are recommended to assess the real time effect. PMID:24328701

  2. Reconstructing exposures from biomarkers using exposure-pharmacokinetic modeling--A case study with carbaryl.

    Science.gov (United States)

    Brown, Kathleen; Phillips, Martin; Grulke, Christopher; Yoon, Miyoung; Young, Bruce; McDougall, Robin; Leonard, Jeremy; Lu, Jingtao; Lefew, William; Tan, Yu-Mei

    2015-12-01

    Sources of uncertainty involved in exposure reconstruction for short half-life chemicals were characterized using computational models that link external exposures to biomarkers. Using carbaryl as an example, an exposure model, the Cumulative and Aggregate Risk Evaluation System (CARES), was used to generate time-concentration profiles for 500 virtual individuals exposed to carbaryl. These exposure profiles were used as inputs into a physiologically based pharmacokinetic (PBPK) model to predict urinary biomarker concentrations. These matching dietary intake levels and biomarker concentrations were used to (1) compare three reverse dosimetry approaches based on their ability to predict the central tendency of the intake dose distribution; and (2) identify parameters necessary for a more accurate exposure reconstruction. This study illustrates the trade-offs between using non-iterative reverse dosimetry methods that are fast, less precise and iterative methods that are slow, more precise. This study also intimates the necessity of including urine flow rate and elapsed time between last dose and urine sampling as part of the biomarker sampling collection for better interpretation of urinary biomarker data of short biological half-life chemicals. Resolution of these critical data gaps can allow exposure reconstruction methods to better predict population-level intake doses from large biomonitoring studies. PMID:26545325

  3. A systems biology approach to dynamic modeling and inter-subject variability of statin pharmacokinetics in human hepatocytes

    Directory of Open Access Journals (Sweden)

    Thasler Wolfgang E

    2011-05-01

    Full Text Available Abstract Background The individual character of pharmacokinetics is of great importance in the risk assessment of new drug leads in pharmacological research. Amongst others, it is severely influenced by the properties and inter-individual variability of the enzymes and transporters of the drug detoxification system of the liver. Predicting individual drug biotransformation capacity requires quantitative and detailed models. Results In this contribution we present the de novo deterministic modeling of atorvastatin biotransformation based on comprehensive published knowledge on involved metabolic and transport pathways as well as physicochemical properties. The model was evaluated on primary human hepatocytes and parameter identifiability analysis was performed under multiple experimental constraints. Dynamic simulations of atorvastatin biotransformation considering the inter-individual variability of the two major involved enzymes CYP3A4 and UGT1A3 based on quantitative protein expression data in a large human liver bank (n = 150 highlighted the variability in the individual biotransformation profiles and therefore also points to the individuality of pharmacokinetics. Conclusions A dynamic model for the biotransformation of atorvastatin has been developed using quantitative metabolite measurements in primary human hepatocytes. The model comprises kinetics for transport processes and metabolic enzymes as well as population liver expression data allowing us to assess the impact of inter-individual variability of concentrations of key proteins. Application of computational tools for parameter sensitivity analysis enabled us to considerably improve the validity of the model and to create a consistent framework for precise computer-aided simulations in toxicology.

  4. Biodistribution and translational pharmacokinetic modeling of a human recombinant alkaline phosphatase.

    Science.gov (United States)

    Peters, Esther; Stevens, Jasper; Arend, Jacques; Guan, Zheng; Raaben, Willem; Laverman, Peter; van Elsas, Andrea; Masereeuw, Rosalinde; Pickkers, Peter

    2015-11-10

    Clinical trials showed renal protective effects of bovine intestinal alkaline phosphatase (AP) in patients with sepsis-associated acute kidney injury (AKI). Subsequently, a human recombinant chimeric AP (recAP) was developed as a pharmaceutically acceptable alternative. Here, we investigated the biodistribution and pharmacokinetics (PK) of recAP and developed a translational population PK model. Biodistribution was studied during LPS-induced AKI in rats. Iodine-125-labeled recAP was primarily taken up by liver, spleen, adrenals, heart, lungs and kidneys followed by the gastro-intestinal tract and thyroid. Tissue distribution was not critically affected by endotoxemia. PK parameters were determined in rats and minipigs during IV bolus injections of recAP, administered once, or once daily during seven consecutive days. Plasma concentrations of recAP increased with increasing dose and disappeared in a biphasic manner. Exposure to recAP, estimated by AUC and Cmax, was similar on days 1 and 7. Subsequently, population approach nonlinear mixed effects modeling was performed with recAP rat and minipig and biAP phase I PK data. Concentration versus time data was accurately described in all species by a two-compartmental model with allometric scaling based on body weight. This model provides a solid foundation for determining the optimal dose and duration of first-in-man recAP studies. PMID:26325308

  5. Pharmacokinetic considerations of nanodelivery to the brain: Using modeling and simulations to predict the outcome of liposomal formulations.

    Science.gov (United States)

    Lindqvist, Annika; Fridén, Markus; Hammarlund-Udenaes, Margareta

    2016-09-20

    The use of nanocarriers is an intriguing solution to increase the brain delivery of novel therapeutics. The aim of this paper was to use pharmacokinetic analysis and simulations to identify key factors that determine the effective drug concentration-time profile at the target site in the brain. Model building and simulations were based on experimental data obtained from the administration of the opioid peptide DAMGO in glutathione tagged PEGylated liposomes to rats. Different pharmacokinetic models were investigated to explore the mechanisms of increased brain delivery. Concentration-time profiles for a set of formulations with varying compound and carrier characteristics were simulated. By controlling the release rate from the liposome, the time profile and the extent of brain delivery can be regulated. The modeling did not support a mechanism of the liposomes passing the brain endothelial cell membrane in an intact form through endocytosis or transcytosis. The most likely process was found to be fusion of the liposome with the endothelial luminal membrane. The simulations revealed that low permeable compounds, independent on efflux, will gain the most from a nanocarrier formulation. The present model based approach is useful to explore and predict possibilities and limitations of carrier-based systems to the brain. PMID:27393342

  6. Population pharmacokinetics of topiramate in adult patients with epilepsy using nonlinear mixed effects modelling

    OpenAIRE

    Vučičević, Katarina; Jovanović, Marija; Vovk, Tomaž; Miljković, Branislava; Sokić, Dragoslav; Grabnar, Iztok; Prostran, Milica

    2015-01-01

    The objective of the study was to develop population pharmacokinetic model of topiramate (TPM) using nonlinear mixed effects modelling approach. Data were collected from 78 adult epilepsy patients on mono- or co-therapy of TPM and other antiepileptic drugs, such as carbamazepine (CBZ), valproic acid, lamotrigine, levetiracetam, phenobarbital and pregabalin. Steady-state TPM concentrations were determined in blood samples by high performance liquid chromatography with fluorescence detection. A...

  7. Physiologically Based Pharmacokinetics Is Impacting Drug Development and Regulatory Decision Making.

    Science.gov (United States)

    Rowland, M; Lesko, L J; Rostami-Hodjegan, A

    2015-06-01

    It is no coincidence that the reports of two meetings, one organized by the US Food and Drug Administration (FDA), in March 2014, and the other by the UK Medicines and Healthcare Products Regulatory (MHRA), in collaboration with ABPI (the Association of British Pharmaceutical Industry), in June 2014, have been published in tandem in CPT-PSP.12 Both reports deal with the same topic, namely, the impact of physiologically based pharmacokinetics (PBPK) in clinical drug development and the best practices for such applications. This reflects the transition of PBPK from academic curiosity to industrial norm, manifested by the regulatory agencies encouraging its use and receiving an increasing number of submissions containing PBPK models. The goal of both meetings was to help determine the need and facilitate the development of regulatory guidances on this subject within the conceptual framework of model informed drug development and regulatory decision-making. A further reflection of this intent is the publication by the European Medicines Agency of a Concept Paper on PBPK.3 One is reminded of a similar train of events surrounding the introduction of population PK/PD and nonlinear mixed effects modeling in the early-late 1990s, again with encouragement and receptivity of regulatory agencies leading to FDA guidance on the topic.4 Indeed, the intention of PBPK modeling and simulation is to complement other approaches, such as compartmental modeling, or, in some cases, replace them with a more mechanistic approach. PBPK models represent an important class of models that characterize absorption, distribution, metabolism, excretion (ADME) processes and their underlying biological and physiological drivers. An increased understanding of these drivers and their unique interactions with drug substance and formulation factors provides critical insights into how drugs will behave in healthy volunteers and patients with disease. PMID:26225258

  8. Prediction of denosumab effects on bone remodeling: A combined pharmacokinetics and finite element modeling.

    Science.gov (United States)

    Hambli, Ridha; Boughattas, Mohamed Hafedh; Daniel, Jean-Luc; Kourta, Azeddine

    2016-07-01

    Denosumab is a fully human monoclonal antibody that inhibits receptor activator of nuclearfactor-kappa B ligand (RANKL). This key mediator of osteoclast activities has been shown to inhibit osteoclast differentiation and hence, to increase bone mineral density (BMD) in treated patients. In the current study, we develop a computer model to simulate the effects of denosumab treatments (dose and duration) on the proximal femur bone remodeling process quantified by the variation in proximal femur BMD. The simulation model is based on a coupled pharmacokinetics model of denosumab with a pharmacodynamics model consisting of a mechanobiological finite element remodeling model which describes the activities of osteoclasts and osteoblasts. The mechanical behavior of bone is described by taking into account the bone material fatigue damage accumulation and mineralization. A coupled strain-damage stimulus function is proposed which controls the level of bone cell autocrine and paracrine factors. The cellular behavior is based on Komarova et al.׳s (2003) dynamic law which describes the autocrine and paracrine interactions between osteoblasts and osteoclasts and computes cell population dynamics and changes in bone mass at a discrete site of bone remodeling. Therefore, when an external mechanical stress is applied, bone formation and resorption is governed by cell dynamics rather than by adaptive elasticity approaches. The proposed finite element model was implemented in the finite element code Abaqus (UMAT routine). In order to perform a preliminary validation, in vivo human proximal femurs were selected and scanned at two different time intervals (at baseline and at a 36-month interval). Then, a 3D FE model was generated and the denosumab-remodeling algorithm was applied to the scans at t0 simulating daily walking activities for a duration of 36 months. The predicted results (density variation) were compared to existing published ones performed on a human cohort (FREEDOM

  9. Pharmacokinetic modelling of multi-decadal luminescence time series in coral skeletons

    Science.gov (United States)

    Llewellyn, Lyndon E.; Everingham, Yvette L.; Lough, Janice M.

    2012-04-01

    As corals grow, they incorporate chemical indicators of seawater conditions into their aragonite skeleton after they have traversed an outer living tissue layer. Long-lived, massive coral skeletons can record decade- and century-long time series of seawater status. One such environmental clue is luminescence intensity which can correspond to river flow patterns and has been attributed to humic acid incorporation. Seawater humic acid levels are linked to river flow as rainfall extracts them from catchment soils to then flow into rivers and coastal seas. However, discrepancies exist when validating coral luminescence records against river flow data with intense luminescence sometimes occurring in the absence of increased flows. This contributes to uncertainty when reconstructing pre-instrumental river flows and rainfall from coral luminescence. Here we demonstrate that a major portion of coral core luminescence time series can be explained using a single-compartment, pharmacokinetic model that incorporates river flow measurements as the equivalent of drug dose. The model was robust for luminescence series in corals from near-shore reefs regularly influenced by river flow. The model implies that after floods, a proportion of subsequent luminescence peaks can be derived from the initial flood. This explains why some luminescence peaks after floods often do not correspond to additional significant river flows. This provides the first mechanism-based explanation for temporal changes in coral skeleton luminescence that incorporates a mathematical link between two independent time series making this proxy even more robust for reconstructing river flow and rainfall.

  10. Bioenergetic and pharmacokinetic model for exposure of common loon (Gavia immer) chicks to methylmercury

    Science.gov (United States)

    Karasov, W.H.; Kenow, K.P.; Meyer, M.W.; Fournier, F.

    2007-01-01

    A bioenergetics model was used to predict food intake of common loon (Gavia immer) chicks as a function of body mass during development, and a pharmacokinetics model, based on first-order kinetics in a single compartment, was used to predict blood Hg level as a function of food intake rate, food Hg content, body mass, and Hg absorption and elimination. Predictions were tested in captive growing chicks fed trout (Salmo gairdneri) with average MeHg concentrations of 0.02 (control), 0.4, and 1.2 ??g/g wet mass (delivered as CH3HgCl). Predicted food intake matched observed intake through 50 d of age but then exceeded observed intake by an amount that grew progressively larger with age, reaching a significant overestimate of 28% by the end of the trial. Respiration in older, nongrowing birds probably was overestimated by using rates measured in younger, growing birds. Close agreement was found between simulations and measured blood Hg, which varied significantly with dietary Hg and age. Although chicks may hatch with different blood Hg levels, their blood level is determined mainly by dietary Hg level beyond approximately two weeks of age. The model also may be useful for predicting Hg levels in adults and in the eggs that they lay, but its accuracy in both chicks and adults needs to be tested in free-living birds. ?? 2007 SETAC.

  11. Elucidation of arctigenin pharmacokinetics after intravenous and oral administrations in rats: integration of in vitro and in vivo findings via semi-mechanistic pharmacokinetic modeling.

    Science.gov (United States)

    Gao, Qiong; Zhang, Yufeng; Wo, Siukwan; Zuo, Zhong

    2014-11-01

    Although arctigenin (AR) has attracted substantial research interests due to its promising and diverse therapeutic effects, studies regarding its biotransformation were limited. The current study aims to provide information regarding the pharmacokinetic properties of AR via various in vitro and in vivo experiments as well as semi-mechanistic pharmacokinetic modeling. Our in vitro rat microsome incubation studies revealed that glucuronidation was the main intestinal and liver metabolic pathway of AR, which occurred with V max, K m, and Clint of 47.5 ± 3.4 nmol/min/mg, 204 ± 22 μM, and 233 ± 9 μl/min/mg with intestinal microsomes and 2.92 ± 0.07 nmol/min/mg, 22.7 ± 1.2 μM, and 129 ± 4 μl/min/mg with liver microsomes, respectively. In addition, demethylation and hydrolysis of AR occurred with liver microsomes but not with intestinal microsomes. In vitro incubation of AR and its metabolites in intestinal content demonstrated that glucuronides of AR excreted in bile could be further hydrolyzed back to the parent compound, suggesting its potential enterohepatic circulation. Furthermore, rapid formation followed by fast elimination of arctigenic acid (AA) and arctigenin-4'-O-glucuronide (AG) was observed after both intravenous (IV) and oral administrations of AR in rats. Linear pharmacokinetics was observed at three different doses for AR, AA, and AG after IV administration of AR (0.48-2.4 mg/kg, r (2) > 0.99). Finally, an integrated semi-mechanistic pharmacokinetic model using in vitro enzyme kinetic and in vivo pharmacokinetic parameters was successfully developed to describe plasma concentrations of AR, AA, and AG after both IV and oral administration of AR at all tested doses. PMID:25274606

  12. Non-linear mixed-effects pharmacokinetic/pharmacodynamic modelling in NLME using differential equations

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Madsen, Henrik;

    2004-01-01

    The standard software for non-linear mixed-effect analysis of pharmacokinetic/phar-macodynamic (PK/PD) data is NONMEM while the non-linear mixed-effects package NLME is an alternative as tong as the models are fairly simple. We present the nlmeODE package which combines the ordinary differential...... equation (ODE) solver package odesolve and the non-Linear mixed effects package NLME thereby enabling the analysis of complicated systems of ODEs by non-linear mixed-effects modelling. The pharmacokinetics of the anti-asthmatic drug theophylline is used to illustrate the applicability of the nlme......ODE package for population PK/PD analysis using the available data analysis tools in R for model inspection and validation. The nlmeODE package is numerically stable and provides accurate parameter estimates which are consistent with NONMEM estimates. (C) 2004 Elsevier Ireland Ltd. ALL rights reserved....

  13. The Impact of Team-Based Learning on a Foundational Pharmacokinetics Course

    Science.gov (United States)

    2012-01-01

    Objective. To assess the impact of team-based learning (TBL) in a foundational pharmacokinetics course. Design. The course was arranged into 5 modules based on the TBL format. Each module contained preclass preparation; readiness-assurance process; and in-class, clinical cases. Survey instruments on professionalism and attitudes of team learning were administered pre- and post-course. Assessment. Examination grades focused at the evaluation/creation level were significantly higher in the TBL format compared with the previous year. Professionalism scores increased over the course of the semester, particularly in altruism and honesty. Other measures of team-learning attitudes significantly increased over time, although there was no change in major subscales. End-of-semester course evaluations showed improvements in active engagement and in various areas of skill development. Conclusion. The TBL format can be used successfully in a foundational pharmacokinetics course to increase higher levels of learning, team-learning skills, and professionalism in pharmacy students. PMID:22438603

  14. Tissue distribution and physiologically based pharmacokinetics of antisense phosphorothioate oligonucleotide ISIS 1082 in rat.

    Science.gov (United States)

    Peng, B; Andrews, J; Nestorov, I; Brennan, B; Nicklin, P; Rowland, M

    2001-02-01

    The aim of this study was to develop a whole body physiologically based model of the pharmacokinetics (PBPK) of the phosphorothioate oligonucleotide (PS-ODN) ISIS 1082 in vivo. Rats were administered an intravenous (i.v.) bolus dose of ISIS 1082 (10 mg/kg plus 3H tracer), and arterial blood and tissues were taken at specific times up to 72 hours. Radioactivity was measured in all samples. The parent compound was determined specifically in blood and tissues at 90 minutes and in liver and kidney also at 24 hours, using capillary gel electrophoresis (CGE). A whole body PBPK model was fitted to the combined blood and tissue radioactivity data using nonlinear regression analysis. CGE analysis indicated that the predominant species in plasma and all tissues is ISIS 1082, together with some n-1 and n-2 metabolites. Total radioactivity primarily reflects these species. The whole body model successfully described temporal events in all tissues. However, to adequately model the experimental data, all tissues had to be partitioned into vascular and extravascular spaces to accommodate the relatively slow distribution of ISIS 1082 out of blood because of a permeability rate limitation. ISIS 1082 distributes extensively into tissues, but the relative affinity varies enormously, being highest for kidney and liver and lowest for muscle and brain. A whole body PBPK model with a permeability rate limited tissue distribution was developed that adequately described events in both blood and tissue for an oligonucleotide. This model has the potential not only to characterize the events in individual tissues throughout the body for such compounds but also to scale across animal species, including human. PMID:11258618

  15. Application of physiologically based pharmacokinetic models in the prediction of drug-drug interactions mediated by transporters%生理药代动力学模型在预测转运体介导药物相互作用中的应用

    Institute of Scientific and Technical Information of China (English)

    陈琳; 刘晓培; 夏春华; 胡锦芳; 熊玉卿

    2015-01-01

    Physiologically based pharmacokinetic ( PBPK ) models are built using a mathematic framework which is similar to these classic phar-macokinetic ( PK ) models, and are parameterized based on known physiology knowledge, and comprise many compartments corresponding to different organs and tissues in the body, which are connected by flow rates that parallel the circulating blood system.The values of PBPK models are gradually appreciated in the industry of drug development, especially in the field of drug -drug interaction due to their robust ability to predict drugs’ kinetic process in vivo.Then some basic concepts, advantages over classic models and their applications in drug-drug interaction fields asso-ciated with transporters of PBPK models are reviewed in the next context.%生理药代动力学模型通过与经典药代动力学模型类似的数学框架构建而成,并按已知的生理学知识设置参数,由大量分别对应于体内不同器官或组织的房室组成,并通过类似血液循环的系统而连接。因能较准确的预测药物在体内过程,故其在药物研发行业,尤其是药物相互作用领域,逐渐崭露头角。本文将从生理药代动力学模型的概念、与经典模型的优势比较及其在转运体介导的药物相互作用中的应用等方面进行综述。

  16. A population pharmacokinetic model for R- and S-citalopram and desmethylcitalopram in Alzheimer’s disease patients with agitation

    OpenAIRE

    Akil, Ayman; Bies, Robert R.; Bruce G Pollock; Avramopoulos, Dimitrios; Devanand, D. P.; Mintzer, Jacobo E.; Porsteinsson, Anton P.; Schneider, Lon S; Weintraub, Daniel; Yesavage, Jerome; Shade, David M.; Lyketsos, Constantine G.

    2015-01-01

    The citalopram for Alzheimer’s disease trial evaluated citalopram for the management for agitation in Alzheimer’s disease patients. Sparse data was available from this elderly patient population. A nonlinear mixed effects population pharmacokinetic modeling approach was used to describe the pharmacokinetics of R- and S-citalopram and their primary metabolite (desmethylcitalopram). A structural model with 4 compartments (one compartment/compound) with linear oral absorption and elimination des...

  17. Pharmacokinetic modelling of methotrexate from routine clinical data in patients with acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Pharmacokinetic modelling was performed in NONMEM (version 6.1) using a dataset including 273 patients (aged 2 to 23 years) who received high-dose MTX (5 g/m/sup 2/ per course) in long-term treatment. Total 2582 methotrexate plasma concentrations were performed by fluorescence polarisation immunoassay (FPIA). A three compartment open model with elimination from the central compartment described the pharmacokinetics of methotrexate. The most important covariates affecting the disposition of methotrexate were age (age, year), body weight (BW, kg), and creatinine clearance (CLR, lh/sup -1/). The final model with exponential disposition of MTX was clearance (CL, Ih/sup -1/) = (6.11 + WT*6.7310/sup -2/) + (1.0810/sup -4/* CLR )* EXP(1.9510/sup -1/), (V, l) = 10,8+(AGE* 9.310/sup -2/) *EXP(9.110/sup -1/), = Q(lh/sup -1/) = 2.0410/sup -3/*WT Pharmacokinetic parameters (percentage CV) in this study were CL, 8.72 lh/sup -1/ (44 %); V1, 17.49 I (95%); V2, 6.048 l (56%); V3, 0.015 I (52%). The model predictions in the qualification group were found to have no bias and satisfactory precision. (author)

  18. The pharmacokinetics of the interstitial space in humans

    OpenAIRE

    Levitt, David G.

    2003-01-01

    Background The pharmacokinetics of extracellular solutes is determined by the blood-tissue exchange kinetics and the volume of distribution in the interstitial space in the different organs. This information can be used to develop a general physiologically based pharmacokinetic (PBPK) model applicable to most extracellular solutes. Methods The human pharmacokinetic literature was surveyed to tabulate the steady state and equilibrium volume of distribution of the solutes mannitol, EDTA, morphi...

  19. Lack of meaningful effect of ridaforolimus on the pharmacokinetics of midazolam in cancer patients: model prediction and clinical confirmation.

    Science.gov (United States)

    Stroh, Mark; Talaty, Jennifer; Sandhu, Punam; McCrea, Jacqueline; Patnaik, Amita; Tolcher, Anthony; Palcza, John; Orford, Keith; Breidinger, Sheila; Narasimhan, Narayana; Panebianco, Deborah; Lush, Richard; Papadopoulos, Kyriakos P; Wagner, John A; Trucksis, Michele; Agrawal, Nancy

    2014-11-01

    Ridaforolimus, a unique non-prodrug analog of rapamycin, is a potent inhibitor of mTOR under development for cancer treatment. In vitro data suggest ridaforolimus is a reversible and time-dependent inhibitor of CYP3A. A model-based evaluation suggested an increase in midazolam area under the curve (AUC(0- ∞)) of between 1.13- and 1.25-fold in the presence of therapeutic concentrations of ridaforolimus. The pharmacokinetic interaction between multiple oral doses of ridaforolimus and a single oral dose of midazolam was evaluated in an open-label, fixed-sequence study, in which cancer patients received a single oral dose of 2 mg midazolam followed by 5 consecutive daily single oral doses of 40 mg ridaforolimus with a single dose of 2 mg midazolam with the fifth ridaforolimus dose. Changes in midazolam exposure were minimal [geometric mean ratios and 90% confidence intervals: 1.23 (1.07, 1.40) for AUC(0-∞) and 0.92 (0.82, 1.03) for maximum concentrations (C(max)), respectively]. Consistent with model predictions, ridaforolimus had no clinically important effect on midazolam pharmacokinetics and is not anticipated to be a perpetrator of drug-drug interactions (DDIs) when coadministered with CYP3A substrates. Model-based approaches can provide reasonable estimates of DDI liability, potentially obviating the need to conduct dedicated DDI studies especially in challenging populations like cancer patients. PMID:24827931

  20. Pharmacokinetic-Pharmacodynamic Analysis of Spiroindolone Analogs and KAE609 in a Murine Malaria Model

    OpenAIRE

    Lakshminarayana, Suresh B.; Freymond, Céline; Fischli, Christoph; Yu, Jing; Weber, Sebastian; Goh, Anne; Yeung, Bryan K. S.; Ho, Paul C.; Dartois, Véronique; Diagana, Thierry T.; Rottmann, Matthias; Blasco, Francesca

    2014-01-01

    Limited information is available on the pharmacokinetic (PK) and pharmacodynamic (PD) parameters driving the efficacy of antimalarial drugs. Our objective in this study was to determine dose-response relationships of a panel of related spiroindolone analogs and identify the PK-PD index that correlates best with the efficacy of KAE609, a selected class representative. The dose-response efficacy studies were conducted in the Plasmodium berghei murine malaria model, and the relationship between ...

  1. In Vivo Efficacy and Pharmacokinetics of Voriconazole in an Animal Model of Dermatophytosis▿

    OpenAIRE

    Saunte, D. M.; Simmel, F.; Frimodt-Moller, N.; Stolle, L. B.; Svejgaard, E. L.; Haedersdal, M.; Kloft, C.; Arendrup, M.C.

    2007-01-01

    The standard treatment for tinea capitis caused by Microsporum species for many years has been oral griseofulvin, which is no longer universally marketed. Voriconazole has been demonstrated to inhibit growth of Microsporum canis in vitro. We evaluated the efficacy and tissue pharmacokinetics of oral voriconazole in a guinea pig model of dermatophytosis. Guinea pigs (n = 16) were inoculated with M. canis conidia on razed skin. Voriconazole was dosed orally at 20 mg/kg/day for 12 days (days 3 t...

  2. In Vivo Pharmacokinetics and Pharmacodynamics of a New Triazole, Voriconazole, in a Murine Candidiasis Model

    OpenAIRE

    Andes, D.; Marchillo, K.; Stamstad, T.; Conklin, R.

    2003-01-01

    In vivo studies have described the pharmacodynamic (PD) characteristics of several triazoles. These investigations have demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio is the critical pharmacokinetic (PK)-PD parameter associated with treatment efficacy. Further analyses from these in vivo studies have demonstrated that a triazole free drug 24-h AUC/MIC of 20 to 25 is predictive of treatment success. We used a neutropenic murine model of disseminated Candida ...

  3. Population pharmacokinetic model of valproate and prediction of valproate serum concentrations in children with epilepsy

    Institute of Scientific and Technical Information of China (English)

    De-chun JIANG; Li WANG

    2004-01-01

    AIM: Using sparse data of valproate (VPA) serum concentrations to build a population pharmacokinetic (PPK)model of VPA in Chinese children with epilepsy and to predict serum concentrations for new patients using a Bayesian approach. METHODS: Two hundred epileptic children, whose VPA serum concentrations were collected,were divided randomly into two groups (A and B, n=100 each). The PPK parameter values of group A were calculated to establish a PPK Model by using the NPEM Program of USC*PACK software. Based on it, VPA serum concentrations of group B were predicted with the Bayesian Fitting Program of the USC*PACK software. To assess the accuracy and precision of prediction, a paired-comparisons t-test was run between predicted and observed concentrations, and then the mean prediction error (MPE), mean square prediction error (MSPE), root mean square prediction error (RMSPE), and coincidence rates for different percentages of prediction error were all calculated. RESULTS: Optimum PPK parameters were: Ka, 2.522+2.743 h-1; Vs, 0.329+0.496 L/kg; and Kel,0.0438±0.0384 h-1. For group B, there was no significant difference between predicted and observed concentrations.MPE was -0.43 mg/L, MSPE was 115.40 (mg/L)2, and RMSPE was 5.47 mg/L. The coincidence rates for percentages of prediction error, which were less than 5%, 10%, 15%, 20%, 25%, and 30%, were 62%, 74%, 82%,85%, 89%, and 93%, respectively. CONCLUSION: A PPK model of VPA in epileptic children was successfully established. Based on it, VPA serum concentrations can be predicted accurately with a Bayesian approach.

  4. Pharmacokinetic modeling: Prediction and evaluation of route dependent dosimetry of bisphenol A in monkeys with extrapolation to humans

    International Nuclear Information System (INIS)

    A physiologically based pharmacokinetic (PBPK) model was developed for bisphenol A (BPA) in adult rhesus monkeys using intravenous (iv) and oral bolus doses of 100 μg d6-BPA/kg (). This calibrated PBPK adult monkey model for BPA was then evaluated against published monkey kinetic studies with BPA. Using two versions of the adult monkey model based on monkey BPA kinetic data from and , the aglycone BPA pharmacokinetics were simulated for human oral ingestion of 5 mg d16-BPA per person (Völkel et al., 2002). Völkel et al. were unable to detect the aglycone BPA in plasma, but were able to detect BPA metabolites. These human model predictions of the aglycone BPA in plasma were then compared to previously published PBPK model predictions obtained by simulating the Völkel et al. kinetic study. Our BPA human model, using two parameter sets reflecting two adult monkey studies, both predicted lower aglycone levels in human serum than the previous human BPA PBPK model predictions. BPA was metabolized at all ages of monkey (PND 5 to adult) by the gut wall and liver. However, the hepatic metabolism of BPA and systemic clearance of its phase II metabolites appear to be slower in younger monkeys than adults. The use of the current non-human primate BPA model parameters provides more confidence in predicting the aglycone BPA in serum levels in humans after oral ingestion of BPA. -- Highlights: ► A bisphenol A (BPA) PBPK model for the infant and adult monkey was constructed. The hepatic metabolic rate of BPA increased with age of the monkey. ► The systemic clearance rate of metabolites increased with age of the monkey. ► Gut wall metabolism of orally administered BPA was substantial across all ages of monkeys. ► Aglycone BPA plasma concentrations were predicted in humans orally given oral doses of deuterated BPA.

  5. Validation of a Best-Fit Pharmacokinetic Model for Scopolamine Disposition after Intranasal Administration

    Science.gov (United States)

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

    2015-01-01

    An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Motion Sickness. Bioavailability and pharmacokinetics (PK) were determined per Investigative New Drug (IND) evaluation guidance by the Food and Drug Administration. Earlier, we reported the development of a PK model that can predict the relationship between plasma, saliva and urinary scopolamine (SCOP) concentrations using data collected from an IND clinical trial with INSCOP. This data analysis project is designed to validate the reported best fit PK model for SCOP by comparing observed and model predicted SCOP concentration-time profiles after administration of INSCOP.

  6. Understanding pharmacokinetics using realistic computational models of fluid dynamics: biosimulation of drug distribution within the CSF space for intrathecal drugs.

    Science.gov (United States)

    Kuttler, Andreas; Dimke, Thomas; Kern, Steven; Helmlinger, Gabriel; Stanski, Donald; Finelli, Luca A

    2010-12-01

    We introduce how biophysical modeling in pharmaceutical research and development, combining physiological observations at the tissue, organ and system level with selected drug physiochemical properties, may contribute to a greater and non-intuitive understanding of drug pharmacokinetics and therapeutic design. Based on rich first-principle knowledge combined with experimental data at both conception and calibration stages, and leveraging our insights on disease processes and drug pharmacology, biophysical modeling may provide a novel and unique opportunity to interactively characterize detailed drug transport, distribution, and subsequent therapeutic effects. This innovative approach is exemplified through a three-dimensional (3D) computational fluid dynamics model of the spinal canal motivated by questions arising during pharmaceutical development of one molecular therapy for spinal cord injury. The model was based on actual geometry reconstructed from magnetic resonance imaging data subsequently transformed in a parametric 3D geometry and a corresponding finite-volume representation. With dynamics controlled by transient Navier-Stokes equations, the model was implemented in a commercial multi-physics software environment established in the automotive and aerospace industries. While predictions were performed in silico, the underlying biophysical models relied on multiple sources of experimental data and knowledge from scientific literature. The results have provided insights into the primary factors that can influence the intrathecal distribution of drug after lumbar administration. This example illustrates how the approach connects the causal chain underlying drug distribution, starting with the technical aspect of drug delivery systems, through physiology-driven drug transport, then eventually linking to tissue penetration, binding, residence, and ultimately clearance. Currently supporting our drug development projects with an improved understanding of systems

  7. Population pharmacokinetic modeling of oxcarbazepine active metabolite in Chinese patients with epilepsy.

    Science.gov (United States)

    Yu, Yunli; Zhang, Quanying; Xu, Wenjun; Lv, Chengzhe; Hao, Gang

    2016-08-01

    The aim of the study was to develop a population pharmacokinetic (PPK) model of oxcarbazepine and optimize the treatment of oxcarbazepine in Chinese patients with epilepsy. A total of 108 oxcarbazepine therapeutic drug monitoring samples from 78 patients with epilepsy were collected in this study. The pharmacologically active metabolite 10,11-dihydro-10-hydrocarbamazepine (MHD) was used as the analytical target for monitoring therapy of oxcarbazepine. Patients' clinical data were retrospectively collected. The PPK model for MHD was developed using Phoenix NLME 1.2 with a non-linear mixed-effect model. MHD pharmacokinetics obeys a one-compartment model with first-order absorption and elimination. The effect of age, gender, red blood cell count, red blood cell specific volume, hemoglobin (HGB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and serum creatine were analyzed. Bootstrap and data splitting were used simultaneously to validate the final PPK models. The mean values of volume of distribution and clearance of MHD in the patients were 14.2 L and 2.38 L h(-1), respectively. BUN and HGB influenced the MHD volume of distribution according to the following equation: V = tvV × (BUN/4.76)(-0.007) × (HGB/140)(-0.001) × e (ηV) . The MHD clearance was dependent on ALT and gender as follows: CL = tvCL × (ALT/30)(0.181) × (gender) × 1.083 × e (ηCL). The final PPK model was demonstrated to be suitable and effective and it can be used to evaluate the pharmacokinetic parameters of MHD in Chinese patients with epilepsy and to choose an optimal dosage regimen of oxcarbazepine on the basis of these parameters. PMID:25700977

  8. 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.

  9. Mathematical Models of the Pharmacokinetic Behavior of Clindamycin in Healthy Subjects after Oral Administration of 150 mg of Clindamycin

    Directory of Open Access Journals (Sweden)

    Mária Ďurišová

    2015-12-01

    Full Text Available The goal of the current study was to provide a further example of a successful use of a non-traditional modeling method in the development of mathematical models in pharmacokinetics. The current study is a companion piece of the earlier study by Forist et al. published in February issue of Journal of Pharmacokinetics and Biopharmaceutics, therefore the data published in the study cited here were used. All mathematical models developed, successfully described the data of all healthy male volunteers enrolled in the study by Forist et al. and in the current study. The modeling method used in the current study is used to developed mathematical models of dynamic systems not only in pharmacokinetics but also in several other scientific and practical fields.

  10. First principles pharmacokinetic modeling: A quantitative study on Cyclosporin

    DEFF Research Database (Denmark)

    Mošat', Andrej; Lueshen, Eric; Heitzig, Martina;

    2013-01-01

    renal and hepatic clearances, elimination half-life, and mass transfer coefficients, to establish drug biodistribution dynamics in all organs and tissues. This multi-scale model satisfies first principles and conservation of mass, species and momentum.Prediction of organ drug bioaccumulation as a...

  11. Exploring flubendazole formulations for use in sheep. Pharmacokinetic evaluation of a cyclodextrin-based solution

    Directory of Open Access Journals (Sweden)

    Ceballos Laura

    2012-05-01

    Full Text Available Abstract Background Flubendazole (FLBZ is a poor water solubility broad-spectrum BZD methylcarbamate anthelmintic compound. Cyclodextrins (CDs are usually used to increase aqueous solubility of poor hydrosoluble compounds. The comparative in vitro aqueous solubility of FLBZ and other BZD anthelmintics in the presence of hydroxypropyl-β-cyclodextrin (HPβCD was evaluated in the current work. Additionally, the comparative pharmacokinetic behaviour of FLBZ (and its metabolites administered by the intraruminal (i.r. or intraabomasal (i.a. routes to sheep as either an aqueous CDs-based solution or a conventional carboximethylcellulose (CMC suspension was assessed. Drug solubility studies involving albendazole, mebendazole, oxfendazole and FLBZ were performed in an aqueous solution (pH 1.2 or 7.4 with or without HPβCD (10%, w/v. The pharmacokinetic study involved two experiments. Experiment 1: In a crossover study, sheep received either a FLBZ-CDs solution (n = 3 or a FLBZ-CMC suspension (n = 3 by the i.r. route (3.8 mg/kg. The treatment Groups were reversed after a 21-days washout period. Experiment 2: sheep (n = 4 were treated by the i.a. route with the FLBZ-CDs solution (3.8 mg/kg. Plasma and abomasal fluid samples were collected between 0 and 72 h post-treatment. Samples were analysed by HPLC. Results Improvement of FLBZ aqueous solubility due to CDs resulted markedly higher than that observed for mebendazole and albendazole. However, oppositely to what was expected, the absorption-related pharmacokinetic parameters did not show any marked formulation-dependant effect. After the i.a. administration of FLBZ, the AUC and the Tmax of the parent compound were significantly (P Conclusion The administration of FLBZ as a CDs-based solution, does not seem to achieve great practical relevance for parasite control in sheep.

  12. Sensitivity Analysis of a Pharmacokinetic Model of Vaginal Anti-HIV Microbicide Drug Delivery.

    Science.gov (United States)

    Jarrett, Angela M; Gao, Yajing; Hussaini, M Yousuff; Cogan, Nicholas G; Katz, David F

    2016-05-01

    Uncertainties in parameter values in microbicide pharmacokinetics (PK) models confound the models' use in understanding the determinants of drug delivery and in designing and interpreting dosing and sampling in PK studies. A global sensitivity analysis (Sobol' indices) was performed for a compartmental model of the pharmacokinetics of gel delivery of tenofovir to the vaginal mucosa. The model's parameter space was explored to quantify model output sensitivities to parameters characterizing properties for the gel-drug product (volume, drug transport, initial loading) and host environment (thicknesses of the mucosal epithelium and stroma and the role of ambient vaginal fluid in diluting gel). Greatest sensitivities overall were to the initial drug concentration in gel, gel-epithelium partition coefficient for drug, and rate constant for gel dilution by vaginal fluid. Sensitivities for 3 PK measures of drug concentration values were somewhat different than those for the kinetic PK measure. Sensitivities in the stromal compartment (where tenofovir acts against host cells) and a simulated biopsy also depended on thicknesses of epithelium and stroma. This methodology and results here contribute an approach to help interpret uncertainties in measures of vaginal microbicide gel properties and their host environment. In turn, this will inform rational gel design and optimization. PMID:27012224

  13. Optimal designs for composed models in pharmacokinetic-pharmacodynamic experiments.

    Science.gov (United States)

    Dette, Holger; Pepelyshev, Andrey; Wong, Weng Kee

    2012-06-01

    We consider two frequently used PK/PD models and provide closed form descriptions of locally optimal designs for estimating individual parameters. In a novel way, we use these optimal designs and construct locally standardized maximin optimal designs for estimating any subset of the model parameters of interest. We do this by maximizing the minimal efficiency of the estimates across all relevant parameters so that these optimal designs are less dependent on the individual parameter or parameters of interest. Additionally, robust designs are proposed to further reduce the dependence on the nominal values of the parameters. We compare efficiencies of our proposed optimal designs with locally optimal designs and designs used in four real studies from the literature and show that our proposed designs provide advantages over those used in practice. PMID:22614634

  14. Pharmacokinetics-Pharmacodynamics Analysis of Bicyclic 4-Nitroimidazole Analogs in a Murine Model of Tuberculosis

    OpenAIRE

    Lakshminarayana, Suresh B.; Helena I M Boshoff; Joseph Cherian; Sindhu Ravindran; Anne Goh; Jan Jiricek; Mahesh Nanjundappa; Amit Nayyar; Meera Gurumurthy; Ramandeep Singh; Thomas Dick; Francesca Blasco; Barry, Clifton E.; Ho, Paul C.; Manjunatha, Ujjini H

    2014-01-01

    PA-824 is a bicyclic 4-nitroimidazole, currently in phase II clinical trials for the treatment of tuberculosis. Dose fractionation pharmacokinetic-pharmacodynamic studies in mice indicated that the driver of PA-824 in vivo efficacy is the time during which the free drug concentrations in plasma are above the MIC (fT>MIC ). In this study, a panel of closely related potent bicyclic 4-nitroimidazoles was profiled in both in vivo PK and efficacy studies. In an established murine TB model, the eff...

  15. Limitations of Single Slice Dynamic Contrast Enhanced MR in Pharmacokinetic Modeling of Bone Sarcomas

    Energy Technology Data Exchange (ETDEWEB)

    Toms, Andoni P. (Dept. of Radiology, The Norfolk and Norwich Univ. Hospital, Norwich, Norfolk (United Kingdom)); White, Lawrence M.; Bleakney, Robert R. (Dept. of Medical Imaging, Mount Sinai Hospital, Toronto, ON (Canada)); Kandel, Rita (Dept. of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON (Canada)); Noseworthy, Michael (Health Sciences Centre, Faculty of Health Sciences, McMaster Univ., Hamilton, ON (Canada)); Lee, Shepstone (Institute of Health, Univ. of East Anglia, Norwich, Norfolk (United Kingdom)); Blackstein, Martin E. (Dept. of Oncology, Mount Sinai Hospital, Toronto, ON (Canada)); Wunder, Jay (Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, ON (Canada))

    2009-06-15

    Background: Single slice dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) appears to provide perfusion data about sarcomas in vivo that correlate with tumor necrosis on equivalent pathological sections. However, sarcomas are heterogeneous and therefore single slice DCE-MRI may not correlate with total tumor necrosis. Purpose: To determine whether changes in pharmacokinetic modeling of DCE-MRI, during chemotherapy for primary bone sarcomas correlated with histological measures of total tumor necrosis. Material and Methods: Twelve patients with appendicular primary bone sarcomas were included in the study. Each patient had DCE-MRI before, and after completion, of pre-operative chemotherapy. The mean arterial slope (A), endothelial permeability coefficient (Ktrans), and extravascular extracellular volume (Ve) were derived from each data set using a modified two compartment pharmacokinetic model. Total tumor necrosis rates were compared with changes in A, Ktrans, and Ve. Results: Six patients had total tumor necrosis of =90% and six had a measure of <90%. The median percentage changes in A, Ktrans, and Ve for the =90% necrosis group were -52.5% (-83 to 6), -66% (-82 to 26), and 23.5% (-26 to 40), respectively. For the <90% necrosis group, A = - 35% (-75 to 132), Ktrans= - 53 (-66 to 149) and Ve= - 14.5% (-42 to 40). One patient with >90% necrosis had increases in all three measures. Comparison of the two groups generated P-values of 0.699 for A, 0.18 for Ktrans, and 0.31 for Ve. Conclusion: There was no statistically significant correlation between changes in pharmacokinetic perfusion parameters and total tumor necrosis. When using single slice DCE-MRI heterogeneous histology of primary bone sarcomas and repair mediated angiogenesis might both be confounding factors

  16. Myotoxicity of gemfibrozil in Cynomolgus monkey model and its relationship to pharmacokinetic properties

    International Nuclear Information System (INIS)

    Fibrate drugs are PPARα agonists prescribed for the treatment of dyslipidemia. Severe myotoxicity has been reportedly associated with their use albeit at a low frequency, especially for gemfibrozil. Few studies have investigated the mechanism of fibrate-induced myotoxicity in vivo. Considering the apparent species-related differences in PPARα agonist-induced hepatotoxicity, we studied the myotoxicity of gemfibrozil in a Cynomolgus monkey model and explored the relationship between myotoxicity and pharmacokinetics. Six Cynomolgus monkeys were dosed with gemfibrozil twice daily at 600 mg/kg/day for the first two periods (P1 and P2, 8 days and 9 days respectively) and 300 mg/kg/day for the third period (P3, 14 days). Creatine kinase and myoglobin were measured, together with hepatotoxicity and nephrotoxicity markers. Behavioral responses were recorded for indication of toxicity. Pharmacokinetics was carried out following the 16th dosage of P1 and 17th dosage of P2 when myotoxicity was identified. Multivariable data analysis was employed to explore the relationship between pharmacokinetic parameters and myotoxicity markers. Consequently, myotoxicity occurred in monkey no. 2 (M2) and M6 in P1, M3 and M4 in P2, M3 and M6 in P3. Data analysis showed T80-150 (sustained time above the given concentration) contributed for myotoxicity discriminance and correlated with myotoxicity risk. This study revealed Cynomolgus monkey may be a good animal model for myotoxicity evaluation with sensitivity, reproducibility and similarities to humans. More interestingly, they exhibited a much higher incidence of myotoxicity than that of humans. Sustained high drug concentration plays an important role for the occurrence of myotoxicity. This may suggest an influence of drug transport and metabolism on myotoxicity

  17. Model-based meta-analysis for development of a population-pharmacokinetic (PPK) model for Vitamin D3 and its 25OHD3 metabolite using both individual and arm-level data.

    Science.gov (United States)

    Ocampo-Pelland, Alanna S; Gastonguay, Marc R; French, Jonathan F; Riggs, Matthew M

    2016-04-01

    Clinical studies investigating relationships between D3 and 25OHD3 vary in dosing regimen, assays, demographics, and control of exogenous D3. This leads to uncertain and conflicting exposure-related associations with D3 and 25OHD3. To elucidate this parent-metabolite system, a PPK model was developed to predict mean D3 and 25OHD3 exposure from varied doses and administration routes. Sources of exposure variability related to metabolite baseline, weight, and assay type were explored. Specific search criteria were used in PUBMED to identify public source PK data pertaining to D3 and 25OHD3 in healthy or osteoporotic populations. Overall 57 studies representing 5395 individuals were selected, including 25 individual-level profiles and treatment-arm data. IV, oral, single and multiple dose data were used, with D3 and 25OHD3 dosing. A nonlinear mixed effects model was developed to simultaneously model PK dispositions of D3 and 25OHD3 (NONMEM v7.2), which were described by 2-compartment models with nonlinear and linear clearances, respectively. Proportional and additive assay variances were included on the 25OHD3 prediction. Unit-level random effects were weighted by treatment-arm size. D3 model estimates, relative to bioavailability were: maximum rate of metabolism ([Formula: see text], 1.62 nmol/h), Michaelis-Menten constant ([Formula: see text], 6.39 nmol/L), central volume of distribution ([Formula: see text], 15.5 L), intercompartmental clearance ([Formula: see text], 0.185 L/h), peripheral volume of distribution ([Formula: see text], 2333 L/h), and baseline concentration ([Formula: see text], 3.75 nmol/L). For 25OHD3 ([Formula: see text] = metabolite): [Formula: see text] = 0.0153 L/h, [Formula: see text] = 4.35 L, [Formula: see text] = 6.87 L, [Formula: see text] = 0.0507 L/h. Simulations of 25OHD3 concentration indicated an inverse relationship between 25OHD3 baseline and response, as well as a less than proportional 25OHD3 response. Estimation of assay bias

  18. Pharmacokinetic modeling of multidrug resistance P-glycoprotein transport of gamma-emitting substrates

    Energy Technology Data Exchange (ETDEWEB)

    Bae, K. T.; Piwnica-Worms, D. [St. Louis, Washington Univ. (United States). Mallinckrodt Institute of Radiology. Lab. of Molecular Radiopharmacology]|[St. Louis, Washington Univ. (United States). Dept. of Molecular Biology and Pharmacology

    1997-06-01

    P-glycoprotein, the human multidrug resistance (MDR1) gene product, is an integral membrane protein expressed on the plasma membrane of MDR tumor cells and is the best characterized of a family of efflux transporters that confer chemotherapeutic resistance. The use of gamma-emitting {sup 99m}Tc-agents to image P-glycoprotein function in human tumors in vivo has been proposed. Net tumor cell content of {sup 99m}Tc-Sestamibi, {sup 99m}Tc-Tetrofosmin and several {sup 99m}Tc-Q-complexes ({sup 99m}Tc-Q58 and {sup 99m}Tc-Q63) are function of passive potential-dependent influx and MDR1 P-glycoprotein-mediated active extrusion. To better understand the overall fidelity of these P-glycoprotein substrates to report MDR activity in vivo in relation to tissue perfusion, a compartmental model of tracer pharmacokinetics was developed. Modeling indicates that tissue perfusion will impact pharmacokinetics in vivo in a manner that will tend to diminish P-glycoprotein-mediated phenotypic differences between tissues when they are perfusion-limited. However, dynamic imaging to extract efflux rate constants is independent of perfusion and may represent the highest quality methodology for collecting the desired information regarding activity of the efflux transporter. Much work remains to translate these concepts and biological targeting properties into clinical practice.

  19. Integration of efficacy, pharmacokinetic and safety assessment of interleukin-1 receptor antagonist in a preclinical model of arthritis.

    Science.gov (United States)

    Zuurmond, Anne-Marie; Koudijs, Angela; van El, Benno; Doornbos, Robert P; van Manen-Vernooij, Babs C T; Bastiaans, Jacqueline H M W; Penninks, André H; van Bilsen, Jolanda H M; Cnubben, Nicole H P; Degroot, Jeroen

    2011-04-01

    Pharmacokinetic properties and safety profile of a drug are likely influenced by the disease state of a patient. In this study, we investigated the influence of arthritic processes on pharmacokinetics and immunotoxicity of interleukin-1 receptor antagonist (Anakinra) in the rat adjuvant arthritis model. Anakinra dose-dependently suppressed joint inflammation and degradation as demonstrated by reduced clinical arthritis score, paw thickness, synovial infiltration and bone degradation. In addition, plasma levels of chemokines MCP-1 and GRO/KC were reduced. Pharmacokinetic behaviour of Anakinra was influenced by disease state of the rats as judged from a decrease in C(max) and an increase of the MRT as the disease progressed at a dose of 24 and 72 mg Anakinra/kg body weight. The pharmacokinetic parameters increased dose-dependently, but non-proportionally with increasing dose. Low level anti-Anakinra antibody formation was observed at prolonged exposure to the biologic. Safety parameters, including haematology, splenic lymphocyte subset analysis, ex vivo stimulation of spleen cells and histopathology of immune system organs were affected by the disease itself to such extent that no additional effects of Anakinra could be observed. In conclusion, we demonstrated that pharmacokinetic behaviour of Anakinra was influenced by the arthritis background of the rats resulting in decreased internal exposure. PMID:21300126

  20. Computational approaches and metrics required for formulating biologically realistic nanomaterial pharmacokinetic models

    International Nuclear Information System (INIS)

    The field of nanomaterial pharmacokinetics is in its infancy, with major advances largely restricted by a lack of biologically relevant metrics, fundamental differences between particles and small molecules of organic chemicals and drugs relative to biological processes involved in disposition, a scarcity of sufficiently rich and characterized in vivo data and a lack of computational approaches to integrating nanomaterial properties to biological endpoints. A central concept that links nanomaterial properties to biological disposition, in addition to their colloidal properties, is the tendency to form a biocorona which modulates biological interactions including cellular uptake and biodistribution. Pharmacokinetic models must take this crucial process into consideration to accurately predict in vivo disposition, especially when extrapolating from laboratory animals to humans since allometric principles may not be applicable. The dynamics of corona formation, which modulates biological interactions including cellular uptake and biodistribution, is thereby a crucial process involved in the rate and extent of biodisposition. The challenge will be to develop a quantitative metric that characterizes a nanoparticle's surface adsorption forces that are important for predicting biocorona dynamics. These types of integrative quantitative approaches discussed in this paper for the dynamics of corona formation must be developed before realistic engineered nanomaterial risk assessment can be accomplished. (paper)

  1. Computational approaches and metrics required for formulating biologically realistic nanomaterial pharmacokinetic models

    Science.gov (United States)

    Riviere, Jim E.; Scoglio, Caterina; Sahneh, Faryad D.; Monteiro-Riviere, Nancy A.

    2013-01-01

    The field of nanomaterial pharmacokinetics is in its infancy, with major advances largely restricted by a lack of biologically relevant metrics, fundamental differences between particles and small molecules of organic chemicals and drugs relative to biological processes involved in disposition, a scarcity of sufficiently rich and characterized in vivo data and a lack of computational approaches to integrating nanomaterial properties to biological endpoints. A central concept that links nanomaterial properties to biological disposition, in addition to their colloidal properties, is the tendency to form a biocorona which modulates biological interactions including cellular uptake and biodistribution. Pharmacokinetic models must take this crucial process into consideration to accurately predict in vivo disposition, especially when extrapolating from laboratory animals to humans since allometric principles may not be applicable. The dynamics of corona formation, which modulates biological interactions including cellular uptake and biodistribution, is thereby a crucial process involved in the rate and extent of biodisposition. The challenge will be to develop a quantitative metric that characterizes a nanoparticle's surface adsorption forces that are important for predicting biocorona dynamics. These types of integrative quantitative approaches discussed in this paper for the dynamics of corona formation must be developed before realistic engineered nanomaterial risk assessment can be accomplished.

  2. Population Pharmacokinetics of Intranasal Scopolamine

    Science.gov (United States)

    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.

  3. Physiologically based predictions of the impact of inhibition of intestinal and hepatic metabolism on human pharmacokinetics of CYP3A substrates.

    Science.gov (United States)

    Fenneteau, Frederique; Poulin, Patrick; Nekka, Fahima

    2010-01-01

    The first objective of the present study was to predict the pharmacokinetics of selected CYP3A substrates administered at a single oral dose to human. The second objective was to predict pharmacokinetics of the selected drugs in presence of inhibitors of the intestinal and/or hepatic CYP3A activity. We developed a whole-body physiologically based pharmacokinetics (WB-PBPK) model accounting for presystemic elimination of midazolam (MDZ), alprazolam (APZ), triazolam (TRZ), and simvastatin (SMV). The model also accounted for concomitant administration of the above-mentioned drugs with CYP3A inhibitors, namely ketoconazole (KTZ), itraconazole (ITZ), diltiazem (DTZ), saquinavir (SQV), and a furanocoumarin contained in grape-fruit juice (GFJ), namely 6',7'-dihydroxybergamottin (DHB). Model predictions were compared to published clinical data. An uncertainty analysis was performed to account for the variability and uncertainty of model parameters when predicting the model outcomes. We also briefly report on the results of our efforts to develop a global sensitivity analysis and its application to the current WB-PBPK model. Considering the current criterion for a successful prediction, judged satisfied once the clinical data are captured within the 5th and 95th percentiles of the predicted concentration-time profiles, a successful prediction has been obtained for a single oral administration of MDZ and SMV. For APZ and TRZ, however, a slight deviation toward the 95th percentile was observed especially for C(max) but, overall, the in vivo profiles were well captured by the PBPK model. Moreover, the impact of DHB-mediated inhibition on the extent of intestinal pre-systemic elimination of MDZ and SMV has been accurately predicted by the proposed PBPK model. For concomitant administrations of MDZ and ITZ, APZ and KTZ, as well as SMV and DTZ, the in vivo concentration-time profiles were accurately captured by the model. A slight deviation was observed for SMV when

  4. Multi-modal pharmacokinetic modelling for DCE-MRI: using diffusion weighted imaging to constrain the local arterial input function

    Science.gov (United States)

    Hamy, Valentin; Modat, Marc; Shipley, Rebecca; Dikaios, Nikos; Cleary, Jon; Punwani, Shonit; Ourselin, Sebastien; Atkinson, David; Melbourne, Andrew

    2014-03-01

    The routine acquisition of multi-modal magnetic resonance imaging data in oncology yields the possibility of combined model fitting of traditionally separate models of tissue structure and function. In this work we hypothesise that diffusion weighted imaging data may help constrain the fitting of pharmacokinetic models to dynamic contrast enhanced (DCE) MRI data. Parameters related to tissue perfusion in the intra-voxel incoherent motion (IVIM) modelling of diffusion weighted MRI provide local information on how tissue is likely to perfuse that can be utilised to guide DCE modelling via local modification of the arterial input function (AIF). In this study we investigate, based on multi-parametric head and neck MRI of 8 subjects (4 with head and neck tumours), the benefit of incorporating parameters derived from the IVIM model within the DCE modelling procedure. Although we find the benefit of this procedure to be marginal on the data used in this work, it is conceivable that a technique of this type will be of greater use in a different application.

  5. Pharmacokinetic digital phantoms for accuracy assessment of image-based dosimetry in 177Lu-DOTATATE peptide receptor radionuclide therapy

    International Nuclear Information System (INIS)

    Patient-specific image-based dosimetry is considered to be a useful tool to limit toxicity associated with peptide receptor radionuclide therapy (PRRT). To facilitate the establishment and reliability of absorbed-dose response relationships, it is essential to assess the accuracy of dosimetry in clinically realistic scenarios. To this end, we developed pharmacokinetic digital phantoms corresponding to patients treated with 177Lu-DOTATATE. Three individual voxel phantoms from the XCAT population were generated and assigned a dynamic activity distribution based on a compartment model for 177Lu-DOTATATE, designed specifically for this purpose. The compartment model was fitted to time-activity data from 10 patients, primarily acquired using quantitative scintillation camera imaging. S values for all phantom source-target combinations were calculated based on Monte-Carlo simulations. Combining the S values and time-activity curves, reference values of the absorbed dose to the phantom kidneys, liver, spleen, tumours and whole-body were calculated. The phantoms were used in a virtual dosimetry study, using Monte-Carlo simulated gamma-camera images and conventional methods for absorbed-dose calculations. The characteristics of the SPECT and WB planar images were found to well represent those of real patient images, capturing the difficulties present in image-based dosimetry. The phantoms are expected to be useful for further studies and optimisation of clinical dosimetry in 177Lu PRRT. (paper)

  6. Pharmacokinetic digital phantoms for accuracy assessment of image-based dosimetry in 177Lu-DOTATATE peptide receptor radionuclide therapy

    Science.gov (United States)

    Brolin, Gustav; Gustafsson, Johan; Ljungberg, Michael; Sjögreen Gleisner, Katarina

    2015-08-01

    Patient-specific image-based dosimetry is considered to be a useful tool to limit toxicity associated with peptide receptor radionuclide therapy (PRRT). To facilitate the establishment and reliability of absorbed-dose response relationships, it is essential to assess the accuracy of dosimetry in clinically realistic scenarios. To this end, we developed pharmacokinetic digital phantoms corresponding to patients treated with 177Lu-DOTATATE. Three individual voxel phantoms from the XCAT population were generated and assigned a dynamic activity distribution based on a compartment model for 177Lu-DOTATATE, designed specifically for this purpose. The compartment model was fitted to time-activity data from 10 patients, primarily acquired using quantitative scintillation camera imaging. S values for all phantom source-target combinations were calculated based on Monte-Carlo simulations. Combining the S values and time-activity curves, reference values of the absorbed dose to the phantom kidneys, liver, spleen, tumours and whole-body were calculated. The phantoms were used in a virtual dosimetry study, using Monte-Carlo simulated gamma-camera images and conventional methods for absorbed-dose calculations. The characteristics of the SPECT and WB planar images were found to well represent those of real patient images, capturing the difficulties present in image-based dosimetry. The phantoms are expected to be useful for further studies and optimisation of clinical dosimetry in 177Lu PRRT.

  7. Investigating the pharmacokinetics and biological distribution of silver-loaded polyphosphoester-based nanoparticles using (111) Ag as a radiotracer.

    Science.gov (United States)

    Aweda, Tolulope A; Zhang, Shiyi; Mupanomunda, Chiedza; Burkemper, Jennifer; Heo, Gyu Seong; Bandara, Nilantha; Lin, Mai; Cutler, Cathy S; Cannon, Carolyn L; Youngs, Wiley J; Wooley, Karen L; Lapi, Suzanne E

    2015-05-30

    Purified (111) Ag was used as a radiotracer to investigate silver loading and release, pharmacokinetics, and biodistribution of polyphosphoester-based degradable shell crosslinked knedel-like (SCK) nanoparticles as a comparison to the previously reported small molecule, N-heterocyclic silver carbene complex analog (SCC1) for the delivery of therapeutic silver ions in mouse models. Biodistribution studies were conducted by aerosol administration of (111) Ag acetate, [(111) Ag]SCC1, and [(111) Ag]SCK doses directly into the lungs of C57BL/6 mice. Nebulization of the (111) Ag antimicrobials resulted in an average uptake of 1.07 ± 0.12% of the total aerosolized dose given per mouse. The average dose taken into the lungs of mice was estimated to be 2.6 ± 0.3% of the dose inhaled per mouse for [(111) Ag]SCC1 and twice as much dose was observed for the [(111) Ag]SCKs (5.0 ± 0.3% and 5.9 ± 0.8% for [(111) Ag]aSCK and [(111) Ag]zSCK, respectively) at 1 h post administration (p.a.). [(111) Ag]SCKs also exhibited higher dose retention in the lungs; 62-68% for [(111) Ag]SCKs and 43% for [(111) Ag]SCC1 of the initial 1 h dose were observed in the lungs at 24 h p.a.. This study demonstrates the utility of (111) Ag as a useful tool for monitoring the pharmacokinetics of silver-loaded antimicrobials in vivo. PMID:25952472

  8. A pharmacokinetic/pharmacodynamic mathematical model accurately describes the activity of voriconazole against Candida spp. in vitro

    OpenAIRE

    Li, Yanjun; Nguyen, M. Hong; Cheng, Shaoji; Schmidt, Stephan; Zhong, Li; Derendorf, Hartmut; Clancy, Cornelius J.

    2008-01-01

    We developed a pharmacokinetic/pharmacodynamic (PK/PD) mathematical model that fits voriconazole time–kill data against Candida isolates in vitro and used the model to simulate the expected kill curves for typical intravenous and oral dosing regimens. A series of Emax mathematical models were used to fit time–kill data for two isolates each of Candida albicans, Candida glabrata and Candida parapsilosis. PK parameters extracted from human data sets were used in the model to simulate kill curve...

  9. Pharmacokinetics/pharmacodynamics of antofloxacin hydrochloride in a neutropenic murine thigh model of Staphylococcus aureus infection

    Institute of Scientific and Technical Information of China (English)

    Xiu-mei XIAO; Yong-hong XIAO

    2008-01-01

    Aim:Antofloxacin hydrochloride is a new fluoroquinolone antibiotic with broad-spectrum in vitro activity.Using the neutropenic murine thigh infection model,we defined the pharmacodynamic profile and property of antofloxacin hydroehloride against Staphylococcus aureus.Methods:Single-dose pharmacokinetic studies of antofloxacin hydrochloride were carried out in thigh infected mice.Therapy was initiated at 2 h postinoculation with 5-640 mg/kg per d fractionated for different dosing regimens.The thighs were removed for bacterial measurement after 24 h of therapy,the best pharmacokinetic/ pharmacodynamic (PK/PD) index correlated with the efficacy was determined by nonlinear regression analysis.A sigmoid Emax dose-response model was used to estimate the daily dose and AUC24 h/MIC (minimal inhibitory concentration) required to achieve a static effect.Results:The PK was linear with similar elimination half-life over the dose range studied.The AUC24 h/MIC ratio was the PK/PD parameter that best correlated with efficacy (R2=92.3%,90.8% for the two organisms,compared with Cmax/MIC and T>MIC [%],respectively).The 24 h static dose ranged from 34.3 to 153.7 mg/kg per d for all S aureus strains,the total AUC24h/MIC ratio to achieve bacteriostatic effect varied from 31.7 to 122.5 (mean,65.7±30.6).Conclusion:Antofloxacin hydrochloride showed powerful antibacterial activity against the S aureus isolates used in our neutropenic infected mice model.Our data suggested that the AUC/MIC ratio appeared to be most closely linked to the bacterial outcome (R290%),and a total AUC24/MIC ratio of 65.7 appears to be the target value to achieve a net bactericidal activity against S aureus,similar to the results of other fluoroquinolones.

  10. Cationic drug-based self-assembled polyelectrolyte complex micelles: Physicochemical, pharmacokinetic, and anticancer activity analysis.

    Science.gov (United States)

    Ramasamy, Thiruganesh; Poudel, Bijay Kumar; Ruttala, Himabindu; Choi, Ju Yeon; Hieu, Truong Duy; Umadevi, Kandasamy; Youn, Yu Seok; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

    2016-10-01

    Nanofabrication of polymeric micelles through self-assembly of an ionic block copolymer and oppositely charged small molecules has recently emerged as a promising method of formulating delivery systems. The present study therefore aimed to investigate the interaction of cationic drugs doxorubicin (DOX) and mitoxantrone (MTX) with the anionic block polymer poly(ethylene oxide)-block-poly(acrylic acid) (PEO-b-PAA) and to study the influence of these interactions on the pharmacokinetic stability and antitumor potential of the formulated micelles in clinically relevant animal models. To this end, individual DOX and MTX-loaded polyelectrolyte complex micelles (PCM) were prepared, and their physicochemical properties and pH-responsive release profiles were studied. MTX-PCM and DOX-PCM exhibited a different release profile under all pH conditions tested. MTX-PCM exhibited a monophasic release profile with no initial burst, while DOX-PCM exhibited a biphasic release. DOX-PCM showed a higher cellular uptake than that shown by MTX-PCM in A-549 cancer cells. Furthermore, DOX-PCM induced higher apoptosis of cancer cells than that induced by MTX-PCM. Importantly, both MTX-PCM and DOX-PCM showed prolonged blood circulation. MTX-PCM improved the AUCall of MTX 4-fold compared to a 3-fold increase by DOX-PCM for DOX. While a definite difference in blood circulation was observed between MTX-PCM and DOX-PCM in the pharmacokinetic study, both MTX-PCM and DOX-PCM suppressed tumor growth to the same level as the respective free drugs, indicating the potential of PEGylated polymeric micelles as effective delivery systems. Taken together, our results show that the nature of interactions of cationic drugs with the polyionic copolymer can have a tremendous influence on the biological performance of a delivery system. PMID:27318960

  11. Pharmacokinetic-Pharmacodynamic Modeling of the D2 and 5-HT2A Receptor Occupancy of Risperidone and Paliperidone in Rats

    OpenAIRE

    Kozielska, Magdalena; Johnson, MArtin; Reddy, Venkatesh Pilla; Vermeulen, An; Li, Cheryl; Grimwood, Sarah; de Greef, Rik; Groothuis, Geny MM; Danhof, Meindert; Proost, Johannes H

    2012-01-01

    ABSTRACT Purpose A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the time course of brain concentration and dopamine D2 and serotonin 5-HT2A receptor occupancy (RO) of the atypical antipsychotic drugs risperidone and paliperidone in rats. Methods A population approach was utilized to describe the PK-PD of risperidone and paliperidone using plasma and brain concentrations and D2 and 5-HT2A RO data. A previously published physiology- and mechanism-based (PBPKPD) model ...

  12. A framework for meta-analysis of veterinary drug pharmacokinetic data using mixed effect modeling.

    Science.gov (United States)

    Li, Mengjie; Gehring, Ronette; Lin, Zhoumeng; Riviere, Jim

    2015-04-01

    Combining data from available studies is a useful approach to interpret the overwhelming amount of data generated in medical research from multiple studies. Paradoxically, in veterinary medicine, lack of data requires integrating available data to make meaningful population inferences. Nonlinear mixed-effects modeling is a useful tool to apply meta-analysis to diverse pharmacokinetic (PK) studies of veterinary drugs. This review provides a summary of the characteristics of PK data of veterinary drugs and how integration of these data may differ from human PK studies. The limits of meta-analysis include the sophistication of data mining, and generation of misleading results caused by biased or poor quality data. The overriding strength of meta-analysis applied to this field is that robust statistical analysis of the diverse sparse data sets inherent to veterinary medicine applications can be accomplished, thereby allowing population inferences to be made. PMID:25641543

  13. Glucosamine sulfate effect on the degenerated patellar cartilage: preliminary findings by pharmacokinetic magnetic resonance modeling

    International Nuclear Information System (INIS)

    Normal and degenerated cartilages have different magnetic resonance (MR) capillary permeability (Ktrans) and interstitial interchangeable volume (ve). Our hypothesis was that glucosamine sulfate treatment modifies these neovascularity abnormalities in osteoarthritis. Sixteen patients with patella degeneration, randomly distributed into glucosamine or control groups, underwent two 1.5-Tesla dynamic contrast-enhanced MR imaging studies (treatment initiation and after 6 months). The pain visual analog scale (VAS) and American Knee Society (AKS) score were used. A two-compartment pharmacokinetic model was used. Percentages of variations (postreatment-pretreatment/pretreatment) were compared (t-test for independent data). In the glucosamine group, pain and functional outcomes statistically improved (VAS: 7.3 ± 1.1 to 3.6 ± 1.3, p trans at 6 months (-54.4 ± 21.2% vs 126.7 ± 56.9%, p trans, allowing its proposal as a surrogate imaging biomarker after 6 months of treatment. (orig.)

  14. Pharmacokinetic modeling of subcutaneous heroin and its metabolites in blood and brain of mice.

    Science.gov (United States)

    Boix, Fernando; Andersen, Jannike M; Mørland, Jørg

    2013-01-01

    High blood-brain permeability and effective delivery of morphine to the brain have been considered as explanations for the high potency of heroin. Results from Andersen et al. indicate that 6-monoacetylmorphine (6-MAM), and not morphine, is the active metabolite responsible for the acute effects observed for heroin. Here, we use pharmacokinetic modeling on data from the aforementioned study to calculate parameters of the distribution of heroin, 6-MAM and morphine in blood and brain tissue after subcutaneous heroin administration in mice. The estimated pharmacokinetic parameters imply that the very low heroin and the high 6-MAM levels observed both in blood and brain in the original experiment are likely to be caused by a very high metabolic rate of heroin in blood. The estimated metabolic rate of heroin in brain was much lower and cannot account for the low heroin and high 6-MAM levels in the brain, which would primarily reflect the concentrations of these compounds in blood. The very different metabolic rates for heroin in blood and brain calculated by the model were confirmed by in vitro experiments. These results show that heroin's fast metabolism in blood renders high concentrations of 6-MAM which, due to its relatively good blood-brain permeability, results in high levels of this metabolite in the brain. Thus, it is the high blood metabolism rate of heroin and the blood-brain permeability to 6-MAM, and not to heroin, which could account for the highly efficient delivery of active metabolites to the brain after heroin administration. PMID:21481103

  15. PROSPECTS FOR DEVELOPMENT OF ANTIDIABETIC POLYPHENOL-BASED DRUGS: MECHANISMS OF HYPOGLYCEMIC ACTION AND PHARMACOKINETICS

    Directory of Open Access Journals (Sweden)

    Ruban E. A.

    2015-12-01

    , activation of insulin receptors and glucose uptake in the insulin-sensitive tissues. On the other hand, most polyphenols are characterized by low bioavailability mostly due to intensive metabolism. Thus absorption of such polyphenols as anthocyanins, phenolcarboxylic acids and some others appears low, but it is supposed that it could have been underestimated because not all metabolites might have been considered. Besides the absorption rate of these compounds is very rapid and may take place already in stomach. In contrary, rutin and other quercetin glycosides are absorbed only after release of the aglycones by the intestinal microflora. The elimination half-lives of most polyphenols tend to be short, especially in the case of anthocyanins. However, some polyphenolic compounds such as quercetin glycosides may have longer half-lives, and even accumulate in plasma with repeated ingestion. Conclusions. Polyphenols have unique therapeutic potential in the treatment of diabetes mellitus. Nevertheless, the possibility to use polyphenols as hypoglycemic agents in clinical practice is limited by their low bioavailability. Taking into account information reported in the literature on the hypoglycemic mechanisms and pharmacokinetics of polyphenols, promising method of increasing their bioavailability is the development of prolonged-release dosage forms based on polyphenol substances. This approach would extend residence time of polyphenols in the small intestine – the main site of hypoglycemic action in their intact, non-metabolized form, and will help maintain a constant concentration of active substances in the blood plasma, the target organs and tissues

  16. 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)

    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.

  17. Pharmacokinetic plasma behaviors of intravenous and oral bioavailability of thymoquinone in a rabbit model.

    Science.gov (United States)

    Alkharfy, Khalid M; Ahmad, Ajaz; Khan, Rao M A; Al-Shagha, Waleed M

    2015-09-01

    Thymoquinone (THQ), the active constituent of Nigella sativa seeds, has demonstrated some potential pharmacological activities. The present study was designed to investigate the pharmacokinetic behavior of THQ following intravenous (IV) and oral (PO) administration using an animal model. THQ was given vascularly (5 mg/kg IV) and extravascularly (20 mg/kg PO) to Vole rabbits, and blood samples were collected at predetermined time points. The concentrations of THQ in plasma were measured by a high-performance liquid chromatography, and the pharmacokinetic parameters were determined using both compartmental and non-compartmental analyses. The calculated clearance (CL) following IV administration was 7.19 ± 0.83 ml/kg/min, and the estimated volume of distribution at steady state (V ss) was 700.90 ± 55.01 ml/kg. Whereas with PO dosing, apparent CL/F value was 12.30 ± 0.30 ml/min/kg and V ss/F was 5,109.46 ± 196.08 ml/kg. These parameters were associated with an elimination half-life (T 1/2) of 63.43 ± 10.69 and 274.61 ± 8.48 min with IV and PO dosing, respectively. The calculated absorption T 1/2 was about 217 min. Compartmental analysis revealed T 1/2α of ~8.9 min and T 1/2β of ~86.6 min. The calculated absolute bioavailability of THQ was ~58 % with a lag time of ~23 min. The estimated THQ protein binding was >99 %. Therefore, THQ represents a compound with rapid elimination and relatively slower absorption following PO administration. PMID:24924310

  18. Prediction of Aortic Contrast-enhancement Curves in Coronary CTA Using Physiologically Based Pharmacokinetic Model%冠脉CTA的主动脉处药物-时间曲线的生理药代动力学模型预测

    Institute of Scientific and Technical Information of China (English)

    原媛; 赵丽琴; 贺文

    2012-01-01

    Objective:Our study focus on evaluating the accuracy of physiologically based pharmacokinetic (PBPK) model in simulation of enhancement at coronary CT angiography (CTA) Examination. Method and materials:80 patients (44 male, 36 female from 32 to 89 years old) underwent coronary CT angiography scan. A simulation software program was developed based on a pharmacokinetic model. For each patient, model parameters were adjusted according to patient age, sex, height, weight, scanning protocol, and contrast media administration protocol such as medium concentration and injection rate. Results:The simulated and actual CTA enhancement curves closely agreed in maximum enhancement and the average error is about 9.447±9.530%. 2 cases were excluded as invalid data. The simulated maximum enhancements of 59 cases were greater than their actual maximum enhancement and the average error was 7.86%. Meanwhile, 19 cases of simulation data were less than their actual data with the average error of 1.58%. The skewness of the whole data was α =-0.131. Conclusion:Our preliminary study suggests that PBPK model may predict the enhancement at coronary CTA with acceptable accuracy. Computer based PBPK model may be used in optimizing the coronary CTA scan protocol.%目的:建立生理药代动力学模型,预测冠脉CTA扫描过程中主动脉处造影剂的脉药物浓度-时间曲线,并对其准确性进行评估。方法:80例患者(年龄32~89岁,其中男44例,女36例)的扫描数据,将每位患者的体征参数(包括年龄、性别、身高、体重、心输出量、脏器血容量等)引入到上述药代动力学模型框架中,得到每位患者的个体化药代动力学模型,将模拟运算得到的主动脉处碘造影剂的药物浓度-时间曲线与实际扫描结果进行对比。结果:实际扫描中,排除两例无效数据后主动脉碘造影剂浓度峰值的误差为9.447±9.530%,其中模拟运算结果大于实际扫描结果的59例,均值为7

  19. Pharmacokinetic Variability of Olanzapine : A Study Based on Therapeutic Drug Monitoring Data

    OpenAIRE

    2012-01-01

    Olanzapine is one of the most commonly used antipsychotic drugs in treatment of schizophrenia and bipolar disorder. The interindividual variability in pharmacokinetics of olanzapine is extensive, with a 10-20-fold difference in serum concentration despite equivalent dosing. The aim of this thesis was to identify and evaluate factors that influence the pharmacokinetics of olanzapine, and thereby provide knowledge that can be applied in order to individualize treatment with olanzapine. Ther...

  20. Pharmacokinetic-pharmacodynamic relationship of anesthetic drugs: from modeling to clinical use [version 1; referees: 4 approved

    Directory of Open Access Journals (Sweden)

    Valerie Billard

    2015-11-01

    Full Text Available Anesthesia is a combination of unconsciousness, amnesia, and analgesia, expressed in sleeping patients by limited reaction to noxious stimulations. It is achieved by several classes of drugs, acting mainly on central nervous system. Compared to other therapeutic families, the anesthetic drugs, administered by intravenous or pulmonary route, are quickly distributed in the blood and induce in a few minutes effects that are fully reversible within minutes or hours. These effects change in parallel with the concentration of the drug, and the concentration time course of the drug follows with a reasonable precision mathematical models based on the Fick principle. Therefore, understanding concentration time course allows adjusting the dosing delivery scheme in order to control the effects.   The purpose of this short review is to describe the basis of pharmacokinetics and modeling, the concentration-effects relationship, and drug interactions modeling to offer to anesthesiologists and non-anesthesiologists an overview of the rules to follow to optimize anesthetic drug delivery.

  1. The Modelling Pharmacokinetic Profile of Freeze-Dried Cyclosporine A-Eudragit S100 Nanoparticle Formulation in Dogs

    Science.gov (United States)

    Liu, Yang; Fang, Zhi-gang; You, Ben-Gang; Ding, Xin-yuan; Zhang, Xue-nong

    The modelling pharmacokinetic profile of freeze-dried cyclosporine A-Eudragit S100 nanoparticles (CyA-S100-NP) was studied with a random two-way crossover study in dogs. The drug blood concentration was determined by internal standard HPLC method after oral administration of CyA-S100-NP and Neoral. Pharmacokinetics modellng parameters were calculated by 3P97modelling program. The concentration-time data were fitted as a two-compartment open model. The AUC of CyA-S100-NP was higher than that of Neoral (P<0.05), while the CL significantly decreased (P<0.05). The relative bioavailability of CyA-S100-NP were 135.9% compared with Neoral. The bioavailability of CyA was significantly improved. CyA-S100-NP was a potential drug for developing a new CyA nanoparticles solid formulation.

  2. Population pharmacokinetic and pharmacodynamic modeling of epinephrine administered using a mobile inhaler.

    Science.gov (United States)

    Frechen, Sebastian; Suleiman, Ahmed Abbas; Mohammad Nejad Sigaroudi, Ali; Wachall, Bertil; Fuhr, Uwe

    2015-12-01

    Inhaled epinephrine is a potential alternative to self-administered intramuscular epinephrine in imminent anaphylactic reactions. The objective was to develop a pharmacokinetic-pharmacodynamic model describing exposure and effects on heart rate of inhaled epinephrine. Data from a 4-phase cross-over clinical trial in 9 healthy volunteers including 0.3 mg intramuscular epinephrine, two doses of inhaled epinephrine (4 mg/mL solution administered during [mean] 18 and 25 min, respectively) using a mobile pocket inhaler, and an inhaled placebo were analyzed using mixed-effects modeling. Inhaled epinephrine was available almost immediately and more rapidly than via the intramuscular route (absorption half-live 29 min). Epinephrine plasma concentrations declined rapidly after terminating inhalation (elimination half-life 4.1 min) offering the option to stop exposure in case of adverse events. While the expected maximum concentration was higher for inhaled epinephrine, this was not associated with safety concerns due to only moderate additional hemodynamic effects compared to intramuscular administration. Bioavailability after inhalation (4.7%) was subject to high interindividual and interoccasional variability highlighting that training of inhalation would be essential for patients. The proposed model suggests that the use of a highly concentrated epinephrine solution via inhalation may offer an effective treatment option in anaphylaxis, while efficacy in patients remains to be shown. PMID:26615448

  3. The method of averaging applied to pharmacokinetic/pharmacodynamic indirect response models.

    Science.gov (United States)

    Dunne, Adrian; de Winter, Willem; Hsu, Chyi-Hung; Mariam, Shiferaw; Neyens, Martine; Pinheiro, José; Woot de Trixhe, Xavier

    2015-08-01

    The computational effort required to fit the pharmacodynamic (PD) part of a pharmacokinetic/pharmacodynamic (PK/PD) model can be considerable if the differential equations describing the model are solved numerically. This burden can be greatly reduced by applying the method of averaging (MAv) in the appropriate circumstances. The MAv gives an approximate solution, which is expected to be a good approximation when the PK profile is periodic (i.e. repeats its values in regular intervals) and the rate of change of the PD response is such that it is approximately constant over a single period of the PK profile. This paper explains the basis of the MAv by means of a simple mathematical derivation. The NONMEM® implementation of the MAv using the abbreviated FORTRAN function FUNCA is described and explained. The application of the MAv is illustrated by means of an example involving changes in glycated hemoglobin (HbA1c%) following administration of canagliflozin, a selective sodium glucose co-transporter 2 inhibitor. The PK/PD model applied to these data is fitted with NONMEM® using both the MAv and the standard method using a numerical differential equation solver (NDES). Both methods give virtually identical results but the NDES method takes almost 8 h to run both the estimation and covariance steps, whilst the MAv produces the same results in less than 30 s. An outline of the NONMEM® control stream and the FORTRAN code for the FUNCA function is provided in the appendices. PMID:26142076

  4. PANSYM: a symbolic equation generator for mathematical modelling, analysis and control of metabolic and pharmacokinetic systems.

    Science.gov (United States)

    Thomaseth, K

    1994-02-14

    Software is presented for automatic generation of first-order ordinary differential equations (ODE) that arise from lumped parameter representations of metabolic and pharmacokinetic systems. The definition of system structures is accomplished by fractional transfer rates between state variables, together with input/output equations and initial conditions of state variables. General non-linear mathematical expressions can be assigned to all structure definition items. The software parses and interprets the system definitions and generates symbolically the mathematical expression of the model's set of ODE. In addition, symbolic derivatives of state equations are determined with respect to model parameters, state variables and external inputs. These derivatives represent the constituents of systems of sensitivity-differential and adjoint-differential equations that arise in identification and optimal control problems. Finally, output routines generate source code that, once compiled and linked to simulation programs, allows efficient numerical integration of the system of ODE. This software has been developed in PROLOG on Macintosh computers and has been extensively used with the programming environment MATLAB. Possible applications of this software include model building, sensitivity analysis, identification, optimal experiment design and numerical solution of optimal control problems. PMID:8205801

  5. Determination of phenazopyridine in human plasma via LC-MS and subsequent development of a pharmacokinetic model.

    Science.gov (United States)

    Shang, Erxin; Xiang, Bingren; Liu, Guangyu; Xie, Shaofei; Wei, Wenyan; Lu, Jun

    2005-05-01

    This paper describes a new LC-MS method for the determination of phenazopyridine and the subsequent development of a pharmacokinetic model for phenazopyridine in vivo. Phenazopyridine hydrochloride is a strong analgesic used in the treatment of urinary tract infections. Although it has been used as a clinical treatment for a very long time, pharmacokinetic data and suitable methods for its determination in plasma are currently lacking. The study described in this paper used high performance liquid chromatography-mass spectrometry, HPLC-MS, to determine the plasma concentrations of phenazopyridine in human subjects after oral administration. After liquid-liquid extraction, the phenazopyridine in the plasma was analyzed on a C18 column under SIM mode. A double-peak phenomenon was observed in most of the concentration-time profiles of the subjects. Although some drugs are known to cause this phenomenon, phenazopyridine has not been reported to do so. Several possible causes were analyzed in order to obtain an explanation. We proposed a two-site absorption compartment model to fit the concentration data in vivo, which has one more absorption site than the classical one-compartment model. The model describes the concentration profiles in different dose groups well and could provide an explanation for the double-peak phenomenon. The three dose groups exhibited similar model parameters and a linear pharmacokinetic process over the dose range used. PMID:15900475

  6. Synergy between vancomycin and nafcillin against Staphylococcus aureus in an in vitro pharmacokinetic/pharmacodynamic model.

    Directory of Open Access Journals (Sweden)

    Steven N Leonard

    Full Text Available INTRODUCTION: Continued pressure from glycopeptide use has led to non-susceptible strains of Staphylococcus aureus including heterogeneously vancomycin-intermediate S. aureus (hVISA. Infections with hVISA are associated with poor patient outcomes, thus incentivizing novel treatments. Evidence suggests that vancomycin and anti-staphylococcal penicillin susceptibility are inversely related which indicates that the use of this combination may be particularly useful against methicillin-resistant S. aureus with reduced susceptibility to vancomycin, such as hVISA. The aim of this study was to evaluate the potential for synergy between vancomycin and nafcillin against hVISA. METHODS: Twenty-five hVISA strains were evaluated for vancomycin and nafcillin minimum inhibitory concentration (MIC by broth microdilution in duplicate. Potential for synergy was assessed by time-kill at 1/2x MIC in triplicate. Five strains were chosen, representing the range nafcillin MIC's available in the cohort -4, 16, 64, 128, and 256 µg/mL, and were run in an in vitro pharmacokinetic/pharmacodynamic (PK/PD model in duplicate over 72 hours to evaluate the potential of the combination with simulated human pharmacokinetics. In addition, 4 fully glycopeptide susceptible strains of S. aureus including 2 methicillin-susceptible (MSSA and 2 methicillin-resistant (MRSA were run in the PK/PD model for comparison. RESULTS: In the time-kill, 92% of strains (23 of 25 displayed synergy with the combination of vancomycin and nafcillin. In the PK/PD model, all five strains of hVISA showed an improvement in overall activity (P≤0.004 and organism burden at 72 hours (P≤0.001 with the combination compared to either drug alone. The combination was also successful against both MRSA and MSSA in overall activity (P≤0.009 and organism burden at 72 hours (P≤0.016, though the magnitude of the effect was diminished against MSSA. CONCLUSIONS: The combination of vancomycin and nafcillin

  7. Pharmacokinetics and Pharmacodynamics of a Novel Triazole, Isavuconazole: Mathematical Modeling, Importance of Tissue Concentrations, and Impact of Immune Status on Antifungal Effect▿

    OpenAIRE

    Warn, Peter A.; Sharp, Andrew; Parmar, Arvind; Majithiya, Jayesh; David W Denning; Hope, William W.

    2009-01-01

    Isavuconazole is a triazole with broad-spectrum activity against medically important fungal pathogens. We investigated the pharmacokinetics and pharmacodynamics of isavuconazole in a murine model of disseminated candidiasis. We determined the pharmacokinetics in both plasma and kidney. The relationship between tissue concentrations and the resultant antifungal effect was described using a mathematical model. The pharmacodynamic parameter that optimally links drug exposure with the antifungal ...

  8. An integrated disease/pharmacokinetic/pharmacodynamic model suggests improved interleukin-21 regimens validated prospectively for mouse solid cancers.

    Directory of Open Access Journals (Sweden)

    Moran Elishmereni

    2011-09-01

    Full Text Available Interleukin (IL-21 is an attractive antitumor agent with potent immunomodulatory functions. Yet thus far, the cytokine has yielded only partial responses in solid cancer patients, and conditions for beneficial IL-21 immunotherapy remain elusive. The current work aims to identify clinically-relevant IL-21 regimens with enhanced efficacy, based on mathematical modeling of long-term antitumor responses. For this purpose, pharmacokinetic (PK and pharmacodynamic (PD data were acquired from a preclinical study applying systemic IL-21 therapy in murine solid cancers. We developed an integrated disease/PK/PD model for the IL-21 anticancer response, and calibrated it using selected "training" data. The accuracy of the model was verified retrospectively under diverse IL-21 treatment settings, by comparing its predictions to independent "validation" data in melanoma and renal cell carcinoma-challenged mice (R(2>0.90. Simulations of the verified model surfaced important therapeutic insights: (1 Fractionating the standard daily regimen (50 µg/dose into a twice daily schedule (25 µg/dose is advantageous, yielding a significantly lower tumor mass (45% decrease; (2 A low-dose (12 µg/day regimen exerts a response similar to that obtained under the 50 µg/day treatment, suggestive of an equally efficacious dose with potentially reduced toxicity. Subsequent experiments in melanoma-bearing mice corroborated both of these predictions with high precision (R(2>0.89, thus validating the model also prospectively in vivo. Thus, the confirmed PK/PD model rationalizes IL-21 therapy, and pinpoints improved clinically-feasible treatment schedules. Our analysis demonstrates the value of employing mathematical modeling and in silico-guided design of solid tumor immunotherapy in the clinic.

  9. Fiber optic-based fluorescence detection system for in vivo studies of exogenous chromophore pharmacokinetics

    Science.gov (United States)

    Doiron, Daniel R.; Dunn, J. B.; Mitchell, W. L.; Dalton, Brian K.; Garbo, Greta M.; Warner, Jon A.

    1995-05-01

    The detection and quantification of the concentration of exogenous chromophores in-vivo by their fluorescence is complicated by many physical and geometrical parameters. Measurement of such signals is advantageous in determining the pharmacokinetics of photosensitizers such as those used in photodynamic therapy (PDT) or to assist in the diagnosis of tissue histological state. To overcome these difficulties a ratio based fiber optic contact fluorometer has been developed. This fluorescence detection system (FDS) uses the ratio of the fluorescence emission peak of the exogenous chromophore to that of endogenous chromophores, i.e. autofluorescence, to correct for a variety of parameters affecting the magnitude of the measured signals. By doing so it also minimizes the range of baseline measurements prior to exogenous drug injection, for various tissue types. Design of the FDS and results of its testing in animals and patients using the second generation photosensitizer Tin ethyletiopurpurin (SnET2) are presented. These results support the feasibility and usefulness of the Ratio FDS system.

  10. In Vivo Pharmacokinetics and Pharmacodynamics of the Lantibiotic NAI-107 in a Neutropenic Murine Thigh Infection Model

    OpenAIRE

    Lepak, Alexander J.; Marchillo, Karen; Craig, William A.; Andes, David R.

    2014-01-01

    NAI-107 is a novel lantibiotic compound with potent in vitro activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The purpose of this study was to examine the activity of NAI-107 against S. aureus strains, including MRSA, in the neutropenic murine thigh infection model. Serum pharmacokinetics were determined and time-kill studies were performed following administration of single subcutaneous doses of 5, 20, and 80 mg/kg body weight. The dose f...

  11. Modeling of Pharmacokinetics of Cocaine in Human Reveals the Feasibility for Development of Enzyme Therapies for Drugs of Abuse

    OpenAIRE

    Fang Zheng; Chang-Guo Zhan

    2012-01-01

    A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on th...

  12. Pharmacokinetic-Pharmacodynamic Modeling of the In Vitro Activities of Oxazolidinone Antimicrobial Agents against Methicillin-Resistant Staphylococcus aureus▿

    OpenAIRE

    Schmidt, Stephan; Sabarinath, Sreedharan Nair; Barbour, April; Abbanat, Darren; Manitpisitkul, Prasarn; Sha, Sue; Derendorf, Hartmut

    2009-01-01

    Linezolid is the first FDA-approved oxazolidinone with activity against clinically important gram-positive pathogens, including methicillin (meticillin)-resistant Staphylococcus aureus (MRSA). RWJ-416457 is a new oxazolidinone with an antimicrobial spectrum similar to that of linezolid. The goal of the present study was to develop a general pharmacokinetic (PK)-pharmacodynamic (PD) model that allows the characterization and comparison of the in vitro activities of oxazolidinones, determined i...

  13. Sphingomyelin-cholesterol liposomes significantly enhance the pharmacokinetic and therapeutic properties of vincristine in murine and human tumour models.

    OpenAIRE

    Webb, M S; Harasym, T. O.; Masin, D.; Bally, M. B.; Mayer, L. D.

    1995-01-01

    This study reports on the development of a liposomal formulation of vincristine with significantly enhanced stability and biological properties. The in vitro and in vivo pharmacokinetic, tumour delivery and efficacy properties of liposomal vincristine formulations based on sphingomyelin (SM) and cholesterol were compared with liposomes composed of distearoylphosphatidylcholine (DSPC) and cholesterol. SM/cholesterol liposomes had significantly greater in vitro stability than did similar DSPC/c...

  14. Physiologically Based Modelling of Dioxins. I. Validation of a rodent toxicokinetic model

    NARCIS (Netherlands)

    Zeilmaker MJ; Slob W

    1993-01-01

    In this report a rodent Physiologically Based PharmacoKinetic (PBPK) model for 2,3,7,8-tetrachlorodibenzodioxin is described. Validation studies, in which model simulations of TCDD disposition were compared with in vivo TCDD disposition in rodents exposed to TCDD, showed that the model adequately p

  15. Pharmacokinetics/pharmacodynamic correlations of fluconazole in murine model of cryptococcosis.

    Science.gov (United States)

    Santos, Julliana Ribeiro Alves; César, Isabela Costa; Costa, Marliete Carvalho; Ribeiro, Noelly Queiroz; Holanda, Rodrigo Assunção; Ramos, Lais Hott; Freitas, Gustavo José Cota; Paixão, Tatiane Alves; Pianetti, Gerson Antônio; Santos, Daniel Assis

    2016-09-20

    The emergence of fluconazole-resistant Cryptococcus gattii is a global concern, since this azole is the main antifungal used worldwide to treat patients with cryptococcosis. Although pharmacokinetic (PK) and pharmacodynamic (PD) indices are useful predictive factors for therapeutic outcomes, there is a scarcity of data regarding PK/PD analysis of antifungals in cryptococcosis caused by resistant strains. In this study, PK/PD parameters were determined in a murine model of cryptococcosis caused by resistant C. gattii. We developed and validated a suitable liquid chromatography-electrospray ionization tandem mass spectrometry method for PK studies of fluconazole in the serum, lungs, and brain of uninfected mice. Mice were infected with susceptible or resistant C. gattii, and the effects of different doses of fluconazole on the pulmonary and central nervous system fungal burden were determined. The peak levels in the serum, lungs, and brain were achieved within 0.5h. The AUC/MIC index (area under the curve/minimum inhibitory concentration) was associated with the outcome of anti-cryptococcal therapy. Interestingly, the maximum concentration of fluconazole in the brain was lower than the MIC for both strains. In addition, the treatment of mice infected with the resistant strain was ineffective even when high doses of fluconazole were used or when amphotericin B was tested, confirming the cross-resistance between these drugs. Altogether, our novel data provide the correlation of PK/PD parameters with antifungal therapy during cryptococcosis caused by resistant C. gattii. PMID:27235581

  16. Pharmacokinetics-pharmacodynamics analysis of bicyclic 4-nitroimidazole analogs in a murine model of tuberculosis.

    Directory of Open Access Journals (Sweden)

    Suresh B Lakshminarayana

    Full Text Available PA-824 is a bicyclic 4-nitroimidazole, currently in phase II clinical trials for the treatment of tuberculosis. Dose fractionation pharmacokinetic-pharmacodynamic studies in mice indicated that the driver of PA-824 in vivo efficacy is the time during which the free drug concentrations in plasma are above the MIC (fT>MIC. In this study, a panel of closely related potent bicyclic 4-nitroimidazoles was profiled in both in vivo PK and efficacy studies. In an established murine TB model, the efficacy of diverse nitroimidazole analogs ranged between 0.5 and 2.3 log CFU reduction compared to untreated controls. Further, a retrospective analysis was performed for a set of seven nitroimidazole analogs to identify the PK parameters that correlate with in vivo efficacy. Our findings show that the in vivo efficacy of bicyclic 4-nitroimidazoles correlated better with lung PK than with plasma PK. Further, nitroimidazole analogs with moderate-to-high volume of distribution and Lung to plasma ratios of >2 showed good efficacy. Among all the PK-PD indices, total lung T>MIC correlated the best with in vivo efficacy (rs = 0.88 followed by lung Cmax/MIC and AUC/MIC. Thus, lung drug distribution studies could potentially be exploited to guide the selection of compounds for efficacy studies, thereby accelerating the drug discovery efforts in finding new nitroimidazole analogs.

  17. Glucosamine sulfate effect on the degenerated patellar cartilage: preliminary findings by pharmacokinetic magnetic resonance modeling

    Energy Technology Data Exchange (ETDEWEB)

    Marti-Bonmati, Luis [Dr Peset University Hospital, Radiology Department, Valencia (Spain); Hospital Quiron Valencia, Radiology Department, Valencia (Spain); Sanz-Requena, Roberto; Alberich-Bayarri, Angel [Hospital Quiron Valencia, Radiology Department, Valencia (Spain); Rodrigo, Jose Luis [Dr Peset University Hospital, Traumatology and Orthopedics Surgery Department, Valencia (Spain); Carot, Jose Miguel [Universidad Politecnica de Valencia, EIO Department, Valencia (Spain)

    2009-06-15

    Normal and degenerated cartilages have different magnetic resonance (MR) capillary permeability (K{sup trans}) and interstitial interchangeable volume (v{sub e}). Our hypothesis was that glucosamine sulfate treatment modifies these neovascularity abnormalities in osteoarthritis. Sixteen patients with patella degeneration, randomly distributed into glucosamine or control groups, underwent two 1.5-Tesla dynamic contrast-enhanced MR imaging studies (treatment initiation and after 6 months). The pain visual analog scale (VAS) and American Knee Society (AKS) score were used. A two-compartment pharmacokinetic model was used. Percentages of variations (postreatment-pretreatment/pretreatment) were compared (t-test for independent data). In the glucosamine group, pain and functional outcomes statistically improved (VAS: 7.3 {+-} 1.1 to 3.6 {+-} 1.3, p < 0.001; AKS: 18.6 {+-} 6.9 to 42.9 {+-} 2.7, p < 0.01). Glucosamine significantly increased K{sup trans} at 6 months (-54.4 {+-} 21.2% vs 126.7 {+-} 56.9%, p < 0.001, control vs glucosamine). In conclusion, glucosamine sulfate decreases pain while improving functional outcome in patients with cartilage degeneration. Glucosamine sulfate increases K{sup trans}, allowing its proposal as a surrogate imaging biomarker after 6 months of treatment. (orig.)

  18. In Vivo Pharmacokinetics/Pharmacodynamics of Cefquinome in an Experimental Mouse Model of Staphylococcus Aureus Mastitis following Intramammary Infusion

    Science.gov (United States)

    Yu, Yang; Zhou, Yu-Feng; Chen, Mei-Ren; Li, Xiao; Qiao, Gui-Lin; Sun, Jian; Liao, Xiao-Ping; Liu, Ya-Hong

    2016-01-01

    Staphylococcus aureus remains the major cause of morbidity of bovine mastitis worldwide leading to massive economic losses. Cefquinome is a fourth generation cephalosporin, which preserves susceptibility and antibacterial activity against S. aureus. This work aims to study the pharmacokinetic (PK) and pharmacodynamic (PD) modeling following intramammary administration of cefquinome against S. aureus mastitis. The mouse model of S. aureus mastitis was developed for the PK/PD experiments. The plasma PK characteristics after intramammary injection of cefquinome at various single doses of 25, 50, 100, 200, 400 μg per gland (both fourth pairs of glands: L4 and R4) were calculated using one-compartment and first-order absorption model. PD study was investigated based on twenty-one intermittent dosing regimens, of which total daily dose ranged from 25 to 4800 μg per mouse and dosage intervals included 8, 12 or 24 h. The sigmoid Emax model of inhibitory effect was employed for PK/PD modeling. The results of PK/PD integration of cefquinome against S. aureus suggested that the percentage of duration that drug concentration exceeded the minimal inhibitory concentration (%T>MIC) and the ratio of area under time-concentration curve over MIC (AUC/MIC) are important indexes to evaluate the antibacterial activity. The PK/PD parameters of %T>MIC and AUC0-24/MIC were 35.98% and 137.43 h to obtain a 1.8 logCFU/gland reduction of bacterial colony counts in vivo, against S. aureus strains with cefquinome MIC of 0.5μg/ml. PMID:27218674

  19. Improvement in intraperitoneal intraoperative cisplatin exposure based on pharmacokinetic analysis in patients with ovarian cancer.

    Science.gov (United States)

    Royer, Bernard; Delroeux, Delphine; Guardiola, Emmanuel; Combe, Marielle; Hoizey, Guillaume; Montange, Damien; Kantelip, Jean-Pierre; Chauffert, Bruno; Heyd, Bruno; Pivot, Xavier

    2008-03-01

    Ovarian cancer is the leading cause of gynecological cancer-related death in Western countries. The present treatment standards for ovarian cancer are based on the association of debulking surgery with platinum-based chemotherapy. Another strategy that could be further investigated is intraperitoneal chemotherapy (IP). We previously described that the 2-h administration of intraoperative IP cisplatin did not reach satisfactory concentrations. In the present study, we present the results of a pharmacokinetic analysis performed after two consecutive 1-h IP 30 mg/l cisplatin administrations. Twenty-seven patients with advanced epithelial cancer classified FIGO stage IIIC were included in the study. Blood and IP samples were taken over a 24-h period, during and after IP treatment. Both total and ultrafiltered (Uf) platinum (Pt) concentration levels were analyzed. Biological and clinical toxicities were also recorded. With this strategy, IP Pt concentrations stayed above the target concentration (10 mg/l) for a satisfactory length of time. The serum Pt concentrations were higher than those observed with the "one-bath" protocol and they induced the occurrence of recoverable renal toxicities (3 grade 1, 7 grade 2 and 4 grade 3). The best predictive parameter for renal failure was the total Pt 24-h Area Under the Curve (AUC) with a threshold value of 25 mg h/l RR = 0.31 (95% CI 0.13 - 0.49, P amount of cisplatin is feasible and a satisfactory level of IP Pt concentrations is obtained. However, this improvement is associated with an increase in serum Pt levels and resulting renal toxicities. An attractive solution would be to decrease Pt transfer from peritoneum to bloodstream. A phase 1 study using intraoperative IP epinephrine in order to decrease this transfer is presently being carried out. PMID:17503047

  20. Pharmacodynamics of the Antibacterial Effect of and Emergence of Resistance to Doripenem in Pseudomonas aeruginosa and Acinetobacter baumannii in an In Vitro Pharmacokinetic Model

    OpenAIRE

    Bowker, Karen E.; Noel, Alan R.; Tomaselli, Sharon G.; Elliott, Heather; MacGowan, Alasdair P.

    2012-01-01

    An in vitro dilutional pharmacokinetic model of infection was used to study the pharmacodynamics of doripenem in terms of the ability to kill Pseudomonas aeruginosa or Acinetobacter baumannii and also changes in their population profiles. In dose-ranging studies, the cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMICs) required for doripenem to produce a 24-h bacteriostatic effect and a −2-log-unit reduction ...

  1. Pharmacokinetic/pharmacodynamic-based optimization of levofloxacin administration in the treatment of MDR-TB

    NARCIS (Netherlands)

    Ghimire, Samiksha; Van't Boveneind-Vrubleuskaya, Natasha; Akkerman, Onno W; de Lange, Wiel C M; van Soolingen, Dick; Kosterink, Jos G W; van der Werf, Tjip S; Wilffert, Bob; Touw, Daniel J; Alffenaar, Jan-Willem C

    2016-01-01

    The emergence of MDR-TB and XDR-TB has complicated TB treatment success. Among many factors that contribute to the development of resistance, low drug exposure is not the least important. This review summarizes the available information on pharmacokinetic properties of levofloxacin in relation to mi

  2. The relationship between the pharmacokinetics and pharmacodynamics of spinal opioids. Minireview based on a doctoral thesis.

    Science.gov (United States)

    Sjöström, S

    1988-01-01

    Spinal opioids have been used clinically since the late seventies to treat acute, traumatic, obstetric and chronic pain. In this article the influence of the pharmacokinetics on the dynamics of intrathecal and epidural opioid administration are discussed with reference to current knowledge. PMID:2905092

  3. Exploration of the Pharmacokinetic-Pharmacodynamic Relationships for Fosfomycin Efficacy Using an In Vitro Infection Model

    Science.gov (United States)

    VanScoy, Brian D.; McCauley, Jennifer; Ellis-Grosse, Evelyn J.; Okusanya, Olanrewaju O.; Bhavnani, Sujata M.; Forrest, Alan

    2015-01-01

    Fosfomycin, a phosphonic class antibiotic with a broad spectrum of antibacterial activity, has been used outside the United States since the early 1970s for the treatment of a variety of infections. In the United States, an oral (tromethamine salt) formulation is used for uncomplicated urinary tract infections. Recently, there has been interest in the use of an intravenous solution (ZTI-01) for the treatment of a broad range of infections associated with multidrug-resistant bacteria. In this era of multidrug-resistant bacteria with few treatment options, it is critical to understand the pharmacokinetic-pharmacodynamic (PK-PD) determinants for fosfomycin efficacy. Since such data are limited, a one-compartment in vitro infection model was used to determine the PK-PD index associated with efficacy and the magnitude of this measure necessary for various levels of effect. One challenge isolate (Escherichia coli ATCC 25922, for which the fosfomycin agar MIC is 0.5 mg/liter and the broth microdilution MIC is 1 mg/liter) was evaluated in the dose fractionation studies, and two additional clinical E. coli isolates were evaluated in the dose-ranging studies. Mutation frequency studies indicated the presence of an inherently fosfomycin resistant E. coli subpopulation (agar MIC = 32 to 64 mg/liter) within the standard starting inoculum of a susceptibility test. Due to the presence of this resistant subpopulation, we identified the percentage of the dosing interval that drug concentrations were above the inherent resistance inhibitory concentration found at baseline to be the PK-PD index associated with efficacy (r2 = 0.777). The magnitudes of this PK-PD index associated with net bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 11.9, 20.9, and 32.8, respectively. These data provide useful information for modernizing and optimizing ZTI-01 dosing regimens for further study. PMID:26100706

  4. Effects of sarizotan in animal models of ADHD: challenging pharmacokinetic-pharmacodynamic relationships.

    Science.gov (United States)

    Danysz, Wojciech; Flik, Gunnar; McCreary, Andrew; Tober, Carsten; Dimpfel, Wilfried; Bizot, Jean C; Kostrzewa, Richard; Brown, Russell W; Jatzke, Claudia C; Greco, Sergio; Jenssen, Ann-Kristin; Parsons, Christopher G

    2015-09-01

    Sarizotan 1-[(2R)-3,4-dihydro-2H-chromen-2-yl]-N-[[5-(4-fluorophenyl) pyridin-3-yl]methyl] methenamine, showed an in vivo pharmaco-EEG profile resembling that of methylphenidate which is used in attention deficit/hyperactivity disorder (ADHD). In turn, we tested sarizotan against impulsivity in juvenile rats measuring the choice for large delayed vs. a small immediate reward in a T-maze and obtained encouraging results starting at 0.03 mg/kg (plasma levels of ~11 nM). Results from rats treated neonatally with 6-hydroxydopamine (6-OHDA), also supported anti-ADHD activity although starting at 0.3 mg/kg. However, microdialysis studies revealed that free brain concentration of sarizotan at active doses were below its affinity for 5-HT1A receptors, the assumed primary target. In contrast, electrophysiological experiments in mid-brain Raphé serotonergic cells paralleled by plasma sampling showed that there was ~60% inhibition of firing rate—indicating significant activation of 5-HT1A receptors—at a plasma concentration of 76 nM. In line with this, we observed that sarizotan concentrations in brain homogenates were similar to total blood levels but over 500 fold higher than free extracellular fluid (ECF) concentrations as measured using brain microdialysis. These data suggest that sarizotan may have potential anti-ADHD effects at low doses free of the previously reported side-effects. Moreover, in this case a classical pharmacokinetic-pharmacodynamic relationship based on free brain concentrations seems to be less appropriate than target engagement pharmacodynamic readouts. PMID:25796190

  5. Doxorubicin-Loaded QuadraSphere Microspheres: Plasma Pharmacokinetics and Intratumoral Drug Concentration in an Animal Model of Liver Cancer

    International Nuclear Information System (INIS)

    The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

  6. Improving pharmacokinetic-pharmacodynamic modeling to investigate anti-infective chemotherapy with application to the current generation of antimalarial drugs.

    Directory of Open Access Journals (Sweden)

    Katherine Kay

    Full Text Available Mechanism-based pharmacokinetic-pharmacodynamic (PK/PD modelling is the standard computational technique for simulating drug treatment of infectious diseases with the potential to enhance our understanding of drug treatment outcomes, drug deployment strategies, and dosing regimens. Standard methodologies assume only a single drug is used, it acts only in its unconverted form, and that oral drugs are instantaneously absorbed across the gut wall to their site of action. For drugs with short half-lives, this absorption period accounts for a significant period of their time in the body. Treatment of infectious diseases often uses combination therapies, so we refined and substantially extended the PK/PD methodologies to incorporate (i time lags and drug concentration profiles resulting from absorption across the gut wall and, if required, conversion to another active form; (ii multiple drugs within a treatment combination; (iii differing modes of action of drugs in the combination: additive, synergistic, antagonistic; (iv drugs converted to an active metabolite with a similar mode of action. This methodology was applied to a case study of two first-line malaria treatments based on artemisinin combination therapies (ACTs, artemether-lumefantrine and artesunate-mefloquine where the likelihood of increased artemisinin tolerance/resistance has led to speculation on their continued long-term effectiveness. We note previous estimates of artemisinin kill rate were underestimated by a factor of seven, both the unconverted and converted form of the artemisinins kill parasites and the extended PK/PD methodology produced results consistent with field observations. The simulations predict that a potentially rapid decline in ACT effectiveness is likely to occur as artemisinin resistance spreads, emphasising the importance of containing the spread of artemisinin resistance before it results in widespread drug failure. We found that PK/PD data is generally very

  7. Evaluation of an Innovative Population Pharmacokinetic-Based Design for Behavioral Pharmacodynamic Endpoints

    OpenAIRE

    Viberg, Anders; Martino, Giovanni; Lessard, Etienne; Laird, Jennifer M. A.

    2012-01-01

    Pre-clinical behavioral pharmacology studies supporting indications like analgesia typically consist of at least three different studies; dose-finding, duration of effect, and tolerance-development studies. Pharmacokinetic (PK) plasma samples are generally taken from a parallel group of animals to avoid disruption of the behavioral pharmacodynamic (PD) endpoint. Our objective was to investigate if pre-clinical behavioral pharmacology studies in rats could be performed effectively by combining...

  8. Exploring flubendazole formulations for use in sheep. Pharmacokinetic evaluation of a cyclodextrin-based solution

    OpenAIRE

    Ceballos Laura; Moreno Laura; Torrado Juan J; Lanusse Carlos; Alvarez Luis

    2012-01-01

    Abstract Background Flubendazole (FLBZ) is a poor water solubility broad-spectrum BZD methylcarbamate anthelmintic compound. Cyclodextrins (CDs) are usually used to increase aqueous solubility of poor hydrosoluble compounds. The comparative in vitro aqueous solubility of FLBZ and other BZD anthelmintics in the presence of hydroxypropyl-β-cyclodextrin (HPβCD) was evaluated in the current work. Additionally, the comparative pharmacokinetic behaviour of FLBZ (and its metabolites) administered by...

  9. Pharmacokinetics and Pharmacodynamics of ASP2151, a Helicase-Primase Inhibitor, in a Murine Model of Herpes Simplex Virus Infection

    OpenAIRE

    Katsumata, Kiyomitsu; Chono, Koji; Kato, Kota; Ohtsu, Yoshiaki; Takakura, Shoji; Kontani, Toru; Suzuki, Hiroshi

    2013-01-01

    ASP2151 (amenamevir) is a helicase-primase inhibitor against herpes simplex virus 1 (HSV-1), HSV-2, and varicella zoster virus. Here, to determine and analyze the correlation between the pharmacodynamic (PD) and pharmacokinetic (PK) parameters of ASP2151, we examined the PD profile of ASP2151 using in vitro plaque reduction assay and a murine model of HSV-1 infection. ASP2151 inhibited the in vitro replication of HSV-1 with a mean 50% effective concentration (EC50) of 14 ng/ml. In the cutaneo...

  10. Metrics for external model evaluation with an application to the population pharmacokinetics of gliclazide.

    OpenAIRE

    Brendel, Karl; Comets, Emmanuelle; Laffont, Céline,; Laveille, Christian; Mentré, France

    2006-01-01

    PURPOSE: The aim of this study is to define and illustrate metrics for the external evaluation of a population model. MATERIALS AND METHODS: In this paper, several types of metrics are defined: based on observations (standardized prediction error with or without simulation and normalized prediction distribution error); based on hyperparameters (with or without simulation); based on the likelihood of the model. All the metrics described above are applied to evaluate a model built from two phas...

  11. Conversion of arterial input functions for dual pharmacokinetic modeling using Gd-DTPA/MRI and 18F-FDG/PET.

    Science.gov (United States)

    Poulin, Eric; Lebel, Réjean; Croteau, Etienne; Blanchette, Marie; Tremblay, Luc; Lecomte, Roger; Bentourkia, M'hamed; Lepage, Martin

    2013-03-01

    Reaching the full potential of magnetic resonance imaging (MRI)-positron emission tomography (PET) dual modality systems requires new methodologies in quantitative image analyses. In this study, methods are proposed to convert an arterial input function (AIF) derived from gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) in MRI, into a (18)F-fluorodeoxyglucose ((18)F-FDG) AIF in PET, and vice versa. The AIFs from both modalities were obtained from manual blood sampling in a F98-Fisher glioblastoma rat model. They were well fitted by a convolution of a rectangular function with a biexponential clearance function. The parameters of the biexponential AIF model were found statistically different between MRI and PET. Pharmacokinetic MRI parameters such as the volume transfer constant (K(trans)), the extravascular-extracellular volume fraction (ν(e)), and the blood volume fraction (ν(p)) calculated with the Gd-DTPA AIF and the Gd-DTPA AIF converted from (18)F-FDG AIF normalized with or without blood sample were not statistically different. Similarly, the tumor metabolic rates of glucose (TMRGlc) calculated with (18) F-FDG AIF and with (18) F-FDG AIF obtained from Gd-DTPA AIF were also found not statistically different. In conclusion, only one accurate AIF would be needed for dual MRI-PET pharmacokinetic modeling in small animal models. PMID:22570280

  12. In vivo pharmacokinetics and pharmacodynamics of a new triazole, voriconazole, in a murine candidiasis model.

    Science.gov (United States)

    Andes, D; Marchillo, K; Stamstad, T; Conklin, R

    2003-10-01

    In vivo studies have described the pharmacodynamic (PD) characteristics of several triazoles. These investigations have demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio is the critical pharmacokinetic (PK)-PD parameter associated with treatment efficacy. Further analyses from these in vivo studies have demonstrated that a triazole free drug 24-h AUC/MIC of 20 to 25 is predictive of treatment success. We used a neutropenic murine model of disseminated Candida albicans infection to similarly characterize the PK-PD of the new triazole voriconazole. PK and PD parameters (percentage of time that the concentration remains above the MIC [T > MIC], AUC/MIC ratio, and peak level in serum/MIC ratio) were correlated with in vivo efficacy, as measured by the organism number in kidney cultures after 24 h of therapy. Voriconazole kinetics and protein binding were studied in infected neutropenic mice. Peak level/dose and AUC/dose values ranged from 0.1 to 0.2 and 0.1 to 0.7, respectively. The serum elimination half-life ranged from 0.7 to 2.9 h. The level of protein binding in mouse serum was 78%. Treatment efficacy with the four dosing intervals studied was similar, supporting the AUC/MIC ratio as the PK-PD parameter predictive of efficacy. Nonlinear regression analysis also suggested that the AUC/MIC ratio was strongly predictive of treatment outcomes (R(2) for AUC/MIC ratio = 82%, R(2) for peak level/MIC ratio = 63%, R(2) for T > MIC = 75%). Similar studies were conducted with nine additional C. albicans isolates with various voriconazole susceptibilities (MICs, 0.007 to 0.25 micro g/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The voriconazole free drug AUC/MIC ratios were similar for all of the organisms studied (range, 11 to 58; mean +/- standard deviation, 24 +/- 17 [P = 0.45]). These AUC/MIC ratios observed for free drug are similar to those observed for other triazoles in this model. PMID:14506026

  13. Pharmacokinetics and efficacy of PEGylated liposomal doxorubicin in an intracranial model of breast cancer.

    Directory of Open Access Journals (Sweden)

    Carey K Anders

    Full Text Available INTRODUCTION: Breast cancer brain metastases (BCBM are a challenging consequence of advanced BC. Nanoparticle agents, including liposomes, have shown enhanced delivery to solid tumors and brain. We compared pharmacokinetics (PK and efficacy of PEGylated liposomal doxorubicin (PLD with non-liposomal doxorubicin (NonL-doxo in an intracranial model of BC. METHODS: Athymic mice were inoculated intracerebrally with MDA-MB-231-BR-luciferase-expressing cells. Tumor-bearing mice were administered PLD or NonL-doxo at 6 mg/kg IV × 1 and were euthanized prior to and 0.083, 1, 3, 6, 24, 72 and 96 h post-treatment. Samples were processed to measure sum total doxorubicin via HPLC. PLD and NonL-doxo were administered IV weekly as single agents (6 mg/kg or in combination (4.5 mg/kg with the PARP inhibitor, ABT-888, PO 25 mg/kg/day. Efficacy was assessed by survival and bioluminescence. RESULTS: Treatment with PLD resulted in approximately 1,500-fold higher plasma and 20-fold higher intracranial tumor sum total doxorubicin AUC compared with NonL-doxo. PLD was detected at 96 h; NonL-doxo was undetectable after 24 h in plasma and tumor. Median survival of PLD-treated animals was 32 days (d, [CI] 31-38, which was significantly longer than controls (26d [CI 25-28]; p = 0.0012 or NonL-doxo treatment (23.5d [CI 18-28], p = 0.0002. Combination treatment with PLD/ABT-888 yielded improved survival compared to NonL-doxo/ABT-888 (35d [CI 31-38] versus 29.5d [CI 25-34]; p = 0.006. CONCLUSIONS: PLD provides both PK and efficacy advantage over NonL-doxo in the treatment of an in vivo model of BCBM. The results provide preclinical rationale to translate findings into early phase trials of PLD, with or without ABT-888, for patients with BCBM.

  14. The pharmacokinetic study of rutin in rat plasma based on an electrochemically reduced graphene oxide modified sensor

    Directory of Open Access Journals (Sweden)

    Pei Zhang

    2016-04-01

    Full Text Available An electrochemical method based on a directly electrochemically reduced graphene oxide (ERGO film coated on a glassy carbon electrode (GCE was developed for the rapid and convenient determination of rutin in plasma. ERGO was modified on the surface of GCE by one-step electro-deposition method. Electrochemical behavior of rutin on ERGO/GCE indicated that rutin underwent a surface-controlled quasi-reversible process and the electrochemical parameters such as charge transfer coefficient (α, electron transfer number (n and electrode reaction standard rate constant (ks were 0.53, 2 and 3.4 s−1, respectively. The electrochemical sensor for rutin in plasma provided a wide linear response range of 4.70×10−7−1.25×10−5 M with the detection limit (s/n=3 of 1.84×10−8 M. The assay was successfully used to the pharmacokinetic study of rutin. The pharmacokinetic parameters such as elimination rate half-life (t1/2, area under curve (AUC, and plasma clearance (CL were calculated to be 3.345±0.647 min, 5750±656.0 µg min/mL, and 5.891±0.458 mL/min/kg, respectively. The proposed method utilized a small sample volume of 10 μL and had no complicated sample pretreatment (without deproteinization, which was simple, eco-friendly, and time- and cost-efficient for rutin pharmacokinetic studies.

  15. Population Pharmacokinetics of Cyclophosphamide and Metabolites in Children with Neuroblastoma: a Report from the Children’s Oncology Group

    OpenAIRE

    McCune, Jeannine S.; Salinger, David H.; Vicini, Paolo; Oglesby, Celeste; Blough, David K.; Park, Julie R.

    2008-01-01

    Cyclophosphamide-based regimens are front-line treatment for numerous pediatric malignancies, however current dosing methods result in considerable interpatient variability in tumor response and toxicity. In this pediatric population, our objectives were to 1. quantify and explain the pharmacokinetic variability of cyclophosphamide, and two of its metabolites, hydroxycyclophosphamide (HCY) and carboxyethylphosphoramide mustard (CEPM); 2. apply a population pharmacokinetic model to describe th...

  16. Pharmacokinetics & Neurophysiology

    Science.gov (United States)

    Davis, Andrew S.; Salpekar, Jay A.

    2009-01-01

    Medications administered in clinical practice obtain their therapeutic effect only to the extent that the drug is present in the appropriate concentration at the desired site. To achieve this goal, the prescribing clinician must be aware of how a drug may interact with the physiology of the patient. Pharmacokinetics is the study of this process…

  17. Fractal Pharmacokinetics

    OpenAIRE

    Pereira, Luis M.

    2010-01-01

    Pharmacokinetics (PK) has been traditionally dealt with under the homogeneity assumption. However, biological systems are nowadays comprehensively understood as being inherently fractal. Specifically, the microenvironments where drug molecules interact with membrane interfaces, metabolic enzymes or pharmacological receptors, are unanimously recognized as unstirred, space-restricted, heterogeneous and geometrically fractal. Therefore, classical Fickean diffusion and the notion of the compartme...

  18. Development of LC-MS determination method and back-propagation ANN pharmacokinetic model of corynoxeine in rat.

    Science.gov (United States)

    Ma, Jianshe; Cai, Jinzhang; Lin, Guanyang; Chen, Huilin; Wang, Xianqin; Wang, Xianchuan; Hu, Lufeng

    2014-05-15

    Corynoxeine(CX), isolated from the extract of Uncaria rhynchophylla, is a useful and prospective compound in the prevention and treatment for vascular diseases. A simple and selective liquid chromatography mass spectrometry (LC-MS) method was developed to determine the concentration of CX in rat plasma. The chromatographic separation was achieved on a Zorbax SB-C18 (2.1 mm × 150 mm, 5 μm) column with acetonitrile-0.1% formic acid in water as mobile phase. Selective ion monitoring (SIM) mode was used for quantification using target ions m/z 383 for CX and m/z 237 for the carbamazepine (IS). After the LC-MS method was validated, it was applied to a back-propagation artificial neural network (BP-ANN) pharmacokinetic model study of CX in rats. The results showed that after intravenous administration of CX, it was mainly distributed in blood and eliminated quickly, t1/2 was less than 1h. The predicted concentrations generated by BP-ANN model had a high correlation coefficient (R>0.99) with experimental values. The developed BP-ANN pharmacokinetic model can be used to predict the concentration of CX in rats. PMID:24732215

  19. Modelling and simulation approaches for waiving in vivo pharmacokinetic formulation studies

    OpenAIRE

    KortejÀrvi, Hanna

    2008-01-01

    The bioavailability and bioequivalency of oral drug depends on gastrointestinal tract physiology and drug-related physicochemical and pharmacokinetic factors. In general, bioavailability of a new drug substance or new formulation is studied in vivo with healthy volunteers. In vivo bioequivalency studies are needed for generic drug products or if a formulation is significantly altered during clinical trials. In certain cases, in vitro dissolution studies can be used as a surrogate for in vivo ...

  20. The Utility of Modeling and Simulation Approaches to Evaluate Immunogenicity Effect on the Therapeutic Protein Pharmacokinetics

    OpenAIRE

    Perez Ruixo, Juan Jose; Ma, Peiming; Chow, Andrew T.

    2012-01-01

    While therapeutic proteins (TP), particularly recombinant human proteins and fully human monoclonal antibodies, are designed to have a low immunogenic potential in humans, a clinical immune response does sometimes occur and cannot be predicted from preclinical studies. Changes in TP pharmacokinetics may be perceived as an early indication of antibody formation and serve as a surrogate for later changes in efficacy and safety in individual subjects. Given the substantial increase in number of ...

  1. Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development

    Directory of Open Access Journals (Sweden)

    Zaloumis Sophie

    2012-08-01

    Full Text Available Abstract Background Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD model for predicting within-host parasite response was performed. Methods Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50, derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach. Results The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle. The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i

  2. Challenges and Opportunities for Increasing the Knowledge Base Related to Drug Biotransformation and Pharmacokinetics during Growth and Development.

    Science.gov (United States)

    Leeder, J Steven; Meibohm, Bernd

    2016-07-01

    It is generally acknowledged that there is a need and role for informative pharmacokinetic models to improve predictions and simulation as well as individualization of drug therapy in pediatric populations of different ages and developmental stages. This special issue contains more than 20 papers responding to the challenge of providing new information on scaling factors, ontogeny functions for drug metabolizing enzymes and transporters, the mechanisms underlying the observed developmental trajectories for these gene products, age-dependent changes in physiologic processes affecting drug disposition in children, as well as in vitro and in vivo studies describing the relative contribution of ontogeny and genetic factors as sources of variability in drug disposition in children. Considered together, these contributions serve to illustrate some of the current limitations regarding sample availability, number, and quality, but also provide a framework that allows for the potential value of the results of a given study to be interpreted within the context of these limitations. Among the challenges for the future are improving our understanding of the mechanisms regulating age-dependent changes in factors influencing drug disposition and response, thereby facilitating generalization to systems lacking detailed data, better integrating age-dependent changes in pharmacokinetics with age-dependent changes in pharmacodynamics, and allowing better predictability and individualization of drug disposition and response across the pediatric age spectrum. PMID:27302933

  3. A supermolecular curcumin for enhanced antiproliferative and proapoptotic activities: molecular characteristics, computer modeling and in vivo pharmacokinetics

    International Nuclear Information System (INIS)

    The supermolecular curcumin (SMCCM) exhibiting remarkably improved solubility and release characteristics was fabricated to increase the oral bioavailability in rat as well as the antiproliferative and proapoptotic activities of curcumin (CCM) against human lung adenocarcinoma cell A549. SMCCM was characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, morphology and structure, aqueous solubility, and release behavior in vitro. Computer modeling of the supermolecular structure was performed. The pharmacokinetics, antiproliferative and proapoptotic activities of SMCCM were evaluated. The mechanisms by which SMCCM inhibited proliferation and induced apoptosis were identified. The formation of SMCCM was testified and the supermolecular structure was studied by a computer modeling technique. Compared to free CCM, SMCCM with much higher aqueous solubility exhibited obviously enhanced release and more favorable pharmacokinetic profiles, and, furthermore, SMCCM showed higher anticancer efficacy, enhanced induction of G2/M-phase arrest and apoptosis in A549 cells, which might be involved with the increases in reactive oxygen species production and intracellular Ca2+ accumulation, and a decrease in mitochondrial membrane potential. SMCCM remarkably enhanced not only the oral bioavailability but also the antiproliferative and proapoptotic activities of CCM along with improved solubility and release characteristics of CCM. (paper)

  4. A supermolecular curcumin for enhanced antiproliferative and proapoptotic activities: molecular characteristics, computer modeling and in vivo pharmacokinetics

    Science.gov (United States)

    Tan, Qunyou; Wu, Jianyong; Li, Yi; Mei, Hu; Zhao, Chunjing; Zhang, Jingqing

    2013-01-01

    The supermolecular curcumin (SMCCM) exhibiting remarkably improved solubility and release characteristics was fabricated to increase the oral bioavailability in rat as well as the antiproliferative and proapoptotic activities of curcumin (CCM) against human lung adenocarcinoma cell A549. SMCCM was characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, morphology and structure, aqueous solubility, and release behavior in vitro. Computer modeling of the supermolecular structure was performed. The pharmacokinetics, antiproliferative and proapoptotic activities of SMCCM were evaluated. The mechanisms by which SMCCM inhibited proliferation and induced apoptosis were identified. The formation of SMCCM was testified and the supermolecular structure was studied by a computer modeling technique. Compared to free CCM, SMCCM with much higher aqueous solubility exhibited obviously enhanced release and more favorable pharmacokinetic profiles, and, furthermore, SMCCM showed higher anticancer efficacy, enhanced induction of G2/M-phase arrest and apoptosis in A549 cells, which might be involved with the increases in reactive oxygen species production and intracellular Ca2+ accumulation, and a decrease in mitochondrial membrane potential. SMCCM remarkably enhanced not only the oral bioavailability but also the antiproliferative and proapoptotic activities of CCM along with improved solubility and release characteristics of CCM.

  5. Pharmacokinetic models of morphine and its metabolites in neonates:: Systematic comparisons of models from the literature, and development of a new meta-model.

    Science.gov (United States)

    Knøsgaard, Katrine Rørbæk; Foster, David John Richard; Kreilgaard, Mads; Sverrisdóttir, Eva; Upton, Richard Neil; van den Anker, Johannes N

    2016-09-20

    Morphine is commonly used for pain management in preterm neonates. The aims of this study were to compare published models of neonatal pharmacokinetics of morphine and its metabolites with a new dataset, and to combine the characteristics of the best predictive models to design a meta-model for morphine and its metabolites in preterm neonates. Moreover, the concentration-analgesia relationship for morphine in this clinical setting was also investigated. A population of 30 preterm neonates (gestational age: 23-32weeks) received a loading dose of morphine (50-100μg/kg), followed by a continuous infusion (5-10μg/kg/h) until analgesia was no longer required. Pain was assessed using the Premature Infant Pain Profile. Five published population models were compared using numerical and graphical tests of goodness-of-fit and predictive performance. Population modelling was conducted using NONMEM® and the $PRIOR subroutine to describe the time-course of plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide, and the concentration-analgesia relationship for morphine. No published model adequately described morphine concentrations in this new dataset. Previously published population pharmacokinetic models of morphine, morphine-3-glucuronide, and morphine-6-glucuronide were combined into a meta-model. The meta-model provided an adequate description of the time-course of morphine and the concentrations of its metabolites in preterm neonates. Allometric weight scaling was applied to all clearance and volume terms. Maturation of morphine clearance was described as a function of postmenstrual age, while maturation of metabolite elimination was described as a function of postnatal age. A clear relationship between morphine concentrations and pain score was not established. PMID:27373670

  6. Oil based nanocarrier system for transdermal delivery of ropinirole: a mechanistic, pharmacokinetic and biochemical investigation.

    Science.gov (United States)

    Azeem, Adnan; Talegaonkar, Sushama; Negi, Lalit M; Ahmad, Farhan J; Khar, Roop K; Iqbal, Zeenat

    2012-01-17

    Ropinirole, a recent introduction in the clinical treatment of Parkinson's disease, suffers with the problems of low oral bioavailability and frequent dosing. An effective transdermal nano-emulsion drug delivery system can however resolve these issues effectively with greater therapeutic benefits and clinical significance. Therefore, the present work focuses precisely on pharmacokinetic, biochemical and mechanistic assessment of transdermal nanoemulsion gel in rats induced with Parkinson lesioned brain by 6-OHDA. DSC and FT-IR studies showed that NEG affects the normal lipid packing of stratum corneum to enhance the drug permeation. Study of pharmacokinetic parameters (AUC, C(max), and T(max)) revealed a greater and more extended release of ropinirole from nanoemulsion gel compared to that from a conventional gel (RPG) and oral marketed tablet (Ropitor). The AUC(0→∞) for RPCNG and RPTNG was found to be 928.07 ± 206.5 and 1055.99 ± 251.7 ngh/mL, respectively in comparison to 137.25 ± 31.3 and 467.15 ± 106.1 ngh/mL for RPG and oral tablet, respectively. The relative bioavailability of ropinirole has been enhanced more than two fold by RPTNG. Furthermore, antiparkinson activity was evaluated in terms of estimating the level of thiobarbituric acid reactive substances, glutathione antioxidant enzymes and catalase in lesioned brain of rats. Formulations were also found to be non-toxic and non-irritant by histological investigations. PMID:22057087

  7. Mutant prevention concentration, pharmacokinetic-pharmacodynamic integration, and modeling of enrofloxacin data established in diseased buffalo calves.

    Science.gov (United States)

    Ramalingam, B; Sidhu, P K; Kaur, G; Venkatachalam, D; Rampal, S

    2015-12-01

    The pharmacokinetic-pharmacodynamic (PK/PD) modeling of enrofloxacin data using mutant prevention concentration (MPC) of enrofloxacin was conducted in febrile buffalo calves to optimize dosage regimen and to prevent the emergence of antimicrobial resistance. The serum peak concentration (Cmax ), terminal half-life (t1/2 K10) , apparent volume of distribution (Vd(area) /F), and mean residence time (MRT) of enrofloxacin were 1.40 ± 0.27 μg/mL, 7.96 ± 0.86 h, 7.74 ± 1.26 L/kg, and 11.57 ± 1.01 h, respectively, following drug administration at dosage 12 mg/kg by intramuscular route. The minimum inhibitory concentration (MIC), minimum bactericidal concentration, and MPC of enrofloxacin against Pasteurella multocida were 0.055, 0.060, and 1.45 μg/mL, respectively. Modeling of ex vivo growth inhibition data to the sigmoid Emax equation provided AUC24 h /MIC values to produce effects of bacteriostatic (33 h), bactericidal (39 h), and bacterial eradication (41 h). The estimated daily dosage of enrofloxacin in febrile buffalo calves was 3.5 and 8.4 mg/kg against P. multocida/pathogens having MIC90 ≤0.125 and 0.30 μg/mL, respectively, based on the determined AUC24 h /MIC values by modeling PK/PD data. The lipopolysaccharide-induced fever had no direct effect on the antibacterial activity of the enrofloxacin and alterations in PK of the drug, and its metabolite will be beneficial for its use to treat infectious diseases caused by sensitive pathogens in buffalo species. In addition, in vitro MPC data in conjunction with in vivo PK data indicated that clinically it would be easier to eradicate less susceptible strains of P. multocida in diseased calves. PMID:25776301

  8. The hamster cheek pouch (HCP) as an experimental model of oral cancer for BNCT: biodistribution and pharmacokinetics of BPA

    International Nuclear Information System (INIS)

    We propose and validate the HCP model of oral cancer for BNCT studies. This model serves to explore new applications of the technique, study the biology of BNCT and assess Boron uptake in clinically relevant oral tissues. Tumors are induced by a process that mimics spontaneous malignant transformation instead of by the growth of implanted tumor cells. Syrian hamsters were submitted to tumor induction with a chemical carcinogenesis protocol and then used for biodistribution and pharmacokinetic studies of BPA. The data reveal selective uptake by tumor and, to a lesser degree, by precancerous tissue. Boron concentration in oral tissues and skin was higher than in blood, an issue of clinical relevance given that these tissues may be dose-limiting. Absolute and relative values of Boron concentration would be potentially therapeutic. Boron concentration exhibited a linear relationship with percentage of viable tissue in HCP tumors. The HCP model would provide a novel, contributory approach to BNCT research. (author)

  9. Pharmacokinetic and Pharmacodynamic Interaction of Boswellic Acids and Andrographolide with Glyburide in Diabetic Rats: Including Its PK/PD Modeling.

    Science.gov (United States)

    Samala, Sujatha; Veeresham, Ciddi

    2016-03-01

    The effect of boswellic acids (BA) and andrographolide (AD) on the pharmacokinetics and pharmacodynamics of glyburide in normal as well as in streptozotocin-induced diabetic rats was studied. In normal and diabetic rats, the combination of glyburide with BA or AD increased significantly (p < 0.01) all the pharmacokinetic parameters, such as Cmax, AUC0-n, AUCtotal, t1/2, and mean residence time, and decreased the clearance, Vd, markedly as compared with the control group. In rat liver, microsomes BA and AD have shown CYP3A4 inhibitory activity significantly (p < 0.01), compared with the vehicle group. The increase in hypoglycemic action by concomitant administration of glyburide with BA or AD was more in diabetic rats than when the drugs were used singly and with the control group, which suggests the enhancement of glucose reduction capacity of glyburide in diabetic rats along with BA or AD. In PK/PD modeling of BA and AD with glyburide, the predicted PK and PD parameters are in line with the observed PK and PD parameters. The results revealed that BA and AD led to the PK/PD changes because of glyburide-increased bioavailability and because of the inhibition of CYP3A4 enzyme. In conclusion, add-on preparations containing BA or AD may increase the bioavailability of glyburide, and hence the dose should be monitored. PMID:26762235

  10. Pharmacokinetic/Pharmacodynamic Modelling of GnRH Antagonist Degarelix: A Comparison of the Non-linear Mixed-Effects Programs NONMEM and NLME

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Nielsen, Henrik Aalborg;

    2004-01-01

    proposed by Lindstrom and Bates. The two programs were tested using clinical PK/PD data of a new gonadotropin-releasing hormone (GnRH) antagonist degarelix currently being developed for prostate cancer treatment. The pharmacokinetics of intravenous administered degarelix was analysed using a three......In this paper, the two non-linear mixed-effects programs NONMEM and NLME were compared for their use in population pharmacokinetic/pharmacodynamic (PK/PD) modelling. We have described the first-order conditional estimation (FOCE) method as implemented in NONMEM and the alternating algorithm in NLME...

  11. Pharmacokinetic/Pharmacodynamic Modelling of GnRH Antagonist Degarelix: A Comparison of the Non-linear Mixed-Effects Programs NONMEM and NLME

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Nielsen, Henrik Aalborg; Madsen, Henrik; Jonsson, E. Niclas

    2004-01-01

    In this paper, the two non-linear mixed-effects programs NONMEM and NLME were compared for their use in population pharmacokinetic/pharmacodynamic (PK/PD) modelling. We have described the first-order conditional estimation (FOCE) method as implemented in NONMEM and the alternating algorithm in NLME...... proposed by Lindstrom and Bates. The two programs were tested using clinical PK/PD data of a new gonadotropin-releasing hormone (GnRH) antagonist degarelix currently being developed for prostate cancer treatment. The pharmacokinetics of intravenous administered degarelix was analysed using a three...

  12. Modelling hemoglobin and hemoglobin:haptoglobin complex clearance in a non-rodent species– pharmacokinetic and therapeutic implications

    Directory of Open Access Journals (Sweden)

    Felicitas S Boretti

    2014-10-01

    Full Text Available Preclinical studies suggest that haptoglobin (Hp supplementation could be an effective therapeutic modality during acute or chronic hemolytic diseases. Hp prevents Hb extravasation and neutralizes Hb’s oxidative and NO scavenging activity in the vasculature. Small animal models such as mouse, rat and guinea pig appear to be valuable to provide proof-of-concept for Hb neutralization by Hp in diverse pre-clinical conditions. However, these species differ significantly from human in the clearance of Hb:Hp complexes, which leads to long persistence of circulating Hb:Hp complexes after administration of human plasma derived Hp. Alternative animal models must therefore be explored to guide pre-clinical development of these potential therapeutics. In contrast to rodents, dogs have high Hp plasma concentrations comparable to human. In this study we show that like human macrophages, dog peripheral blood monocyte derived macrophages express a glucocorticoid inducible endocytic clearance pathways with a high specificity for the Hb:Hp complex. Evaluating the Beagle dog as a non-rodent model species we provide the first pharmacokinetic parameter estimates of free Hb and Hb:Hp phenotype complexes. The data reflect a drastically reduced volume of distribution (Vc of the complex compared to free Hb, increased exposures (Cmax and AUC and significantly reduced total body clearance (CL with a terminal half-life (t1/2 of approximately 12 hours. Distribution and clearance was identical for dog and human Hb (± glucocorticoid stimulation and for dimeric and multimeric Hp preparations bound to Hb. Collectively, our study supports the dog as a non-rodent animal model to study pharmacological and pharmacokinetic aspects of Hb clearance systems and apply the model to studying Hp therapeutics.

  13. Pharmacokinetic-Pharmacodynamic Analysis on Inflammation Rat Model after Oral Administration of Huang Lian Jie Du Decoction.

    Directory of Open Access Journals (Sweden)

    Wei Ren

    Full Text Available Huang-Lian-Jie-Du Decoction (HLJDD is a classical Traditional Chinese Medicine (TCM formula with heat-dissipating and detoxifying effects. It is used to treat inflammation-associated diseases. However, no systematic pharmacokinetic (PK and pharmacodynamic (PD data concerning the activity of HLJDD under inflammatory conditions is available to date. In the present study, the concentration-time profiles and the hepatic clearance rates (HCR of 41 major components in rat plasma in response to the oral administration of a clinical dose of HLJDD were investigated by LC-QqQ-MS using a dynamic multiple reaction monitoring (DMRM method. Additionally, the levels of 7 cytokines (CKs in the plasma and the body temperature of rats were analyzed. Furthermore, a PK-PD model was established to describe the time course of the hemodynamic and anti-inflammatory effects of HLJDD. As one of the three major active constituents in HLJDD, iridoids were absorbed and eliminated more easily and quickly than alkaloids and flavonoids. Compared with the normal controls, the flavonoids, alkaloids and iridoids in inflamed rats exhibited consistently changing trends of PK behaviors, such as higher bioavailability, slower elimination, delays in reaching the maximum concentration (Tmax and longer substantivity. The HCR of iridoids was different from that of alkaloids and flavonoids in inflamed rats. Furthermore, excellent pharmacodynamic effects of HLJDD were observed in inflamed rats. The levels of tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6, IL-1β, IL-10, and macrophage inflammatory protein-2 (MIP-2 and body temperature significantly decreased after the administration of HLJDD. Based on PK-PD modeling with the three-phase synchronous characterization of time-concentration-effect, flavonoids exhibited one mechanism of action in the anti-inflammatory process, while iridoids and alkaloids showed another mechanism of action. Taken together, the results demonstrated that

  14. Pharmacokinetic-Pharmacodynamic Analysis on Inflammation Rat Model after Oral Administration of Huang Lian Jie Du Decoction

    Science.gov (United States)

    Wang, Yao-Nan; Wang, Hong-Jie; Yang, Jian; Xin, Shao-Kun; Han, Ling-Yu; Zhao, Hai-Yu; Han, Shu-Yan; Gao, Bo; Hu, Hao; Hu, Yuan-Jia; Bian, Bao-Lin; Si, Nan

    2016-01-01

    Huang-Lian-Jie-Du Decoction (HLJDD) is a classical Traditional Chinese Medicine (TCM) formula with heat-dissipating and detoxifying effects. It is used to treat inflammation-associated diseases. However, no systematic pharmacokinetic (PK) and pharmacodynamic (PD) data concerning the activity of HLJDD under inflammatory conditions is available to date. In the present study, the concentration-time profiles and the hepatic clearance rates (HCR) of 41 major components in rat plasma in response to the oral administration of a clinical dose of HLJDD were investigated by LC-QqQ-MS using a dynamic multiple reaction monitoring (DMRM) method. Additionally, the levels of 7 cytokines (CKs) in the plasma and the body temperature of rats were analyzed. Furthermore, a PK-PD model was established to describe the time course of the hemodynamic and anti-inflammatory effects of HLJDD. As one of the three major active constituents in HLJDD, iridoids were absorbed and eliminated more easily and quickly than alkaloids and flavonoids. Compared with the normal controls, the flavonoids, alkaloids and iridoids in inflamed rats exhibited consistently changing trends of PK behaviors, such as higher bioavailability, slower elimination, delays in reaching the maximum concentration (Tmax) and longer substantivity. The HCR of iridoids was different from that of alkaloids and flavonoids in inflamed rats. Furthermore, excellent pharmacodynamic effects of HLJDD were observed in inflamed rats. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, IL-10, and macrophage inflammatory protein-2 (MIP-2) and body temperature significantly decreased after the administration of HLJDD. Based on PK-PD modeling with the three-phase synchronous characterization of time-concentration-effect, flavonoids exhibited one mechanism of action in the anti-inflammatory process, while iridoids and alkaloids showed another mechanism of action. Taken together, the results demonstrated that HLJDD may

  15. Mucosal tissue pharmacokinetics of the integrase inhibitor raltegravir in a humanized mouse model: Implications for HIV pre-exposure prophylaxis.

    Science.gov (United States)

    Veselinovic, Milena; Yang, Kuo-Hsiung; Sykes, Craig; Remling-Mulder, Leila; Kashuba, Angela D M; Akkina, Ramesh

    2016-02-01

    Orally administered anti-retroviral drugs show considerable promise for HIV/AIDS pre-exposure prophylaxis (PrEP). For the success of these strategies, pharmacokinetic (PK) data defining the optimal concentration of the drug needed for protection in relevant mucosal exposure sites is essential. Here we employed a humanized mouse model to derive comprehensive PK data on the HIV integrase inhibitor raltegravir (RAL), a leading PrEP drug candidate. Under steady state conditions following oral dosing, plasma and multiple mucosal tissues were sampled simultaneously. RAL exhibited higher drug exposure in mucosal tissues relative to that in plasma with one log higher exposure in vaginal and rectal tissue and two logs higher exposure in intestinal mucosa reflecting the trends seen in the human studies. These data demonstrate the suitability of RAL for HIV PrEP and validate the utility of humanized mouse models for deriving important preclinical PK-PD data. PMID:26771889

  16. Predicting Pharmacokinetics of Drugs Using Physiologically Based Modeling—Application to Food Effects

    OpenAIRE

    Parrott, N.; Lukacova, V.; Fraczkiewicz, G.; Bolger, M. B.

    2009-01-01

    Our knowledge of the major mechanisms underlying the effect of food on drug absorption allows reliable qualitative prediction based on biopharmaceutical properties, which can be assessed during the pre-clinical phase of drug discovery. Furthermore, several recent examples have shown that physiologically based absorption models incorporating biorelevant drug solubility measurements can provide quite accurate quantitative prediction of food effect. However, many molecules currently in developme...

  17. Biodistribution and pharmacokinetics of monoclonal antibody T1h and variant anti-CD6 murine 10D12 in healthy animals and in experimental arthritis model

    International Nuclear Information System (INIS)

    Biodistribution and pharmacokinetic of two radio labeled monoclonal antibodies was performed with the help of imaging techniques. Isotopic labeling was carried out by means of standardized methods. Pharmacokinetic evaluation was performed using the population approach and sparse data design. Introduction: Targeted therapy with monoclonal antibodies (MAb) is an efficient option for the treatment of rheumatoid arthritis. Th1 is a MAb anti human CD6 developed for the treatment of autoimmune disease and 10D12 is its counterpart anti murine CD6 developed as a pharmacological tool to get deep into the response mechanisms in animals models of rheumatoid arthritis.To investigate the behavior of both antibodies in the assay system, molecules were labeled with 125I to evaluate pharmacokinetic in healthy animals and with 99mTc to evaluate the antibody uptake in inflamed area of induced arthritis. Materials and methods: Antibodies were supplied by the Center of Molecular immunology. Iodination was performed by the iodogen method and technetium labeling was carried out directly by Schwarz method. Female C57BL6 from CENPALAB were used for experiments. Biodistribution and pharmacokinetic was performed by a sparse data design using the population approach. Uptake in region of inflammation was quantified by gammagraphy at the same time points of blood sampling. A compartmental model was build to quantify uptake kinetic. Pharmacokinetic profiles were analyzed using MONOLIX software version 4.2. Results: Minor pharmacokinetic differences were found between monoclonal antibodies labeled with 125I and 99mTc. As a humanized antibody, T1h shows a faster clearance than 10D12 and a biodistribution pattern reflecting preference for excretion mechanisms. The arthritis accumulation was not consistent with a targeted mediated uptake. On the other hand, radio labeled 10D12 shows an accumulation profile in arthritis with two peaks of maximum concentration representing an initial transit to

  18. Estimation of drug dosage regimens with a pharmacokinetic slide rule.

    Science.gov (United States)

    Straughn, A B; Cruze, C A; Meyer, M C

    1977-02-01

    A pharmacokinetic slide rule to facilitate the computations based on relatively simple pharmacokinetic principles involved in the development of individualized drug dosage regimens is described. The calculations are based on the assumption that the body can be conceived as a one-compartment open model with drug elimination proceeding by apparent first-order kinetics. Examples are presented (1) to illustrate the clinical application of a slide rule to compute the time-course of drug in the body, (2) to calculate steady-state maximum and minimum levels, and accumulation during multiple dosage and (3) to estimate appropriate maintenance doses and intravenous infusion rates. PMID:842548

  19. Pharmacokinetics of [18F]flutemetamol in wild-type rodents and its binding to beta amyloid deposits in a mouse model of Alzheimer's disease

    International Nuclear Information System (INIS)

    The aim of this study was to investigate the potential of [18F]flutemetamol as a preclinical PET tracer for imaging β-amyloid (Aβ) deposition by comparing its pharmacokinetics to those of [11C]Pittsburgh compound B ([11C]PIB) in wild-type Sprague Dawley rats and C57Bl/6N mice. In addition, binding of [18F]flutemetamol to Aβ deposits was studied in the Tg2576 transgenic mouse model of Alzheimer's disease. [18F]Flutemetamol biodistribution was evaluated using ex vivo PET methods and in vivo PET imaging in wild-type rats and mice. Metabolism and binding of [11C]PIB and [18F]flutemetamol to plasma proteins were analysed using thin-layer chromatography and ultrafiltration methods, respectively. Radiation dose estimates were calculated from rat ex vivo biodistribution data. The binding of [18F]flutemetamol to Aβ deposits was also studied using ex vivo and in vitro autoradiography. The location of Aβ deposits in the brain was determined with thioflavine S staining and immunohistochemistry. The pharmacokinetics of [18F]flutemetamol resembled that of [11C]PIB in rats and mice. In vivo studies showed that both tracers readily entered the brain, and were excreted via the hepatobiliary pathway in both rats and mice. The metabolism of [18F]flutemetamol into radioactive metabolites was faster than that of [11C]PIB. [18F]Flutemetamol cleared more slowly from the brain than [11C]PIB, particularly from white matter, in line with its higher lipophilicity. Effective dose estimates for [11C]PIB and [18F]flutemetamol were 2.28 and 6.65 μSv/MBq, respectively. Autoradiographs showed [18F]flutemetamol binding to fibrillar Aβ deposits in the brain of Tg2576 mice. Based on its pharmacokinetic profile, [18F]flutemetamol showed potential as a PET tracer for preclinical imaging. It showed good brain uptake and was bound to Aβ deposits in the brain of Tg2576 mice. However, its high lipophilicity might complicate the analysis of PET data, particularly in small-animal imaging. (orig.)

  20. Development of a population pharmacokinetic model to describe azithromycin whole-blood and plasma concentrations over time in healthy subjects.

    Science.gov (United States)

    Pene Dumitrescu, T; Anic-Milic, T; Oreskovic, K; Padovan, J; Brouwer, K L R; Zuo, P; Schmith, V D

    2013-07-01

    Azithromycin (AZI), a broad-spectrum antibiotic, accumulates in polymorphonuclear cells and peripheral blood mononuclear cells. The distribution of AZI in proinflammatory cells may be important to the anti-inflammatory properties. Previous studies have described plasma AZI pharmacokinetics. The objective of this study was to describe the pharmacokinetics of AZI in whole blood (concentration in whole blood [Cb]) and plasma (concentration in plasma [Cp]) of healthy subjects. In this study, 12 subjects received AZI (500 mg once a day for 3 days). AZI Cb and Cp were quantified in serial samples collected up to 3 weeks after the last dose and analyzed using noncompartmental and compartmental methods. After the last dose, Cb was greater than Cp. Importantly, Cb, but not Cp, was quantifiable in all but one subject at 3 weeks. The blood area under the curve during a 24-h dosing interval (AUC24) was ∼2-fold greater than the plasma AUC24, but simulations suggested that Cb was not at steady state by day 3. Upon exploration of numerous models, an empirical 3-compartment model adequately described Cp and Cb, but Cp was somewhat underestimated. Intercompartmental clearance (CL; likely representing cells) was lower than apparent oral CL (18 versus 118 liters/h). Plasma, peripheral, and cell compartmental volumes were 439 liters, 2,980 liters, and 3,084 liters, respectively. Interindividual variability in CL was low (26.2%), while the volume of distribution variability was high (107%). This is the first report to describe AZI Cb in healthy subjects, the distribution parameters between Cp and Cb, and AZI retention in blood for up to 3 weeks following 3 daily doses. The model can be used to predict Cb from Cp for AZI under various dosing regimens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01026064.). PMID:23629714

  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)

    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. 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.)

  3. PK-PD Modeling of Fluoroquinolones and ABC Transporters in Poultry

    NARCIS (Netherlands)

    Haritova, A.M.

    2006-01-01

    In the first part of this thesis advance pharmacokinetic models, based on an integration of pharmacokinetic and pharmacodynamic data for selected fluotoquinolones, are presented. The comparative investigations with danofloxacin mesylate and marbofloxacin indicated that with both fluoroquinolones a c

  4. Pharmacokinetic Analysis of 11C-PBR28 in the Rat Model of Herpes Encephalitis: Comparison with (R)-11C-PK11195.

    Science.gov (United States)

    Parente, Andrea; Feltes, Paula Kopschina; Vállez García, David; Sijbesma, Jurgen W A; Moriguchi Jeckel, Cristina M; Dierckx, Rudi A J O; de Vries, Erik F J; Doorduin, Janine

    2016-05-01

    (11)C-PBR28 is a second-generation translocator protein (TSPO) tracer with characteristics supposedly superior to the most commonly used tracer for neuroinflammation, (R)-(11)C-PK11195. Despite its use in clinical research, no studies on the imaging properties and pharmacokinetic analysis of (11)C-PBR28 in rodent models of neuroinflammation have been published yet. Therefore, this study aimed to evaluate (11)C-PBR28 as a tool for detection and quantification of neuroinflammation in preclinical research and to compare its imaging properties with (R)-(11)C-PK11195. The herpes simplex encephalitis (HSE) model was used for induction of neuroinflammation in male Wistar rats. Six or 7 d after virus inoculation, a dynamic (11)C-PBR28 or (R)-(11)C-PK11195 PET scan with arterial blood sampling was obtained. Pharmacokinetic modeling was performed on the PET data and analyzed using volumes of interest and a voxel-based approach. Volume-of-interest- and voxel-based analysis of (11)C-PBR28 images showed overexpression of TSPO in brain regions known to be affected in the HSE rat model. (11)C-PBR28 was metabolized faster than (R)-(11)C-PK11195, with a metabolic half-life in plasma of 5 and 21 min, respectively. Overall, (11)C-PBR28 was more sensitive than (R)-(11)C-PK11195 in detecting neuroinflammation. The binding potential (BPND) of (11)C-PBR28 was significantly higher (P < 0.05) in the medulla (176%), pons (146%), midbrain (101%), hippocampus (85%), thalamus (73%), cerebellum (54%), and hypothalamus (49%) in HSE rats than in control rats, whereas (R)-(11)C-PK11195 showed a higher BPND only in the medulla (32%). The BPND in control animals was not significantly different between tracers, suggesting that the nonspecific binding of both tracers is similar. (11)C-PBR28 was more sensitive than (R)-(11)C-PK11195 in the detection of TSPO overexpression in the HSE rat model, because more brain regions with significantly increased tracer uptake could be found, irrespective of the data

  5. Integrative pharmacokinetic-pharmacodynamic modeling and simulation of amenamevir (ASP2151) for treatment of recurrent genital herpes.

    Science.gov (United States)

    Takada, Akitsugu; Katashima, Masataka; Kaibara, Atsunori; Chono, Koji; Katsumata, Kiyomitsu; Sawamoto, Taiji; Suzuki, Hiroshi; Yano, Yoshitaka

    2016-08-01

    Amenamevir is a novel drug that targets the viral helicase-primase complex. While dose-dependent efficacy had been observed in non-clinical studies, no clear dose dependence has been observed in humans. We therefore developed a pharmacokinetic/pharmacodynamic (PK/PD) model to explain this inconsistency between species and to clarify the immune-related healing of amenamevir in humans. The model consisted of a non-linear kinetic model for a virtual number of virus plaques as a built-in biomarker. Lesion score was defined as an endpoint of antiviral efficacy, and logit model analysis was applied to the ordered-categorical lesion score. The modeling results suggested the time course profiles of lesion score could be explained with the efficacy terms in the logit model, using change in number of virus plaques as an indicator of the effects of amenamevir and time elapsed as an indicator of the healing of the immune response. In humans, the PD effect was almost dose-independent, and immune-related healing may have been the driving force behind the reduction in lesion scores. Drug efficacy is occasionally masked in diseases healed by the immune response, such as genital herpes. The PK/PD model proposed in the present study must be useful for explanation the PK/PD relationship of such drugs. PMID:27461507

  6. Physiologically based synthetic models of hepatic disposition.

    Science.gov (United States)

    Hunt, C Anthony; Ropella, Glen E P; Yan, Li; Hung, Daniel Y; Roberts, Michael S

    2006-12-01

    Current physiologically based pharmacokinetic (PBPK) models are inductive. We present an additional, different approach that is based on the synthetic rather than the inductive approach to modeling and simulation. It relies on object-oriented programming. A model of the referent system in its experimental context is synthesized by assembling objects that represent components such as molecules, cells, aspects of tissue architecture, catheters, etc. The single pass perfused rat liver has been well described in evaluating hepatic drug pharmacokinetics (PK) and is the system on which we focus. In silico experiments begin with administration of objects representing actual compounds. Data are collected in a manner analogous to that in the referent PK experiments. The synthetic modeling method allows for recognition and representation of discrete event and discrete time processes, as well as heterogeneity in organization, function, and spatial effects. An application is developed for sucrose and antipyrine, administered separately and together. PBPK modeling has made extensive progress in characterizing abstracted PK properties but this has also been its limitation. Now, other important questions and possible extensions emerge. How are these PK properties and the observed behaviors generated? The inherent heuristic limitations of traditional models have hindered getting meaningful, detailed answers to such questions. Synthetic models of the type described here are specifically intended to help answer such questions. Analogous to wet-lab experimental models, they retain their applicability even when broken apart into sub-components. Having and applying this new class of models along with traditional PK modeling methods is expected to increase the productivity of pharmaceutical research at all levels that make use of modeling and simulation. PMID:17051440

  7. Tolerability and Pharmacokinetic Evaluation of Inhaled Dry Powder Tobramycin Free Base in Non-Cystic Fibrosis Bronchiectasis Patients.

    Directory of Open Access Journals (Sweden)

    Marcel Hoppentocht

    Full Text Available Bronchiectasis is a condition characterised by dilated and thick-walled bronchi. The presence of Pseudomonas aeruginosa in bronchiectasis is associated with a higher hospitalisation frequency and a reduced quality of life, requiring frequent and adequate treatment with antibiotics.To assess local tolerability and the pharmacokinetic parameters of inhaled excipient free dry powder tobramycin as free base administered with the Cyclops dry powder inhaler to participants with non-cystic fibrosis bronchiectasis. The free base and absence of excipients reduces the inhaled powder dose.Eight participants in the study were trained in handling the device and inhaling correctly. During drug administration the inspiratory flow curve was recorded. Local tolerability was assessed by spirometry and recording adverse events. Serum samples were collected before, and 15, 30, 45, 60, 75, 90, 105, 120 min; 4, 8 and 12 h after inhalation.Dry powder tobramycin base was well tolerated and mild tobramycin-related cough was reported only once. A good drug dose-serum concentration correlation was obtained. Relatively small inhaled volumes were computed from the recorded flow curves, resulting in presumably substantial deposition in the central airways-i.e., at the site of infection.In this first study of inhaled dry powder tobramycin free base in non-cystic fibrosis bronchiectasis patients, the free base of tobramycin and the administration with the Cyclops dry powder device were well tolerated. Our data support further clinical studies to evaluate safety and efficacy of this compound in this population.

  8. Tolerability and Pharmacokinetic Evaluation of Inhaled Dry Powder Tobramycin Free Base in Non-Cystic Fibrosis Bronchiectasis Patients

    Science.gov (United States)

    Hagedoorn, Paul; Alffenaar, Jan-Willem C.; van der Werf, Tjip S.; Kerstjens, Huib A. M.; Frijlink, Henderik W.; de Boer, Anne H.

    2016-01-01

    Rationale Bronchiectasis is a condition characterised by dilated and thick-walled bronchi. The presence of Pseudomonas aeruginosa in bronchiectasis is associated with a higher hospitalisation frequency and a reduced quality of life, requiring frequent and adequate treatment with antibiotics. Objectives To assess local tolerability and the pharmacokinetic parameters of inhaled excipient free dry powder tobramycin as free base administered with the Cyclops dry powder inhaler to participants with non-cystic fibrosis bronchiectasis. The free base and absence of excipients reduces the inhaled powder dose. Methods Eight participants in the study were trained in handling the device and inhaling correctly. During drug administration the inspiratory flow curve was recorded. Local tolerability was assessed by spirometry and recording adverse events. Serum samples were collected before, and 15, 30, 45, 60, 75, 90, 105, 120 min; 4, 8 and 12 h after inhalation. Results and Discussion Dry powder tobramycin base was well tolerated and mild tobramycin-related cough was reported only once. A good drug dose-serum concentration correlation was obtained. Relatively small inhaled volumes were computed from the recorded flow curves, resulting in presumably substantial deposition in the central airways—i.e., at the site of infection. Conclusions In this first study of inhaled dry powder tobramycin free base in non-cystic fibrosis bronchiectasis patients, the free base of tobramycin and the administration with the Cyclops dry powder device were well tolerated. Our data support further clinical studies to evaluate safety and efficacy of this compound in this population. PMID:26959239

  9. Exploration and Pharmacokinetic Profiling of Phenylalanine Based Carbamates as Novel Substance P 1–7 Analogues

    Science.gov (United States)

    2014-01-01

    The bioactive metabolite of Substance P, the heptapeptide SP1–7 (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), has been shown to attenuate signs of hyperalgesia in diabetic mice, which indicate a possible use of compounds targeting the SP1–7 binding site as analgesics for neuropathic pain. Aiming at the development of drug-like SP1–7 peptidomimetics we have previously reported on the discovery of H-Phe-Phe-NH2 as a high affinity lead compound. Unfortunately, the pharmacophore of this compound was accompanied by a poor pharmacokinetic (PK) profile. Herein, further lead optimization of H-Phe-Phe-NH2 by substituting the N-terminal phenylalanine for a benzylcarbamate group giving a new type of SP1–7 analogues with good binding affinities is reported. Extensive in vitro as well as in vivo PK characterization is presented for this compound. Evaluation of different C-terminal functional groups, i.e., hydroxamic acid, acyl sulfonamide, acyl cyanamide, acyl hydrazine, and oxadiazole, suggested hydroxamic acid as a bioisosteric replacement for the original primary amide. PMID:25516784

  10. Exploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance p 1-7 analogues.

    Science.gov (United States)

    Fransson, Rebecca; Nordvall, Gunnar; Bylund, Johan; Carlsson-Jonsson, Anna; Kratz, Jadel M; Svensson, Richard; Artursson, Per; Hallberg, Mathias; Sandström, Anja

    2014-12-11

    The bioactive metabolite of Substance P, the heptapeptide SP1-7 (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), has been shown to attenuate signs of hyperalgesia in diabetic mice, which indicate a possible use of compounds targeting the SP1-7 binding site as analgesics for neuropathic pain. Aiming at the development of drug-like SP1-7 peptidomimetics we have previously reported on the discovery of H-Phe-Phe-NH2 as a high affinity lead compound. Unfortunately, the pharmacophore of this compound was accompanied by a poor pharmacokinetic (PK) profile. Herein, further lead optimization of H-Phe-Phe-NH2 by substituting the N-terminal phenylalanine for a benzylcarbamate group giving a new type of SP1-7 analogues with good binding affinities is reported. Extensive in vitro as well as in vivo PK characterization is presented for this compound. Evaluation of different C-terminal functional groups, i.e., hydroxamic acid, acyl sulfonamide, acyl cyanamide, acyl hydrazine, and oxadiazole, suggested hydroxamic acid as a bioisosteric replacement for the original primary amide. PMID:25516784

  11. Effects of Ginkgo biloba extracts on pharmacokinetics and efficacy of atorvastatin based on plasma indices.

    Science.gov (United States)

    Guo, Cheng-Xian; Pei, Qi; Yin, Ji-Ye; Peng, Xiang-Dong; Zhou, Bo-Ting; Zhao, Ying-Chun; Wu, Lan-Xiang; Meng, Xiang-Guang; Wang, Guo; Li, Qing; Ouyang, Dong-Sheng; Liu, Zhao-Qian; Zhang, Wei; Zhou, Hong-Hao

    2012-08-01

    Ginkgo biloba extract (GBE) is one of the most widely used herbal medicines in the world. It is often administered in combination with statins to treat diseases, especially some nervous system disorders. We aimed to investigate the influences of GBE on pharmacokinetics and efficacy of atorvastatin, which are currently unclear. Sixteen volunteers received a single oral dose of 40 mg atorvastatin, followed by a wash-out period of at least 5 days. Then the volunteers took 360 mg GBE daily for 14 days, followed by a single dose of 40 mg atorvastatin. Serial blood samples obtained over a period of 48 h after atorvastatin ingestion were subjected to determination of atorvastatin plasma concentrations and markers of cholesterol synthesis (lathosterol) and cholesterol absorption (sitosterol). With GBE administration, AUC₀₋₄₈, AUC(₀-∞) and C(max) of atorvastatin were reduced by 14.27% (p = 0.005), 10.00% (p = 0.03) and 28.93% (p = 0.002), respectively; Vd/F and CL/F of atorvastatin were increased by 31.95% (p = 0.017) and 6.48% (p = 0.044). After 14 days of treatment, GBE has no significant effects on cholesterol-lowering efficacy of atorvastatin. This study suggests that GBE slightly decreases the plasma atorvastatin concentrations, but has no meaningful effect on the cholesterol-lowering efficacy of atorvastatin. PMID:22381135

  12. Pharmacokinetic modelling of N-(4-[{sup 18}F]fluorobenzoyl)interleukin-2 binding to activated lymphocytes in an xenograft model of inflammation

    Energy Technology Data Exchange (ETDEWEB)

    di Gialleonardo, Valentina; Signore, Alberto [University, Nuclear Medicine Unit, Faculty of Medicine and Psychology, Rome (Italy); University, Medicina Nucleare, Ospedale S.Andrea, Rome (Italy); Willemsen, Antoon T.M.; Sijbesma, Jurgen W.A.; Dierckx, Rudi A.J.O.; Vries, Erik F.J. de [University, Nuclear Medicine Unit, Faculty of Medicine and Psychology, Rome (Italy)

    2012-10-15

    N-(4-[{sup 18}F]Fluorobenzoyl)interleukin-2 ([{sup 18}F]FB-IL2) specifically binds to interleukin-2 receptors (IL-2R) and thus may be used to detect inflammation processes using positron emission tomography (PET). We now validated whether [{sup 18}F]FB-IL2 can be used to quantify activated human peripheral blood mononuclear cells (hPBMC) in rats by pharmacokinetic modelling. Eleven Wistar rats were subcutaneously inoculated in the shoulder with different amounts of phytohaemagglutinin (PHA) activated hPBMC 15 min before i.v. injection of [{sup 18}F]FB-IL2. A 60-min dynamic PET scan was acquired and arterial blood sampling and metabolite analysis were performed. At the end of the scan, animals were terminated and the inflammatory lesion dissected. PET data were analysed using Logan and Patlak analysis as well as one-tissue and two-tissue compartment models. Model preferences according to the Akaike information criterion (AIC) and correlation between PET measurements and the number of CD25-positive cells were evaluated. A high correlation between ex vivo tracer uptake (standardized uptake value) in the xenograft and the number of inoculated CD25-positive cells was observed (R {sup 2} = 0.90). Plasma time-activity curves showed a rapid washout of the radiopharmaceutical from blood, while the time-activity curves of the inflammatory lesions showed slower washout. Time-activity curves could be fitted well by the Logan analysis method, indicating that the binding between [{sup 18}F]FB-IL2 and CD25 is reversible. AIC indicated that data could be modelled best by a two-tissue reversible compartment model. A high correlation was observed between the binding potential and the number of CD25-positive cells (R {sup 2} = 0.876, p < 0.0001). Based on binding potential measured by PET, the limit of detection was about 160,000 CD25-positive cells per 200 {mu}l lesion (95 % confidence). [{sup 18}F]FB-IL2 kinetics in this animal model of inflammation could be best described by a

  13. Modeling of pharmacokinetics of cocaine in human reveals the feasibility for development of enzyme therapies for drugs of abuse.

    Directory of Open Access Journals (Sweden)

    Fang Zheng

    Full Text Available A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly dependent on the initial cocaine concentration in plasma. The threshold concentration of cocaine in brain required to produce physiological effects has been estimated to be 0.22±0.07 µM, and the threshold area under the cocaine concentration versus time curve (AUC value in brain (denoted by AUC2(∞ required to produce physiological effects has been estimated to be 7.9±2.7 µM·min. It has been demonstrated that administration of a cocaine hydrolase/esterase (CocH/CocE can considerably decrease the cocaine half-lives in both brain and plasma, the peak cocaine concentration in brain, and the AUC2(∞. The estimated maximum cocaine plasma concentration which a given concentration of drug-metabolizing enzyme can effectively prevent from entering brain and producing physiological effects can be used to guide future preclinical/clinical studies on cocaine-metabolizing enzymes. Understanding of drug-metabolizing enzymes is key to the science of pharmacokinetics. The general insights into the effects of a drug-metabolizing enzyme on drug kinetics in human should be valuable also in future development of enzyme therapies for other drugs of abuse.

  14. Transform-both-sides nonlinear models for in vitro pharmacokinetic experiments.

    Science.gov (United States)

    Latif, A H M Mahbub; Gilmour, Steven G

    2015-06-01

    Transform-both-sides nonlinear models have proved useful in many experimental applications including those in pharmaceutical sciences and biochemistry. The maximum likelihood method is commonly used to fit transform-both-sides nonlinear models, where the regression and transformation parameters are estimated simultaneously. In this paper, an analysis of variance-based method is described in detail for estimating transform-both-sides nonlinear models from randomized experiments. It estimates the transformation parameter from the full treatment model and then the regression parameters are estimated conditionally on this estimate of the transformation parameter. The analysis of variance method is computationally simpler compared with the maximum likelihood method of estimation and allows a more natural separation of different sources of lack of fit. Simulation studies show that the analysis of variance method can provide unbiased estimators of complex transform-both-sides nonlinear models, such as transform-both-sides random coefficient nonlinear regression models and transform-both-sides fixed coefficient nonlinear regression models with random block effects. PMID:25038072

  15. Pharmacokinetics of ciprofloxacin in ponies.

    Science.gov (United States)

    Dowling, P M; Wilson, R C; Tyler, J W; Duran, S H

    1995-02-01

    The pharmacokinetics of ciprofloxacin was investigated in healthy, mature ponies. Ciprofloxacin was administered intravenously to six ponies at a dose of 5 mg per kg body weight. Seven days later, ciprofloxacin was administered orally to each pony at the same dose. Intravenous ciprofloxacin concentration vs. time data best fit a two-compartment open model with first-order elimination from the central compartment. Mean plasma half-life, based on the terminal phase, was 157.89 min (harmonic mean). Total body clearance of ciprofloxacin was 18.12 +/- 3.99 mL/min/kg. Volume of distribution at steady-state was 3.45 +/- 0.72 L/kg. From the pharmacokinetic data and reported minimum inhibitory concentrations for equine gram-negative pathogens, the appropriate dosage of ciprofloxacin was determined to be 5.32 mg per kg body weight at 12 h intervals. Bioavailability of oral ciprofloxacin in ponies was 6.8 +/- 5.33%. Owing to the poor bioavailability, a dosage regimen could not be proposed for oral ciprofloxacin administration in horses. Ciprofloxacin concentrations were determined in tissues and body fluids at 1, 2 and 4 h after intravenous administration. At all times, tissue concentrations exceeded plasma concentrations of ciprofloxacin. Highest concentrations were achieved in kidneys and urine. Potentially therapeutic concentrations were obtained in cerebrospinal and joint fluid, but low concentrations were achieved in aqueous humour. PMID:7752310

  16. Marginal iodide deficiency and thyroid function: Dose-response analysis for quantitative pharmacokinetic modeling

    International Nuclear Information System (INIS)

    Severe iodine deficiency (ID) results in adverse health outcomes and remains a benchmark for understanding the effects of developmental hypothyroidism. The implications of marginal ID, however, remain less well known. The current study examined the relationship between graded levels of ID in rats and serum thyroid hormones, thyroid iodine content, and urinary iodide excretion. The goals of this study were to provide parametric and dose-response information for development of a quantitative model of the thyroid axis. Female Long Evans rats were fed casein-based diets containing varying iodine (I) concentrations for 8 weeks. Diets were created by adding 975, 200, 125, 25, or 0 μg/kg I to the base diet (∼25 μg I/kg chow) to produce 5 nominal I levels, ranging from excess (basal + added I, Treatment 1: 1000 μg I/kg chow) to deficient (Treatment 5: 25 μg I/kg chow). Food intake and body weight were monitored throughout and on 2 consecutive days each week over the 8-week exposure period, animals were placed in metabolism cages to capture urine. Food, water intake, and body weight gain did not differ among treatment groups. Serum T4 was dose-dependently reduced relative to Treatment 1 with significant declines (19 and 48%) at the two lowest I groups, and no significant changes in serum T3 or TSH were detected. Increases in thyroid weight and decreases in thyroidal and urinary iodide content were observed as a function of decreasing I in the diet. Data were compared with predictions from a recently published biologically based dose-response (BBDR) model for ID. Relative to model predictions, female Long Evans rats under the conditions of this study appeared more resilient to low I intake. These results challenge existing models and provide essential information for development of quantitative BBDR models for ID during pregnancy and lactation.

  17. Pharmacokinetic Properties of Cytokines in Their Targeted Delivery Based on Autologous Erythrocyte Pharmacocytes

    Directory of Open Access Journals (Sweden)

    Zhaxybay Zhumadilov

    2014-12-01

    Full Text Available Introduction. Using autologous erythrocytes as drug carriers for targeted delivery of cytokines to the sites of inflammation could potentially provide new opportunities for treatment of patients with purulent diseases. The targeted characteristic of erythrocytes is associated with the nature of purulent inflammation, where a large amount of erythrocytes is phagocytized and drugs encapsulated into the erythrocytes could be easily released. On the other hand, autologous erythrocytes meet all the criteria for the ideal drug carrier. They are nontoxic, not immunogenic, and able to bear a large number of drug molecules while preserving an original conformation of the drugs. Thus, in this study, we aimed to analyze pharmacokinetic profiles of IL-1β encapsulated into erythrocytes’ ghosts (pharmacocytes in comparison to intravenously injected free IL-1β.Material and methods. Albino rats were randomly divided into two groups, each group receiving a different kind of IV injection via the tail vein. Group A (control received 500 µg of free IL-1β, and group B received an injection of 1 ml of pharmacocytes loaded with 500 µg of test substance. At fixed time points after injection (15, 30, 60, 180, 540, 720, and 1,440 minutes serum samples were collected. Homogenates of liver, spleen, lung, heart, kidney, and adipose tissue were obtained 24 hours after injections. Concentration of the tested substance in the collected organs and blood plasma were measured by ELISA. Results. We have observed an increased half-life period (T1/2 for encapsulated IL-1β compared to the control. T1/2 for free IL-1β was one hour, while administration of loaded pharmacocytes allowed the half-life period to increase by more than 15 fold (1,043.40 ± 137.92 min preserving high level of IL-1β activity in the blood samples up to 24 hours. The increased time of IL-1β presence in the body when administered in the form of pharmacocytes could be explained by reduction of

  18. Pharmacokinetics and pharmacodynamics evaluation of a thermosensitive chitosan based hydrogel containing liposomal doxorubicin.

    Science.gov (United States)

    Ren, Shuangxia; Dai, Yu; Li, Cuiyun; Qiu, Zhixia; Wang, Xin; Tian, Fengjie; Zhou, Sufeng; Liu, Qi; Xing, Han; Lu, Yang; Chen, Xijing; Li, Ning

    2016-09-20

    In situ gelling thermosensitive hydrogel formulation has been reported to effectively sustain the release of macromolecules for a long time. However, the low-molecular-weight hydrophilic drugs, such as doxorubicin (DOX), are not suitable for intratumoral injection because the release will complete within one day. In this study, liposomal doxorubicin (LipDOX) was added into the hydrogel to form a novel thermosensitive formulation which prolonged the sustained release of DOX. DOX+C/GP (doxorubicin in chitosan/β-glycerophosphate) was prepared to compare with LipDOX+C/GP (liposomal doxorubicin in chitosan/β-glycerophosphate hydrogel). The particle size of DOX-loaded liposome was 94.2nm and the encapsulation efficiency of DOX was near 98%. In vitro release experiments, the release of DOX in both DOX+C/GP group and LipDOX+C/GP group increased along with the increasing pH of buffers. However, the LipDOX+C/GP group with lower initial burst release had a much longer releasing duration than DOX+C/GP group (21days vs. 24h). In vitro and in vivo antitumor experiments demonstrated that LipDOX+C/GP group had better antineoplastic effect and less toxicity than DOX+C/GP group. Pharmacokinetics study showed LipDOX+C/GP exhibited a higher AUC0-t and longer MRT than DOX+C/GP in blood and tumor, which indicated that LipDOX+C/GP obtained an enhanced antitumor activity compared with DOX+C/GP. In addition, the lower distribution index (the ratio of AUC of normal tissue/AUC of tumor tissue) of the LipDOX+C/GP implied it had lower toxicity to normal tissues than DOX+C/GP. Therefore, the novel thermosensitive hydrogel formulation was potential for clinical application in cancer treatment. PMID:27388491

  19. 4-Aminopyridyl-based CYP51 inhibitors as anti-Trypanosoma cruzi drug leads with improved pharmacokinetic profile and in vivo potency.

    Science.gov (United States)

    Calvet, Claudia M; Vieira, Debora F; Choi, Jun Yong; Kellar, Danielle; Cameron, Michael D; Siqueira-Neto, Jair Lage; Gut, Jiri; Johnston, Jonathan B; Lin, Li; Khan, Susan; McKerrow, James H; Roush, William R; Podust, Larissa M

    2014-08-28

    CYP51 is a P450 enzyme involved in the biosynthesis of the sterol components of eukaryotic cell membranes. CYP51 inhibitors have been developed to treat infections caused by fungi, and more recently the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. To specifically optimize drug candidates for T. cruzi CYP51 (TcCYP51), we explored the structure-activity relationship (SAR) of a N-indolyl-oxopyridinyl-4-aminopropanyl-based scaffold originally identified in a target-based screen. This scaffold evolved via medicinal chemistry to yield orally bioavailable leads with potent anti-T. cruzi activity in vivo. Using an animal model of infection with a transgenic T. cruzi Y luc strain expressing firefly luciferase, we prioritized the biaryl and N-arylpiperazine analogues by oral bioavailability and potency. The drug-target complexes for both scaffold variants were characterized by X-ray structure analysis. Optimization of both binding mode and pharmacokinetic properties of these compounds led to potent inhibitors against experimental T. cruzi infection. PMID:25101801

  20. Physiologically based pharmacokinetics in Drug Development and Regulatory Science: A workshop report (Georgetown University, Washington, DC, May 29–30, 2002)

    OpenAIRE

    Rowland, Malcolm; Balant, Luc; Peck, Carl

    2004-01-01

    A 2-day workshop on “Physiologically Based Pharmacokinetics (PBPK) in Drug Development and Regulatory Science” came to a successful conclusion on May 30, 2002, in Washington, DC. More than 120 international participants from the environmental and predominantly pharmaceutical industries, Food and Drug Administration (FDA), and universities attended this workshop, organized by the Center for Drug Development Science, Georgetown University, Washington, DC. The first of its kind specifically devo...

  1. Population Pharmacokinetic Analysis of Voriconazole from a Pharmacokinetic Study with Immunocompromised Japanese Pediatric Subjects

    OpenAIRE

    Muto, Chieko; Shoji, Satoshi; Tomono, Yoshiro; Liu, Ping

    2015-01-01

    A population pharmacokinetic (PK) analysis was conducted to characterize the voriconazole pharmacokinetic profiles in immunocompromised Japanese pediatric subjects and to compare them to those in immunocompromised non-Japanese pediatric subjects. A previously developed two-compartment pharmacokinetic model with first-order absorption and mixed linear and nonlinear elimination adequately described the voriconazole intravenous and oral data from Japanese pediatric subjects with few modification...

  2. Quantitative 2- and 3-dimensional analysis of pharmacokinetic model-derived variables for breast lesions in dynamic, contrast-enhanced MR mammography

    International Nuclear Information System (INIS)

    Purpose: 2- and 3-dimensional evaluation of quantitative pharmacokinetic parameters derived from the Tofts model modeling dynamic contrast enhancement of lesions in MR mammography. Materials and methods: In 95 patients, MR mammography revealed 127 suspicious lesions. The initial rate of enhancement was coded by color intensity, the post-initial enhancement change is coded by color hue. 2D and 3D analysis of distribution of color hue and intensity, vascular permeability and extracellular volume were performed. Results: In 2D, malignant lesions showed significant higher number of bright red, medium red, dark red, bright green, medium green, dark green and bright blue pixels than benign lesions. In 3D, statistical significant differences between malignant and benign lesions was found for all this parameters. Vascular permeability was significant higher in malignant lesions than in benign lesions. Regression model using the 3D data found that the best discriminator between malignant and benign lesions was combined number of voxels and medium green pixels, with a sensitivity of 79.4% and a specificity of 83.1%. Conclusions: Quantitative analysis of pharmacokinetic variables of contrast kinetics showed significant differences between malignant and benign lesions. 3D analysis showed superior diagnostic differentiation between malignant and benign lesions than 2D analysis. The parametric analysis using a pharmacokinetic model allows objective analysis of contrast enhancement in breast lesions

  3. A Bloch-McConnell simulator with pharmacokinetic modeling to explore accuracy and reproducibility in the measurement of hyperpolarized pyruvate

    Science.gov (United States)

    Walker, Christopher M.; Bankson, James A.

    2015-03-01

    Magnetic resonance imaging (MRI) of hyperpolarized (HP) agents has the potential to probe in-vivo metabolism with sensitivity and specificity that was not previously possible. Biological conversion of HP agents specifically for cancer has been shown to correlate to presence of disease, stage and response to therapy. For such metabolic biomarkers derived from MRI of hyperpolarized agents to be clinically impactful, they need to be validated and well characterized. However, imaging of HP substrates is distinct from conventional MRI, due to the non-renewable nature of transient HP magnetization. Moreover, due to current practical limitations in generation and evolution of hyperpolarized agents, it is not feasible to fully experimentally characterize measurement and processing strategies. In this work we use a custom Bloch-McConnell simulator with pharmacokinetic modeling to characterize the performance of specific magnetic resonance spectroscopy sequences over a range of biological conditions. We performed numerical simulations to evaluate the effect of sequence parameters over a range of chemical conversion rates. Each simulation was analyzed repeatedly with the addition of noise in order to determine the accuracy and reproducibility of measurements. Results indicate that under both closed and perfused conditions, acquisition parameters can affect measurements in a tissue dependent manner, suggesting that great care needs to be taken when designing studies involving hyperpolarized agents. More modeling studies will be needed to determine what effect sequence parameters have on more advanced acquisitions and processing methods.

  4. Synergistic Activity of Colistin and Rifampin Combination against Multidrug-Resistant Acinetobacter baumannii in an In Vitro Pharmacokinetic/Pharmacodynamic Model

    OpenAIRE

    Lee, Hee Ji; Bergen, Phillip J.; Bulitta, Jurgen B.; Tsuji, Brian; Forrest, Alan; Nation, Roger L; Jian LI

    2013-01-01

    Combination therapy may be required for multidrug-resistant (MDR) Acinetobacter baumannii. This study systematically investigated bacterial killing and emergence of colistin resistance with colistin and rifampin combinations against MDR A. baumannii. Studies were conducted over 72 h in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model at inocula of ∼106 and ∼108 CFU/ml using two MDR clinical isolates of A. baumannii, FADDI-AB030 (colistin susceptible) and FADDI-AB156 (colistin resis...

  5. The Combination of Colistin and Doripenem Is Synergistic against Klebsiella pneumoniae at Multiple Inocula and Suppresses Colistin Resistance in an In Vitro Pharmacokinetic/Pharmacodynamic Model

    OpenAIRE

    Deris, Zakuan Z.; Yu, Heidi H.; Davis, Kathryn; Soon, Rachel L; Jacob, Jovan; Ku, Caron K.; Poudyal, Anima; Bergen, Phillip J.; Tsuji, Brian T.; Bulitta, Jurgen B.; Forrest, Alan; Paterson, David L.; Velkov, Tony; Jian LI; Nation, Roger L

    2012-01-01

    Multidrug-resistant (MDR) Klebsiella pneumoniae may require combination therapy. We systematically investigated bacterial killing with colistin and doripenem mono- and combination therapy against MDR K. pneumoniae and emergence of colistin resistance. A one-compartment in vitro pharmacokinetic/pharmacodynamic model was employed over a 72-h period with two inocula (∼106 and ∼108 CFU/ml); a colistin-heteroresistant reference strain (ATCC 13883) and three clinical isolates (colistin-susceptible ...

  6. Bama Miniature Pigs (Sus scrofa domestica) as a Model for Drug Evaluation for Humans: Comparison of In Vitro Metabolism and In Vivo Pharmacokinetics of Lovastatin

    OpenAIRE

    Liu, Yu; Zeng, Ben-Hua; Shang, Hai-tao; Cen, Yan-Yan; Wei, Hong

    2008-01-01

    The objective of this study was to demonstrate that Bama miniature pigs are a suitable experimental animal model for the evaluation of drugs for man. To this end, in vitro lovastatin metabolism at the minipig liver microsomal level and in vivo pharmacokinetics were studied. Results were compared with those obtained from humans. Our data indicate that the main metabolites and enzyme kinetic parameters of lovastatin metabolism are similar in pigs and humans. Triacetyloleandomycin, a specific in...

  7. Elucidation of the pharmacokinetic/pharmacodynamic determinant of colistin activity against Pseudomonas aeruginosa in murine thigh and lung infection models.

    Science.gov (United States)

    Dudhani, Rajesh V; Turnidge, John D; Coulthard, Kingsley; Milne, Robert W; Rayner, Craig R; Li, Jian; Nation, Roger L

    2010-03-01

    Colistin is increasingly used as last-line therapy against Gram-negative pathogens. The pharmacokinetic (PK)/pharmacodynamic (PD) index that best correlates with the efficacy of colistin remains undefined. The activity of colistin against three strains of Pseudomonas aeruginosa was studied in neutropenic mouse thigh and lung infection models. The PKs of unbound colistin were determined from single-dose PK studies together with extensive plasma protein binding analyses. Dose-fractionation studies were conducted over 24 h with a dose range of 5 to 160 mg/kg of body weight/day. The bacterial burden in the thigh or lung was measured at 24 h after the initiation of treatment. Relationships between antibacterial effect and measures of exposure to unbound (f) colistin (area under the concentration-time curve [fAUC/MIC], maximum concentration of drug in plasma [fC(max)]/MIC, and the time that the concentration in plasma is greater than the MIC [fT > MIC]) were examined by using an inhibitory sigmoid maximum-effect model. Nonlinearity in the PKs of colistin, including its plasma protein binding, was observed. The PK/PD index that correlated best with its efficacy was fAUC/MIC in both the thigh infection model (R(2) = 87%) and the lung infection model (R(2) = 89%). The fAUC/MIC targets required to achieve 1-log and 2-log kill against the three strains were 15.6 to 22.8 and 27.6 to 36.1, respectively, in the thigh infection model, while the corresponding values were 12.2 to 16.7 and 36.9 to 45.9 in the lung infection model. The findings of this in vivo study indicate the importance of achieving adequate time-averaged exposure to colistin. The results will facilitate efforts to define the more rational design of dosage regimens for humans. PMID:20028824

  8. Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model

    International Nuclear Information System (INIS)

    Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1 or 6 h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED50 values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1 h; > 200 fold at 6 h) than with tiotropium (1.5 and 4.2 fold at 1 h; 4.6 and 5.5 fold at 6 h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M2 muscarinic receptor occupancy, which predicted significantly higher M2 receptor blockade at ED50 doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium. - Highlights: • We use an in vivo rat model to study CV safety of inhaled muscarinic antagonists. • We integrate protein and receptor binding and PK of tiotropium and glycopyrrolate. • At ED50 doses for bronchoprotection we model systemic M2 receptor occupancy. • Glycopyrrolate demonstrates lower M2 occupancy at bronchoprotective

  9. Fully Bayesian Experimental Design for Pharmacokinetic Studies

    Directory of Open Access Journals (Sweden)

    Elizabeth G. Ryan

    2015-03-01

    Full Text Available Utility functions in Bayesian experimental design are usually based on the posterior distribution. When the posterior is found by simulation, it must be sampled from for each future dataset drawn from the prior predictive distribution. Many thousands of posterior distributions are often required. A popular technique in the Bayesian experimental design literature, which rapidly obtains samples from the posterior, is importance sampling, using the prior as the importance distribution. However, importance sampling from the prior will tend to break down if there is a reasonable number of experimental observations. In this paper, we explore the use of Laplace approximations in the design setting to overcome this drawback. Furthermore, we consider using the Laplace approximation to form the importance distribution to obtain a more efficient importance distribution than the prior. The methodology is motivated by a pharmacokinetic study, which investigates the effect of extracorporeal membrane oxygenation on the pharmacokinetics of antibiotics in sheep. The design problem is to find 10 near optimal plasma sampling times that produce precise estimates of pharmacokinetic model parameters/measures of interest. We consider several different utility functions of interest in these studies, which involve the posterior distribution of parameter functions.

  10. Investigation of ifosfamide and chloroacetaldehyde renal toxicity through integration of in vitro liver-kidney microfluidic data and pharmacokinetic-system biology models.

    Science.gov (United States)

    Leclerc, Eric; Hamon, Jeremy; Bois, Frederic Yves

    2016-02-01

    We have integrated in vitro and in silico data to describe the toxicity of chloroacetaldehyde (CAA) on renal cells via its production from the metabolism of ifosfamide (IFO) by hepatic cells. A pharmacokinetic (PK) model described the production of CAA by the hepatocytes and its transport to the renal cells. A system biology model was coupled to the PK model to describe the production of reactive oxygen species (ROS) induced by CAA in the renal cells. In response to the ROS production, the metabolism of glutathione (GSH) and its depletion were modeled by the action of an NFE2L2 gene-dependent pathway. The model parameters were estimated in a Bayesian context via Markov Chain Monte Carlo (MCMC) simulations based on microfluidic experiments and literature in vitro data. Hepatic IFO and CAA in vitro intrinsic clearances were estimated to be 1.85 x 10(-9) μL s(-1) cell(-1) and 0.185 x 10(-9) μL s(-1) cell(-1) ,respectively (corresponding to an in vivo intrinsic IFO clearance estimate of 1.23 l h(-1) , to be compared to IFO published values ranging from 3 to 10 l h(-1) ). After model calibration, simulations made at therapeutic doses of IFO showed CAA renal intracellular concentrations ranging from 11 to 131 μM. Intracellular CAA concentrations above 70 μM induced intense ROS production and GSH depletion. Those responses were time and dose dependent, showing transient and non-linear kinetics. Those results are in agreement with literature data reporting that intracellular CAA toxic concentrations range from 35 to 320 μM, after therapeutic ifosfamide dosing. The results were also consistent with in vitro CAA renal cytotoxicity data. PMID:26152902

  11. [Contribution of computers to pharmacokinetics, Bayesian approach and population pharmacokinetics].

    Science.gov (United States)

    Hecquet, B

    1995-12-01

    A major objective for pharmacokineticians is to help practicians to define drug administration protocols. Protocols are generally designed for all the patients but inter individual variability would need monitoring for each patient. Computers are widely used to determine pharmacokinetic parameters and to try to individualize drug administration. Severals examples are summarily described: terminal half-life determination by regression; model fitting to experimental data; Bayesian statistics for individual dose adaptation; population pharmacokinetic methods for parameter evaluation. These methods do not replace the pharmacokinetician thought but could make possible drug administration taking into account individual characteristics. PMID:8680074

  12. Pharmacokinetic-pharmacodynamic modeling of the antitumor effect of TM208 and EGFR-TKI resistance in human breast cancer xenograft mice

    Science.gov (United States)

    Ji, Xi-wei; Ji, Shuang-min; Li, Run-tao; Wu, Ke-hua; Zhu, Xiao; Lu, Wei; Zhou, Tian-yan

    2016-01-01

    Aim: The novel anticancer compound TM208 is an EGFR tyrosine kinase inhibitor (EGFR-TKI). Since the development of resistance to EGFR-TKIs is a major challenge in their clinical usage, we investigated the profiles of resistance following continuous treatment with TM208 in human breast cancer xenograft mice, and identified the relationship between the tumor pEGFR levels and tumor growth inhibition. Methods: Female BALB/c nude mice were implanted with human breast cancer MCF-7 cells, and the xenograft mice received TM208 (50 or 150 mg·kg−1·d−1, ig) or vehicle for 18 d. The pharmacokinetics (PK) and pharmacodynamics (PD) of TM208 were evaluated. Results: The PK properties of TM208 were described by a one-compartment model with first-order absorption kinetics. Our study showed the inhibitory effects of TM208 on tumor pEGFR levels gradually reached a maximum effect, after which it became weaker over time, which was characterized by a combined tolerance/indirect response PD model with an estimated EC50 (55.9 μg/L), as well as three parameters ('a' of 27.2%, 'b' of 2730%, 'c' of 0.58 h−1) denoting the maximum, extent and rate of resistance, respectively. The relationship between the tumor pEGFR levels and tumor growth inhibition was characterized by a combined logistic tumor growth/transit compartment model with estimated parameters associated with tumor growth characteristics kng (0.282 day−1), drug potency kTM208 (0.0499 cm3/day) and the kinetics of tumor cell death k1 (0.141 day−1), which provided insight into drug mechanisms and behaviors. Conclusion: The proposed PK/PD model provides a better understanding of the pharmacological properties of TM208 in the treatment of breast cancer. Furthermore, simulation based on a tolerance model allows prediction of the occurrence of resistance. PMID:27133303

  13. Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model.

    Science.gov (United States)

    Trifilieff, Alexandre; Ethell, Brian T; Sykes, David A; Watson, Kenny J; Collingwood, Steve; Charlton, Steven J; Kent, Toby C

    2015-08-15

    Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1 or 6h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED50 values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1h; >200 fold at 6h) than with tiotropium (1.5 and 4.2 fold at 1h; 4.6 and 5.5 fold at 6h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M2 muscarinic receptor occupancy, which predicted significantly higher M2 receptor blockade at ED50 doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium. PMID:26026369

  14. Pharmacological and pharmacokinetic studies with agaricoglycerides, extracted from Grifola frondosa, in animal models of pain and inflammation.

    Science.gov (United States)

    Han, Chuncho; Cui, Bo

    2012-08-01

    The objective of the present study was to demonstrate the anti-inflammatory and antinociceptive properties of agaricoglycerides of the fermented mushroom of Grifola frondosa (AGF). The effects of AGF on interleukin-1β (IL-1β) levels, tumor necrosis factor-α (TNF-α) levels, nuclear factor kappa B (NF-κB) levels, intercellular adhesion molecule-1 (ICAM-1) levels, cyclooxygenase-2 (COX-2) levels, and inducible nitric oxide synthase (iNOS) levels were determined by ELISA. The antinociceptive effects of AGF were also analyzed in acetic acid-induced pain model and formalin-induced inflammatory pain model, respectively. At the same time, the pharmacokinetic assay of AGF was also made. AGF at the dose level of 500 mg/kg significantly inhibited LPS-induced upregulation of NF-κB activation and the production of IL-1β, TNF-α, iNOS, ICAM-1, and COX-2. Moreover, AGF at the dose level of 500 mg/kg suppressed the acetic acid-induced abdominal constrictions (p < 0.05) and the formalin-induced spontaneous nociceptive behaviors (p < 0.05) in rats. The total plasma concentrations of drug after oral administration of AGF at the dose level of 500 mg/kg led to an improvement in oral bioavailability. It accounts for the anti-inflammatory and antinociceptive activity of AGF. The present study demonstrated that AGF at the dose level of 500 mg/kg has important anti-inflammatory and antinociceptive effects in preclinical models of inflammation and in some models of pain and thus may be used as an alternative medicine for inflammatory pain. PMID:22327864

  15. Population Pharmacokinetics of Rifampicin in Chinese Patients With Pulmonary Tuberculosis.

    Science.gov (United States)

    Jing, Ying; Zhu, Li Qin; Yang, Jian Wei; Huang, Shu Ping; Wang, Qian; Zhang, Jie

    2016-05-01

    Rifampicin (RIF) induces cytochrome P450, which in turn catalyzes drug metabolism; however, pharmacokinetic studies on this phenomenon in the Chinese population, especially in the context of disease, are limited. Therefore, we sought to establish population-based pharmacokinetic models of RIF in a Chinese population with pulmonary tuberculosis (TB). Clinical data were retrospectively collected from 54 patients with pulmonary TB and analyzed alongside RIF blood levels from 95 samples collected prior to RIF administration and between 2 and 12 hours after treatment. HPLC was used to measure serum RIF concentrations. A nonlinear mixed model used to characterize RIF pharmacokinetics and the data generated from the present study were validated using a bootstrap method. Covariates, including demographics, as well as hematological and biological indicators were analyzed. We observed a 1-compartment model with first-order absorption. Typical population values of apparent clearance (CL/F) and apparent volume of distribution (VD /F) were 4.02 L/h and 57.8 L, respectively. No covariate significantly changed the parameters of CL/F and VD . The present study may serve as a foundation for individualized therapy and offer a basis for pharmacokinetic-pharmacodynamic (PK-PD) analysis. PMID:26387492

  16. Pharmacokinetic modeling of an induction regimen for in vivo combined testing of novel drugs against pediatric acute lymphoblastic leukemia xenografts.

    Directory of Open Access Journals (Sweden)

    Barbara Szymanska

    Full Text Available Current regimens for induction therapy of pediatric acute lymphoblastic leukemia (ALL, or for re-induction post relapse, use a combination of vincristine (VCR, a glucocorticoid, and L-asparaginase (ASP with or without an anthracycline. With cure rates now approximately 80%, robust pre-clinical models are necessary to prioritize active new drugs for clinical trials in relapsed/refractory patients, and the ability of these models to predict synergy/antagonism with established therapy is an essential attribute. In this study, we report optimization of an induction-type regimen by combining VCR, dexamethasone (DEX and ASP (VXL against ALL xenograft models established from patient biopsies in immune-deficient mice. We demonstrate that the VXL combination was synergistic in vitro against leukemia cell lines as well as in vivo against ALL xenografts. In vivo, VXL treatment caused delays in progression of individual xenografts ranging from 22 to >146 days. The median progression delay of xenografts derived from long-term surviving patients was 2-fold greater than that of xenografts derived from patients who died of their disease. Pharmacokinetic analysis revealed that systemic DEX exposure in mice increased 2-fold when administered in combination with VCR and ASP, consistent with clinical findings, which may contribute to the observed synergy between the 3 drugs. Finally, as proof-of-principle we tested the in vivo efficacy of combining VXL with either the Bcl-2/Bcl-xL/Bcl-w inhibitor, ABT-737, or arsenic trioxide to provide evidence of a robust in vivo platform to prioritize new drugs for clinical trials in children with relapsed/refractory ALL.

  17. Pharmacokinetics of mitragynine in man

    Science.gov (United States)

    Trakulsrichai, Satariya; Sathirakul, Korbtham; Auparakkitanon, Saranya; Krongvorakul, Jatupon; Sueajai, Jetjamnong; Noumjad, Nantida; Sukasem, Chonlaphat; Wananukul, Winai

    2015-01-01

    Background Kratom, known botanically as Mitragyna speciosa (Korth.), is an indigenous tree in Southeast Asia. Kratom is currently easily available worldwide via special shops and the Internet to use as a drug of abuse, opioid alternative, or pain killer. So far, the pharmacokinetics of this plant has been studied only in animals, and there is no such study in humans. The major abundant active alkaloid in Kratom, mitragynine, is one of the promising new chemical substances to be developed as a new drug. The aim of this study was to examine the pharmacokinetics of mitragynine and assess the linearity in pharmacokinetics in chronic users. Methods Since Kratom is illegal in Thailand, studies in healthy subjects would be unethical. We therefore conducted a prospective study by enrolling ten chronic, regular, healthy users. We adjusted the steady state in each subject by giving a known amount of Kratom tea for 7 days before commencement of the experiment. We admitted and gave different oral doses to subjects to confirm linearity in pharmacokinetics. The mitragynine blood concentrations at 17 times points and the urine concentrations during the 24-hour period were collected and measured by liquid chromatography-tandem mass spectrometry method. Results Ten male subjects completed 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

  18. Modeling hepatitis C virus kinetics under therapy using pharmacokinetic and pharmacodynamic information

    Energy Technology Data Exchange (ETDEWEB)

    Perelson, Alan S [Los Alamos National Laboratory; Shudo, Emi [Los Alamos National Laboratory; Ribeiro, Ruy M [Los Alamos National Laboratory

    2008-01-01

    Mathematical models have proven helpful in analyzing the virological response to antiviral therapy in hepatitis C virus (HCY) infected subjects. Objective: To summarize the uses and limitations of different models for analyzing HCY kinetic data under pegylated interferon therapy. Methods: We formulate mathematical models and fit them by nonlinear least square regression to patient data in order estimate model parameters. We compare the goodness of fit and parameter values estimated by different models statistically. Results/Conclusion: The best model for parameter estimation depends on the availability and the quality of data as well as the therapy used. We also discuss the mathematical models that will be needed to analyze HCV kinetic data from clinical trials with new antiviral drugs.

  19. A new goldfish model to evaluate pharmacokinetic and pharmacodynamic effects of drugs used for motion sickness in different gravity loads

    Science.gov (United States)

    Lathers, Claire M.; Mukai, Chiaki; Smith, Cedric M.; Schraeder, Paul L.

    2001-08-01

    This paper proposes a new goldfish model to predict pharmacodynamic/pharmacokinetic effects of drugs used to treat motion sickness administered in differing gravity loads. The assumption of these experiments is that the vestibular system is dominant in producing motion sickness and that the visual system is secondary or of small import in the production of motion sickness. Studies will evaluate the parameter of gravity and the contribution of vision to the role of the neurovestibular system in the initiation of motion sickness with and without pharmacologic agents. Promethazine will be studied first. A comparison of data obtained in different groups of goldfish will be done (normal vs. acutely and chronically bilaterally blinded vs. sham operated). Some fish will be bilaterally blinded 10 months prior to initiation of the experiment (designated the chronically bilaterally blinded group of goldfish) to evaluate the neuroplasticity of the nervous system and the associated return of neurovestibular function. Data will be obtained under differing gravity loads with and without a pharmacological agent for motion sickness. Experiments will differentiate pharmacological effects on vision vs. neurovestibular input to motion sickness. Comparison of data obtained in the normal fish and in acutely and chronically bilaterally blinded fish with those obtained in fish with intact and denervated otoliths will differentiate if the visual or neurovestibular system is dominant in response to altered gravity and/or drugs. Experiments will contribute to validation of the goldfish as a model for humans since plasticity of the central nervous system allows astronauts to adapt to the altered visual stimulus conditions of 0-g. Space motion sickness may occur until such an adaptation is achieved.

  20. First dose in children: physiological insights into pharmacokinetic scaling approaches and their implications in paediatric drug development

    OpenAIRE

    Strougo, Ashley; Eissing, Thomas; Yassen, Ashraf; Willmann, Stefan; Danhof, Meindert; Freijer, Jan

    2012-01-01

    Dose selection for “first in children” trials often relies on scaling of the pharmacokinetics from adults to children. Commonly used approaches are physiologically-based pharmacokinetic modeling (PBPK) and allometric scaling (AS) in combination with maturation of clearance for early life. In this investigation, a comparison of the two approaches was performed to provide insight into the physiological meaning of AS maturation functions and their interchangeability. The analysis focused on the ...

  1. Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model

    Energy Technology Data Exchange (ETDEWEB)

    Trifilieff, Alexandre; Ethell, Brian T. [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); Sykes, David A. [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); School of Life Sciences, Queen' s Medical Centre, University of Nottingham, Nottingham, NG7 2UH (United Kingdom); Watson, Kenny J.; Collingwood, Steve [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); Charlton, Steven J. [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); School of Life Sciences, Queen' s Medical Centre, University of Nottingham, Nottingham, NG7 2UH (United Kingdom); Kent, Toby C., E-mail: tobykent@me.com [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom)

    2015-08-15

    Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1 or 6 h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED{sub 50} values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1 h; > 200 fold at 6 h) than with tiotropium (1.5 and 4.2 fold at 1 h; 4.6 and 5.5 fold at 6 h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M{sub 2} muscarinic receptor occupancy, which predicted significantly higher M{sub 2} receptor blockade at ED{sub 50} doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium. - Highlights: • We use an in vivo rat model to study CV safety of inhaled muscarinic antagonists. • We integrate protein and receptor binding and PK of tiotropium and glycopyrrolate. • At ED{sub 50} doses for bronchoprotection we model systemic M{sub 2} receptor occupancy. • Glycopyrrolate demonstrates lower M

  2. Exposure reconstruction for reducing uncertainty in risk assessment: example using MTBE biomarkers and a simple pharmacokinetic model.

    Science.gov (United States)

    Pleil, J D; Kim, D; Prah, J D; Rappaport, S M

    2007-01-01

    Adverse health risks from environmental agents are generally related to average (long-term) exposures. Because a given individual's contact with a pollutant is highly variable and dependent on activity patterns, local sources and exposure pathways, simple 'snapshot' measurements of surrounding environmental media may not accurately assign the exposure level. Furthermore, susceptibility to adverse effects from contaminants is considered highly variable in the population so that even similar environmental exposure levels may result in differential health outcomes in different individuals. The use of biomarker measurements coupled to knowledge of rates of uptake, metabolism and elimination has been suggested as a remedy for reducing this type of uncertainty. To demonstrate the utility of such an approach, we invoke results from a series of controlled human exposure tests and classical first-order rate kinetic calculations to estimate how well spot measurements of methyl tertiary butyl ether and the primary metabolite, tertiary butyl alcohol, can be expected to predict different hypothetical scenarios of previous exposures. We found that blood and breath biomarker measurements give similar results and that the biological damping effect of the metabolite production gives more stable estimates of previous exposure. We also explore the value of a potential urinary biomarker, 2-hydroxyisobutyrate suggested in the literature. We find that individual biomarker measurements are a valuable tool in reconstruction of previous exposures and that a simple pharmacokinetic model can identify the time frames over which an exogenous chemical and the related chemical biomarker are useful. These techniques could be applied to broader ranges of environmental contaminants to assess cumulative exposure risks if ADME (Absorption, Distribution, Metabolization and Excretion) is understood and systemic biomarkers can be measured. PMID:17564841

  3. Pretargeted radioimmunotherapy of colorectal cancer metastases: models and pharmacokinetics predict influence of the physical and radiochemical properties of the radionuclide

    Energy Technology Data Exchange (ETDEWEB)

    Frampas, Eric; Maurel, Catherine; Remaud-Le Saec, Patricia; Mauxion, Thibault; Faivre-Chauvet, Alain; Davodeau, Francois; Bardies, Manuel; Barbet, Jacques [Universite de Nantes, Inserm, UMR 892, Centre de Recherche en Cancerologie Nantes-Angers (CRCNA), Nantes (France); Goldenberg, David M. [Immunomedics, Inc., Morris Plains, NJ (United States); Center for Molecular Medicine and Immunology, Garden State Cancer Center, Morris Plains, NJ (United States)

    2011-12-15

    We investigated influences of pretargeting variables, tumor location, and radionuclides in pretargeted radioimmunotherapy (PRIT) as well as estimated tumor absorbed doses. LS-174T human colonic carcinoma cells expressing carcinoembryonic antigen (CEA) were inoculated in nude mice. Biodistribution of a bispecific anti-CEA x anti-hapten antibody, TF2, and of a TF2-pretargeted peptide was assessed and a multi-compartment pharmacokinetic model was devised. Tissue absorbed doses were calculated for {sup 131}I, {sup 177}Lu, {sup 90}Y, {sup 211}At, and {sup 213}Bi using realistic specific activities. Under conditions optimized for tumor imaging (10:1 TF2 to peptide molar ratio, interval time 15-24 h), tumor uptake reached {proportional_to}9 ID/g in subcutaneous tumors at 2 h with very low accretion in normal tissues (tumor to blood ratio >20:1 after 2 h). For a low dose of peptide (0.04 nmol), {sup 211}At is predicted to deliver a high absorbed dose to tumors [41.5 Gy considering a relative biologic effect (RBE) of 5], kidneys being dose-limiting. {sup 90}Y and {sup 213}Bi would also deliver high absorbed doses to tumor (18.6 for {sup 90}Y and 26.5 Gy for {sup 213}Bi, taking RBE into account, for 0.1 nmol) and acceptable absorbed doses to kidneys. With hepatic metastases, a twofold higher tumor absorbed dose is expected. Owing to the low activities measured in blood, the bone marrow absorbed dose is expected to be without significant toxicity. Pretargeting achieves high tumor uptake and higher tumor to background ratios compared to direct RIT. Short-lived radionuclides are predicted to deliver high tumor absorbed doses especially {sup 211}At, with kidneys being the dose-limiting organ. {sup 177}Lu and {sup 131}I should be considered for repeated injections. (orig.)

  4. Gadolinium MRI Contrast Agents Based on Triazine Dendrimers: Relaxivity and In Vivo Pharmacokinetics

    OpenAIRE

    Lim, Jongdoo; Turkbey, Baris; Bernardo, Marcelino; Bryant, L. Henry; Garzoni, Matteo; Pavan, Giovanni M.; Nakajima, Takahito; Choyke, Peter L; Simanek, Eric E; Kobayashi, Hisataka

    2012-01-01

    Four gadolinium (Gd)-based macromolecular contrast agents, G3-(Gd-DOTA)24, G5-(Gd-DOTA)96, G3-(Gd-DTPA)24, and G5-(Gd-DTPA)96, were prepared that varied in the size of dendrimer (generation three and five), the type of chelate group (DTPA or DOTA), and the theoretical number of metallated chelates (24 and 96). Synthesis relied on a dichlorotriazine derivatized with a DOTA or DTPA ligand that was incorporated into the dendrimer and ultimately metallated with Gd ions. Paramagnetic characteristi...

  5. Bioavailability, Pharmacokinetics and Tissue Distribution of P57AS3 (P57) from Hoodia gordonii Mouse Model

    Science.gov (United States)

    P57AS3, an oxypregnane steroidal glycoside (P57) is known to be responsible for the diet suppressing activity of Hoodia gordonii, a dietary supplement used for weight loss. In this study, bioavailability, pharmacokinetics and tissue distribution of P57 was determined in CD1 female mice after adminis...

  6. Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT—Part I: Program Implementation and Lessons Learned

    Directory of Open Access Journals (Sweden)

    David C. Dorman

    2012-01-01

    Full Text Available Concerns have been raised regarding environmental manganese exposure since high exposures have been associated with neurological disorders. The USA Environmental Protection Agency most recent human health risk assessment of inhaled manganese conducted in 1993 identified specific areas of uncertainty regarding manganese pharmacokinetics. This led to the development of a test rule under the USA Clean Air Act that required the generation of pharmacokinetic information on the inorganic manganese combustion products of the organometallic fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT. The Alternative Tier 2 testing program for MMT, described in this paper, has yielded substantial pharmacokinetic data and has enabled the generation of physiologically based pharmacokinetic (PBPK models for manganese. These models are capable of predicting tissue manganese concentrations across a variety of dose routes, levels, and durations while accounting for factors such as age, gender, and reproductive status, enabling the consideration of tissue dosimetry in future risk assessments.

  7. Pharmacokinetic model for the absorption of subcutaneously injected soluble insulin and monomeric insulin analogues.

    Science.gov (United States)

    Trajanoski, Z; Wach, P; Kotanko, P; Ott, A; Skraba, F

    1993-09-01

    A subcutaneous insulin absorption model is presented for parameter estimation from the time course of plasma insulin. Modifications of a published model were made for the absorption of soluble insulin and monomeric insulin analogues in the range of therapeutic concentrations and volumes. The modified diffusion-dissociation model with distributed parameters was approximated by a multiple-compartment model. Subcutaneous absorption of soluble insulin and monomeric insulin analogues with various volumes, concentrations, and injection depths was simulated. The model for soluble insulin exhibits volume, concentration, and injection depth dependent absorption, as experimentally observed. It was found that binding of soluble insulin in the subcutaneous tissue is negligible for U-40 and U-100 strengths. The absorption of identical doses (10 U) of soluble U-40 insulin was markedly faster (T-50% = 159.4 min) than the absorption of U-100 (T-50% = 196.2 min). According to the simulation results, the absorption rate of monomeric analogues is not dependent on concentration. No significant chances of the absorption rate could also be observed by varying volume and injection depth of the monomeric analogues. PMID:8218870

  8. Model-based geostatistics

    CERN Document Server

    Diggle, Peter J

    2007-01-01

    Model-based geostatistics refers to the application of general statistical principles of modeling and inference to geostatistical problems. This volume provides a treatment of model-based geostatistics and emphasizes on statistical methods and applications. It also features analyses of datasets from a range of scientific contexts.

  9. Rifampin reduces oral morphine absorption: a case of transdermal buprenorphine selection based on morphine pharmacokinetics.

    Science.gov (United States)

    Fudin, Jeffrey; Fontenelle, Dania Vanesta; Payne, Annette

    2012-12-01

    A 51-year-old male was referred to the Stratton Veterans Affairs Medical Center Pain Service after hospital admission for endocarditis with a history of heroin use and chronic low back pain. During his hospital stay he experienced a reduction in his serum morphine level ostensibly as a result of concomitant rifampin administration. We hypothesize that diminished absorption was from rifampin-mediated intestinal P-glycoprotein induction, ultimately decreasing serum free morphine and metabolites. The case became more complex in an attempt to balance managed pain, history of substance abuse, completion of antibiotic therapy, and a reasonable pain regimen upon discharge. Ultimately, the patient was titrated onto a buprenorphine transdermal patch, the initiation of which was based on serum free morphine and an extrapolated oral morphine dose by calculation. PMID:23216174

  10. Population pharmacokinetic modeling of a subcutaneous depot for GnRH antagonist degarelix

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Nielsen, Henrik Aalborg;

    -concentration dependent absorption. Methods. The PK analysis is made in NONMEM through joint analysis of data from two phase I clinical studies; an intravenous infusion study and a single SC dose escalation study. The SC absorption is modeled using an approximation to Ficks' second law of diffusion out of a spherical...

  11. Population Pharmacokinetic Modeling of a Subcutaneous Depot for GnRH Antagonist Degarelix

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Nielsen, Henrik Aalborg;

    2004-01-01

    -concentration dependent absorption. Methods. The PK analysis is made in NONMEM through joint analysis of data from two phase I clinical studies; an intravenous infusion study and a single SC dose escalation study. The SC absorption is modeled using an approximation to Ficks' second law of diffusion out of a spherical...

  12. Myotoxicity of Gemfibrozil in Cynomolgus Monkey Model and Its Relationship to Pharmacokinetic Properties

    OpenAIRE

    Liu, Aiming; Xie, Shuilin; Sun, He; Frank J. Gonzalez; Wei, Xiaoxiong; Dai, Renke

    2008-01-01

    Fibrate drugs are PPARα agonists prescribed for the treatment of dyslipidemia. Severe myotoxicity has been reported associated with their use albeit at a low frequency, especially for gemfibrozil. Few studies have investigated the mechanism of fibrate-induced myotoxicity in vivo. Considering the apparent species-related differences in PPARα agonist-induced hepatotoxicity, we studied the myotoxicity of gemfibrozil in a Cynomolgus monkey model and explored the relationship between myotoxicity a...

  13. Pharmacokinetics of ricobendazole in calves.

    Science.gov (United States)

    Formentini, E A; Mestorino, O N; Mariño, E L; Errecalde, J O

    2001-06-01

    The pharmacokinetics of ricobendazole (RBZ) and its major metabolite albendazole sulphone (ABZSO2) were studied in six calves, after administration of RBZ (7.5 mg/kg), using a 10% experimental solution by the intravenous (i.v.) route, a 10% commercial solution by the subcutaneous (s.c.) route, and a 10% experimental suspension by the intraruminal (i.r.) route. Blood samples were drawn during a 60-h period. Plasma drug and metabolite concentrations were determined by HPLC. The pharmacokinetic evaluation in each case was prepared by weighted least-squares nonlinear regression analysis. Ricobendazole i.v. data were best fitted by a two-compartment model. The best pharmacokinetic exponents and coefficients were estimated, and the pharmacokinetic variables for RBZ and ABZSO2 were calculated from them. Similar patterns of plasma disposition were found for RBZ after i.r. and s.c. administration, suggesting delayed release from the s.c. site resembling the slow release of the drug from the rumen. PMID:11442798

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

    International Nuclear Information System (INIS)

    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)

  15. Incorporating pharmacokinetic differences between children and adults in assessing children's risks to environmental toxicants

    International Nuclear Information System (INIS)

    Children's risks from environmental toxicant exposure can be affected by pharmacokinetic factors that affect the internal dose of parent chemical or active metabolite. There are numerous physiologic differences between neonates and adults that affect pharmacokinetics including size of lipid, and tissue compartments, organ blood flows, protein binding capacity, and immature function of renal and hepatic systems. These factors combine to decrease the clearance of many therapeutic drugs, which can also be expected to occur with environmental toxicants in neonates. The net effect may be greater or lesser internal dose of active toxicant depending upon how the agent is distributed, metabolized, and eliminated. Child/adult pharmacokinetic differences decrease with increasing postnatal age, but these factors should still be considered in any children's age group, birth through adolescence, for which there is toxicant exposure. Physiologically based pharmacokinetic (PBPK) models can simulate the absorption, distribution, metabolism, and excretion of xenobiotics in both children and adults, allowing for a direct comparison of internal dose and risk across age groups. This review provides special focus on the development of hepatic cytochrome P-450 enzymes (CYPs) in early life and how this information, along with many factors unique to children, can be applied to PBPK models for this receptor population. This review describes a case study involving the development of neonatal PBPK models for the CYP1A2 substrates caffeine and theophylline. These models were calibrated with pharmacokinetic data in neonates and used to help understand key metabolic differences between neonates and adults across these two drugs

  16. Pharmacokinetic-Pharmacodynamic Model To Evaluate Intramuscular Tetracycline Treatment Protocols To Prevent Antimicrobial Resistance in Pigs

    DEFF Research Database (Denmark)

    Ahmad, Amais; Græsbøll, Kaare; Christiansen, Lasse Engbo;

    2015-01-01

    which resistant strains outcompete susceptible strains under antimicrobial pressure may depend not only on the antimicrobial treatment strategies but also on the epidemiological parameters, such as the composition of the bacterial strains in a pig. This study evaluated how variation in the dosing......High instances of antimicrobial resistance are linked to both routine and excessive antimicrobial use, but excessive or inappropriate use represents an unnecessary risk. The competitive growth advantages of resistant bacteria may be amplified by the strain dynamics; in particular, the extent to...... protocol for intramuscular administration of tetracycline and the composition of bacterial strains in a pig affect the level of resistance in the intestine of a pig. Predictions were generated by a mathematical model of competitive growth of Escherichia coli strains in pigs under specified plasma...

  17. Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT

    Science.gov (United States)

    Grudzinski, Joseph J.; Floberg, John M.; Mudd, Sarah R.; Jeffery, Justin J.; Peterson, Eric T.; Nomura, Alice; Burnette, Ronald R.; Tomé, Wolfgang A.; Weichert, Jamey P.; Jeraj, Robert

    2012-03-01

    We have previously developed a model that provides relative dosimetry estimates for targeted radionuclide therapy (TRT) agents. The whole-body and tumor pharmacokinetic (PK) parameters of this model can be noninvasively measured with molecular imaging, providing a means of comparing potential TRT agents. Parameter sensitivities and noise will affect the accuracy and precision of the estimated PK values and hence dosimetry estimates. The aim of this work is to apply a PK model for TRT to two agents with different magnitudes of clearance rates, NM404 and FLT, explore parameter sensitivity with respect to time and investigate the effect of noise on parameter precision and accuracy. Twenty-three tumor bearing mice were injected with a ‘slow-clearing’ agent, 124I-NM404 (n = 10), or a ‘fast-clearing’ agent, 18F-FLT (3‧-deoxy-3‧-fluorothymidine) (n = 13) and imaged via micro-PET/CT pseudo-dynamically or dynamically, respectively. Regions of interest were drawn within the heart and tumor to create time-concentration curves for blood pool and tumor. PK analysis was performed to estimate the mean and standard error of the central compartment efflux-to-influx ratio (k12/k21), central elimination rate constant (kel), and tumor influx-to-efflux ratio (k34/k43), as well as the mean and standard deviation of the dosimetry estimates. NM404 and FLT parameter estimation results were used to analyze model accuracy and parameter sensitivity. The accuracy of the experimental sampling schedule was compared to that of an optimal sampling schedule found using Cramer-Rao lower bounds theory. Accuracy was assessed using correlation coefficient, bias and standard error of the estimate normalized to the mean (SEE/mean). The PK parameter estimation of NM404 yielded a central clearance, kel (0.009 ± 0.003 h-1), normal body retention, k12/k21 (0.69 ± 0.16), tumor retention, k34/k43 (1.44 ± 0.46) and predicted dosimetry, Dtumor (3.47 ± 1.24 Gy). The PK parameter estimation of FLT

  18. Pharmacokinetic-pharmacodynamic model to evaluate intramuscular tetracycline treatment protocols to prevent antimicrobial resistance in pigs.

    Science.gov (United States)

    Ahmad, Amais; Græsbøll, Kaare; Christiansen, Lasse Engbo; Toft, Nils; Matthews, Louise; Nielsen, Søren Saxmose

    2015-03-01

    High instances of antimicrobial resistance are linked to both routine and excessive antimicrobial use, but excessive or inappropriate use represents an unnecessary risk. The competitive growth advantages of resistant bacteria may be amplified by the strain dynamics; in particular, the extent to which resistant strains outcompete susceptible strains under antimicrobial pressure may depend not only on the antimicrobial treatment strategies but also on the epidemiological parameters, such as the composition of the bacterial strains in a pig. This study evaluated how variation in the dosing protocol for intramuscular administration of tetracycline and the composition of bacterial strains in a pig affect the level of resistance in the intestine of a pig. Predictions were generated by a mathematical model of competitive growth of Escherichia coli strains in pigs under specified plasma concentration profiles of tetracycline. All dosing regimens result in a clear growth advantage for resistant strains. Short treatment duration was found to be preferable, since it allowed less time for resistant strains to outcompete the susceptible ones. Dosing frequency appeared to be ineffective at reducing the resistance levels. The number of competing strains had no apparent effect on the resistance level during treatment, but possession of fewer strains reduced the time to reach equilibrium after the end of treatment. To sum up, epidemiological parameters may have more profound influence on growth dynamics than dosing regimens and should be considered when designing improved treatment protocols. PMID:25547361

  19. Pharmacokinetics and modeling of immune cell trafficking: quantifying differential influences of target tissues versus lymphocytes in SJL and lipopolysaccharide-treated mice

    Directory of Open Access Journals (Sweden)

    Banks William A

    2012-10-01

    Full Text Available Abstract Background Immune cell trafficking into the CNS and other tissues plays important roles in health and disease. Rapid quantitative methods are not available that could be used to study many of the dynamic aspects of immune cell-tissue interactions. Methods We used pharmacokinetics and modeling to quantify and characterize the trafficking of radioactively labeled lymphocytes into brain and peripheral tissues. We used variance from two-way ANOVAs with 2 × 2 experimental designs to model the relative influences of lymphocytes and target tissues in trafficking. Results We found that in male CD-1 mice, about 1 in 5,000 intravenously injected lymphocytes entered each gram of brain. Uptake by brain was 2 to 3 times higher in naïve SJL females, but uptake by spleen and clearance from blood was lower, demonstrating a dichotomy in immune cell distribution. Treatment of CD-1 mice with lipopolysaccharide (LPS increased immune cell uptake into brain but decreased uptake by spleen and axillary nodes. Conclusions Differences in brain uptake and in uptake by spleen between SJL and CD-1 mice were primarily determined by lymphocytes, whereas differences in uptake with LPS were primarily determined by lymphocytes for the brain but by the tissues for the spleen and the axillary lymph node. These results show that immune cells normally enter the CNS and that tissues and immune cells interact in ways that can be quantified by pharmacokinetic models.

  20. Exploratory Pharmacokinetics of Geniposide in Rat Model of Cerebral Ischemia Orally Administered with or without Baicalin and/or Berberine

    OpenAIRE

    Linmei Pan; Wenzhe Wang; Feiyan Shi; Jing Zhou; Meng Zhang; Huaxu Zhu; Mingfei Zeng

    2013-01-01

    Huang-Lian-Jie-Du-Tang (HLJDT), a classical Chinese prescription, has been clinically employed to treat cerebral ischemia for thousands of years. Geniposide is the major active ingredient in HLJDT. The aim is to investigate the comparative evaluations on pharmacokinetics of geniposide in MCAO rats in pure geniposide, geniposide : berberine, and geniposide : berberine : baicalin. Obviously, the proportions of geniposide : berberine, geniposide : baicalin, and geniposide : berberine : baicalin ...

  1. Pharmacokinetics of Aminoglycosides

    Institute of Scientific and Technical Information of China (English)

    Lokangu Lombo(Congo); HE Hua

    2004-01-01

    The Pharmacokinetics informations of aminoglycosides, their monograph and clinical Pharmacokinetics parameters are reported in this review. The Aminoglycosides are highly polarity and in reserve for serious infections caused by aerobic gram-negative bacteria and some gram-positive bacteria but their toxicity are major limitations in clinical use.

  2. Alteration in Intrapulmonary Pharmacokinetics of Aerosolized Model Compounds Due to Disruption of the Alveolar Epithelial Barriers Following Bleomycin-Induced Pulmonary Fibrosis in Rats.

    Science.gov (United States)

    Togami, Kohei; Chono, Sumio; Tada, Hitoshi

    2016-03-01

    Idiopathic pulmonary fibrosis is a lethal lung disease that is characterized by the accumulation of extracellular matrix and a change in lung structure. In this study, intrapulmonary pharmacokinetics of aerosolized model compounds were evaluated using rats with bleomycin-induced pulmonary fibrosis. Aerosol formulations of indocyanine green, 6-carboxyfluorescein (6-CF), and fluorescein isothiocyanate dextrans (FD; 4.4, 10, 70, and 250 kDa) were administered to rat lungs using a MicroSprayer. Indocyanine green fluorescence signals were significantly weaker in fibrotic lungs than in control lungs and 6-CF and FD concentrations in the plasma of pulmonary fibrotic animals were markedly higher than in the plasma of control animals. Moreover, disrupted epithelial tight junctions, including claudins-1, -3, and -5, were observed in pulmonary fibrotic lesions using immunofluorescence microscopy. In addition, destruction of tight junctions on model alveolar epithelial cells (NCI-H441) by transforming growth factor-β1 treatment enhanced the permeability of 6-CF and FDs through NCI-H441 cell monolayers. These results indicate that aerosolized drugs are easily distributed into the plasma after leakage through damaged tight junctions of alveolar epithelium. Therefore, the development of delivery systems for anti-fibrotic agents to improve intrapulmonary pharmacokinetics may be necessary for effective idiopathic pulmonary fibrosis therapy. PMID:26886341

  3. Pharmacokinetics and PBPK Models

    Energy Technology Data Exchange (ETDEWEB)

    Corley, Richard A.

    2010-07-01

    Since the landmark report Pesticides in the Diets of Infants and Children (NRC 1993), children at all stages of development, from fertilization through postnatal maturation, have explicitly been identified as an area of emphasis in human health risk assessments. Exposure to drugs or chemicals at any point in development has the potential for causing irreversible changes that can be unique to each stage of development (Grabowski and Daston 1983; Rodier 1978; Wilson 1973). While exposures of a developing embryo or fetus are mediated by the mother, postnatal exposures consist of maternal influences via breastfeeding as well as environmental factors (Figure 1). As a result, risk assessments for developmental toxicity must consider the sources as well as timing of potential exposures to adequately protect children when they may be the most exposed or the most sensitive to adverse consequences (NRC 1993).

  4. Pharmacokinetics of mitragynine in man

    Directory of Open Access Journals (Sweden)

    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

  5. Pharmacokinetics, Safety, and Tolerability of Voriconazole in Immunocompromised Children▿

    OpenAIRE

    Walsh, Thomas J.; Driscoll, Timothy; Milligan, Peter A; Wood, Nolan D.; Schlamm, Haran; Groll, Andreas H.; Jafri, Hasan; Arrieta, Antonio C.; Klein, Nigel J; Lutsar, Irja

    2010-01-01

    The pharmacokinetics of voriconazole in children receiving 4 mg/kg intravenously (i.v.) demonstrate substantially lower plasma exposures (as defined by area under the concentration-time curve [AUC]) than those in adults receiving the same therapeutic dosage. These differences in pharmacokinetics between children and adults limit accurate prediction of pediatric voriconazole exposure based on adult dosages. We therefore studied the pharmacokinetics and tolerability of higher dosages of an i.v....

  6. Dermal pharmacokinetics of microemulsion formulations determined by in vivo microdialysis

    DEFF Research Database (Denmark)

    Kreilgaard, Mads

    2001-01-01

    To investigate the potential of improving dermal drug delivery of hydrophilic and lipophilic substances by formulation in microemulsion vehicles and to establish a reliable pharmacokinetic model to analyze cutaneous microdialysis data.......To investigate the potential of improving dermal drug delivery of hydrophilic and lipophilic substances by formulation in microemulsion vehicles and to establish a reliable pharmacokinetic model to analyze cutaneous microdialysis data....

  7. Physiologically Based Models in Regulatory Submissions: Output From the ABPI/MHRA Forum on Physiologically Based Modeling and Simulation

    Science.gov (United States)

    Shepard, T; Scott, G; Cole, S; Nordmark, A; Bouzom, F

    2015-01-01

    Under the remit of the Ministerial Industry Strategy Group (MISG), the Association of the British Pharmaceutical Industry (ABPI) and Medicines and Healthcare products Regulatory Agency (MHRA) hosted a meeting to explore physiologically based pharmacokinetic modeling and simulation, focusing on the clinical component of regulatory applications. The meeting took place on 30 June 2014 with international representatives from industry, academia, and regulatory agencies. Discussion topics were selected to be complementary to those discussed at an earlier US Food and Drug Administration (FDA) meeting. This report summarizes the meeting outcomes, focusing on the European regulatory perspective. PMID:26225245

  8. Physiologically Based Models in Regulatory Submissions: Output From the ABPI/MHRA Forum on Physiologically Based Modeling and Simulation.

    Science.gov (United States)

    Shepard, T; Scott, G; Cole, S; Nordmark, A; Bouzom, F

    2015-04-01

    Under the remit of the Ministerial Industry Strategy Group (MISG), the Association of the British Pharmaceutical Industry (ABPI) and Medicines and Healthcare products Regulatory Agency (MHRA) hosted a meeting to explore physiologically based pharmacokinetic modeling and simulation, focusing on the clinical component of regulatory applications. The meeting took place on 30 June 2014 with international representatives from industry, academia, and regulatory agencies. Discussion topics were selected to be complementary to those discussed at an earlier US Food and Drug Administration (FDA) meeting. This report summarizes the meeting outcomes, focusing on the European regulatory perspective. PMID:26225245

  9. Population pharmacokinetics of propofol in Chinese patients

    Institute of Scientific and Technical Information of China (English)

    LIYu-Hong; RUIJian-Zhong; ZHOUYong-Gang; WANGLi-Qin; FUSu-E; YANGJian-Jun; LIuFu-Kun; HUShu-Ya; WENQuan; XUJian-Guo

    2003-01-01

    AIM:To analyze population pharmacokinetics of propofol in Chinese surgical patients using a nonlinear mixedeffect model (NONMEM) program and to quantitate the effects of covariance of gender, age, and body weight. METHODS: The population pharmacokinetics of propofol was investigated in 76 selective surgical patients (37 males and 39 females aged 19-77a, weighing 39-86kg). A total of 1439 blood samples were analyzed using NONMEM(NONMEM Projeft Group, University of California, San Francisco, CA). Interindividual variability was estimated fro clearances and distribution volumes. The effects of age, body weight, and gender were in vestigated. RESULTS: The pharmacokinetics of propofol in Chinese patients was best described by a three-compartment pharmacokinetic model. Body weight was found to be a significant factor for the elimination clearance, the two inter-compartmental clearances, and the volume of the central compartment. The volumes of the shallow peripheral compartment and deep peripheral compartment remain constant for all individuals. The estimates of these parameters for a 60-kg adult were 1.56L/min, 0.737L/min, 0.360L/min, 12.1L, 43L, and 213L, respectively. For old patients, the elimination clearance and volume of the central compartment decreased. CONCLUSION:The pharmacokinetics of propofol in Chinese patients can be well described by a standard three-compartment pharmacokinetic model. Inclusion of age and body weight as covariances significantly improved the model. Adjusting pharmacokinetics to the individual patients should improve the precision of target-controlled infusion system.

  10. Development of a paediatric population pharmacokinetic model for valacyclovir from literature non-compartmental values originating from sparse studies and Bayesian priors: a simulation study.

    Science.gov (United States)

    Kechagia, Irene-Ariadne; Dokoumetzidis, Aristides

    2015-06-01

    A preliminary population pharmacokinetic (PopPK) model of valacyclovir in children was developed from non-compartmental analysis (NCA) parameter values from literature, including several age groups, combined with Bayesian priors from a PopPK model of acyclovir, the active metabolite of valacyclovir, from literature too. Also a simulation study was carried out to evaluate the performance of various modelling choices related to the estimation of model parameters from NCA parameters originating from sparse PK studies. Assuming a one-compartment model with first order absorption, a mixed effects, meta-analysis approach was utilized which allows accounting the random intergroup variability, the detection of covariates and the application of informative Bayesian priors on the parameters. The conclusions from the simulation study calculating bias and precision for various cases, were that a model which takes explicitly into account the sampling schedule, performs better than a model using the theoretical expressions of calculating the NCA parameters. Also by using the geometric rather than the arithmetic means of NCA parameters, less biased results are obtained. These findings guided the choices for the valacyclovir model, for which informative priors from a PopPK model of acyclovir were applied for some of the parameters, in order to include a richer covariate model for clearance, not supported by the NCA dataset and a value for bioavailability. This preliminary valacyclovir model can be used in simulations to provide dosage recommendations for children of various ages and to help design more efficiently prospective clinical trials. PMID:25821006

  11. Pharmacokinetic modelling of N-(4-[18F]fluorobenzoyl)interleukin-2 binding to activated lymphocytes in an xenograft model of inflammation

    International Nuclear Information System (INIS)

    N-(4-[18F]Fluorobenzoyl)interleukin-2 ([18F]FB-IL2) specifically binds to interleukin-2 receptors (IL-2R) and thus may be used to detect inflammation processes using positron emission tomography (PET). We now validated whether [18F]FB-IL2 can be used to quantify activated human peripheral blood mononuclear cells (hPBMC) in rats by pharmacokinetic modelling. Eleven Wistar rats were subcutaneously inoculated in the shoulder with different amounts of phytohaemagglutinin (PHA) activated hPBMC 15 min before i.v. injection of [18F]FB-IL2. A 60-min dynamic PET scan was acquired and arterial blood sampling and metabolite analysis were performed. At the end of the scan, animals were terminated and the inflammatory lesion dissected. PET data were analysed using Logan and Patlak analysis as well as one-tissue and two-tissue compartment models. Model preferences according to the Akaike information criterion (AIC) and correlation between PET measurements and the number of CD25-positive cells were evaluated. A high correlation between ex vivo tracer uptake (standardized uptake value) in the xenograft and the number of inoculated CD25-positive cells was observed (R 2 = 0.90). Plasma time-activity curves showed a rapid washout of the radiopharmaceutical from blood, while the time-activity curves of the inflammatory lesions showed slower washout. Time-activity curves could be fitted well by the Logan analysis method, indicating that the binding between [18F]FB-IL2 and CD25 is reversible. AIC indicated that data could be modelled best by a two-tissue reversible compartment model. A high correlation was observed between the binding potential and the number of CD25-positive cells (R 2 = 0.876, p 18F]FB-IL2 kinetics in this animal model of inflammation could be best described by a reversible two-tissue compartment model. The [18F]FB-IL2 binding potential is a suitable measure for accurate quantification of lymphocytic infiltration in pathological conditions with PET. (orig.)

  12. Solution space of pharmacokinetics and its application on mice brain with 18F-FECNT

    International Nuclear Information System (INIS)

    Objective: To forward the concept of solution space of pharmacokinetics for studying radiopharmaceutical distributions in animal models. Methods: On the basis of special solutions of differential equations of pharmacokinetics, the solution space was established using the characteristics of linearly independent particular solutions and used to express the pharmacokinetics of pharmaceuticals in vivo. 0. 2 ml (7.4 MBq) 2β-carbomethoxy-3β-(4-corophenyl)-8-(2-18F-fluoroethyl) nortropane (18F-FECNT) was injected through tail vein into normal mice. The mice were sacrificed by decapitation at 5, 15, 30, 60, 120 and 180 min post-injection. Brain tissues were removed and weighed, and radioactivity was counted with the γ-counter. The solution space theory was used to study pharmacokinetics of 18F-FECNT in brain tissues of mice. Results: The result showed that all solutions of pharmacokinetics models, based on differential equations, were included in the solution space. The solution of any organ or tissue could be linearly expressed by bases of the solution space. When the dimension number of the solution space was no more than 3, the solution could be directly expressed with coordinate picture. By this rule in our theory, the quantity of 18F-FECNT in brain tissues of mice changed with time, which was accorded with the experiment. The coordinates of striatum, frontal cortex, temporal cortex, occipital cortex, parietal cortex, hippocampus and cerebellum in the solution space were (10.13, 1.49), (4.27, 0.84), (4.48, 0.81), (2.89, 0.98), (3.65, 0.83),(3.55, 0.98) and (2.03, 1.25), respectively. Conclusion: The theory of solution space could be used to study pharmacokinetics of 18F-FECNT in mice brain. (authors)

  13. Dynamics of Mutator and Antibiotic-Resistant Populations in a Pharmacokinetic/Pharmacodynamic Model of Pseudomonas aeruginosa Biofilm Treatment

    DEFF Research Database (Denmark)

    Macià, María D.; Pérez, José L.; Molin, Søren;

    2011-01-01

    Biofilm growth, antibiotic resistance, and mutator phenotypes are key components of chronic respiratory infections by Pseudomonas aeruginosa in cystic fibrosis patients. We examined the dynamics of mutator and antibiotic-resistant populations in P. aeruginosa flow-cell biofilms, using fluorescently...... monitored by confocal laser scanning microscopy (CLSM), and the numbers of viable cells and resistant mutants (4- and 16-fold MICs) were determined. Despite optimized pharmacokinetic/pharmacodynamic (PK/PD) parameters, CIP treatment did not suppress resistance development in P. aeruginosa biofilms. One.......01 proportion, took over the whole biofilm after only 2 days of CIP treatment outnumbering PAO1 by 3 log at t4. Our results show that mutational mechanisms play a major role in biofilm antibiotic resistance and that theoretically optimized PK/PD parameters fail to suppress resistance development, suggesting...

  14. Human-on-a-chip design strategies and principles for physiologically based pharmocokinetics/pharmacodynamics modeling

    OpenAIRE

    Abaci, Hasan Erbil; Shuler, Michael L.

    2015-01-01

    Advances in maintaining multiple human tissues on microfluidic platforms has led to a growing interest in developing microphysiological systems for drug development studies. Determining the proper design principles and scaling rules for body-on-a-chip systems is critical for their strategic incorporation into physiologically based pharmacokinetic (PBPK)/pharmacodynamic model (PD) -aided drug development. While the need for a functional design considering organ-organ interactions has been cons...

  15. Management of antipsychotic treatment discontinuation and interruptions using model-based simulations

    OpenAIRE

    Samtani, Mahesh

    2012-01-01

    Mahesh N Samtani,1 John J Sheehan,2 Dong-Jing Fu,2 Bart Remmerie,3 Jennifer Kern Sliwa,2 Larry Alphs21Janssen Research and Development, Raritan, NJ, USA; 2Janssen Scientific Affairs, Titusville, NJ, USA; 3Janssen Research and Development, Division of Janssen Pharmaceutica, Beerse, BelgiumBackground: Medication nonadherence is a well described and prevalent clinical occurrence in schizophrenia. These pharmacokinetic model-based simulations analyze predicted antipsychotic plasma concentrations ...

  16. Two cholesterol derivative-based PEGylated liposomes as drug delivery system, study on pharmacokinetics and drug delivery to retina

    Science.gov (United States)

    Geng, Shengyong; Yang, Bin; Wang, Guowu; Qin, Geng; Wada, Satoshi; Wang, Jin-Ye

    2014-07-01

    In this study, two cholesterol derivatives, (4-cholesterocarbonyl-4‧-(N,N,N-triethylamine butyloxyl bromide) azobenzene (CAB) and 4-cholesterocarbonyl-4‧-(N,N-diethylamine butyloxyl) azobenzene (ACB), one of which is positively charged while the other is neutral, were synthesized and incorporated with phospholipids and cholesterol to form doxorubicin (DOX)-loaded liposomes. PEGylation was achieved by including 1,2-distearoyl-sn-glycero-3-phosphatiylethanol-amine-N-[methoxy-(polyethylene glycol)-2000 (DSPE-PEG2000). Our results showed that PEGylated liposomes displayed significantly improved stability and the drug leakage was decreased compared to the non-PEGylated ones in vitro. The in vivo study with rats also revealed that the pharmacokinetics and circulation half-life of DOX were significantly improved when liposomes were PEGylated (p cholesterol derivative ACB played some role in improving liposomes’ stability in systemic circulation compared to the conventional PC liposome and the positively charged CAB liposome, with or without PEGylation. In addition, in the case of local drug delivery, the positively charged PEG-liposome not only delivered much more of the drug into the rats’ retinas (p , but also maintained much longer drug retention time compared to the neutral PEGylated liposomes.

  17. Pharmacokinetics, dosimetry and comparative efficacy of 188Re-liposome and 5-FU in a CT26-luc lung-metastatic mice model.

    Science.gov (United States)

    Chen, Liang-Cheng; Wu, Yu-Hsien; Liu, I-Hshiang; Ho, Chung-Li; Lee, Wan-Chi; Chang, Chih-Hsien; Lan, Keng-Li; Ting, Gann; Lee, Te-Wei; Shien, Jui-Hung

    2012-01-01

    The biodistribution, pharmacokinetics, dosimetry and comparative therapeutic efficacy of intravenously administrated (188)Re-N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposome ((188)Re-liposome) and 5-FU were investigated in a CT26-luc lung-metastatic model. After intravenous administration of (188)Re-liposome, tumor accumulation from the radioactivity was observed. Levels of radioactivity in tumors were maintained at steady levels (from 5.40 to 5.67 %ID/g) after 4 to 24 h. In pharmacokinetics, the AUC((0→∞)), MRT((0→∞)) and Cl of (188)Re-liposome in blood via intravenous route were 998 h %ID/ml, 28.7 h and 0.1 ml/h, respectively. The total excreted fractions of feces and urine were 0.61 and 0.26, respectively. Absorbed doses for (188)Re-liposome in the liver and red marrow were 0.31 and 0.08 mSv/MBq, respectively. Tumor-absorbed doses for (188)Re-liposome ranged from 48.4 to 1.73 mGy/MBq at 10 to 300 g tumor spheres. In therapeutic efficacy, the survival times of mice after (188)Re-liposome [80% maximum tolerated dose (MTD); 29.6 MBq], 5-FU (80% MTD; 144 mg/kg), liposome or normal saline treatments were evaluated. Consequently, radiotherapeutics of (188)Re-liposome attained a longer lifespan (increase of 34.9%; P=.005) in mice than in the normal saline group. The increase in lifespan of the (188)Re-liposome group was 2.5-fold greater than that of the 5-FU group. Therefore, intravenous administration of (188)Re-liposome could provide a benefit and it is a promising strategy for delivery of passive nanotargeted radiotherapeutics in oncology applications. PMID:21958858

  18. Pharmacokinetics, dosimetry and comparative efficacy of 188Re-liposome and 5-FU in a CT26-luc lung-metastatic mice model

    International Nuclear Information System (INIS)

    The biodistribution, pharmacokinetics, dosimetry and comparative therapeutic efficacy of intravenously administrated 188Re-N,N-bis(2-mercaptoethyl)-N′,N′-diethylethylenediamine (BMEDA)-labeled pegylated liposome (188Re-liposome) and 5-FU were investigated in a CT26-luc lung-metastatic model. After intravenous administration of 188Re-liposome, tumor accumulation from the radioactivity was observed. Levels of radioactivity in tumors were maintained at steady levels (from 5.40 to 5.67 %ID/g) after 4 to 24 h. In pharmacokinetics, the AUC(0→∞), MRT(0→∞) and Cl of 188Re-liposome in blood via intravenous route were 998 h %ID/ml, 28.7 h and 0.1 ml/h, respectively. The total excreted fractions of feces and urine were 0.61 and 0.26, respectively. Absorbed doses for 188Re-liposome in the liver and red marrow were 0.31 and 0.08 mSv/MBq, respectively. Tumor-absorbed doses for 188Re-liposome ranged from 48.4 to 1.73 mGy/MBq at 10 to 300 g tumor spheres. In therapeutic efficacy, the survival times of mice after 188Re-liposome [80% maximum tolerated dose (MTD); 29.6 MBq], 5-FU (80% MTD; 144 mg/kg), liposome or normal saline treatments were evaluated. Consequently, radiotherapeutics of 188Re-liposome attained a longer lifespan (increase of 34.9%; P=.005) in mice than in the normal saline group. The increase in lifespan of the 188Re-liposome group was 2.5-fold greater than that of the 5-FU group. Therefore, intravenous administration of 188Re-liposome could provide a benefit and it is a promising strategy for delivery of passive nanotargeted radiotherapeutics in oncology applications.

  19. Model-Based Once-Daily Darunavir/Ritonavir Dosing Recommendations in Pediatric HIV-1-Infected Patients Aged ≥3 to <12 Years

    OpenAIRE

    Brochot, A.; Kakuda, TN; Van de Casteele, T; Opsomer, M; Tomaka, FL; Vermeulen, A.; Vis, P.

    2015-01-01

    An existing population pharmacokinetic model of darunavir in adults was updated using pediatric data from two studies evaluating weight-based, once-daily dosing of darunavir/ritonavir (ARIEL, NCT00919854 and DIONE, NCT00915655). The model was then used to provide once-daily dosing recommendations for darunavir/ritonavir in pediatric patients aged ≥3 to

  20. Theophylline Population Pharmacokinetics and Dosing in Children Following Congenital Heart Surgery With Cardiopulmonary Bypass.

    Science.gov (United States)

    Frymoyer, Adam; Su, Felice; Grimm, Paul C; Sutherland, Scott M; Axelrod, David M

    2016-09-01

    Children undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) frequently develop acute kidney injury due to renal ischemia. Theophylline, which improves renal perfusion via adenosine receptor inhibition, is a potential targeted therapy. However, children undergoing cardiac surgery and CPB commonly have alterations in drug pharmacokinetics. To help understand optimal aminophylline (salt formulation of theophylline) dosing strategies in this population, a population-based pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM) from 71 children (median age 5 months; 90% range 1 week to 10 years) who underwent cardiac surgery requiring CPB and received aminophylline as part of a previous randomized controlled trial. A 1-compartment model with linear elimination adequately described the pharmacokinetics of theophylline. Weight scaled via allometry was a significant predictor of clearance and volume. In addition, allometric scaled clearance increased with age implemented as a power maturation function. Compared to prior reports in noncardiac children, theophylline clearance was markedly reduced across age. In the final population pharmacokinetic model, optimized empiric dosing regimens were developed via Monte Carlo simulations. Doses 50% to 75% lower than those recommended in noncardiac children were needed to achieve target serum concentrations of 5 to 10 mg/L. PMID:26712558

  1. Model-based segmentation

    OpenAIRE

    Heimann, Tobias; Delingette, Hervé

    2011-01-01

    This chapter starts with a brief introduction into model-based segmentation, explaining the basic concepts and different approaches. Subsequently, two segmentation approaches are presented in more detail: First, the method of deformable simplex meshes is described, explaining the special properties of the simplex mesh and the formulation of the internal forces. Common choices for image forces are presented, and how to evolve the mesh to adapt to certain structures. Second, the method of point...

  2. A systems approach for tumor pharmacokinetics.

    Directory of Open Access Journals (Sweden)

    Greg Michael Thurber

    Full Text Available Recent advances in genome inspired target discovery, small molecule screens, development of biological and nanotechnology have led to the introduction of a myriad of new differently sized agents into the clinic. The differences in small and large molecule delivery are becoming increasingly important in combination therapies as well as the use of drugs that modify the physiology of tumors such as anti-angiogenic treatment. The complexity of targeting has led to the development of mathematical models to facilitate understanding, but unfortunately, these studies are often only applicable to a particular molecule, making pharmacokinetic comparisons difficult. Here we develop and describe a framework for categorizing primary pharmacokinetics of drugs in tumors. For modeling purposes, we define drugs not by their mechanism of action but rather their rate-limiting step of delivery. Our simulations account for variations in perfusion, vascularization, interstitial transport, and non-linear local binding and metabolism. Based on a comparison of the fundamental rates determining uptake, drugs were classified into four categories depending on whether uptake is limited by blood flow, extravasation, interstitial diffusion, or local binding and metabolism. Simulations comparing small molecule versus macromolecular drugs show a sharp difference in distribution, which has implications for multi-drug therapies. The tissue-level distribution differs widely in tumors for small molecules versus macromolecular biologic drugs, and this should be considered in the design of agents and treatments. An example using antibodies in mouse xenografts illustrates the different in vivo behavior. This type of transport analysis can be used to aid in model development, experimental data analysis, and imaging and therapeutic agent design.

  3. Nanodrugs: pharmacokinetics and safety

    Directory of Open Access Journals (Sweden)

    Onoue S

    2014-02-01

    Full Text Available Satomi Onoue,1 Shizuo Yamada,1 Hak-Kim Chan2 1Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; 2Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia Abstract: To date, various nanodrug systems have been developed for different routes of administration, which include dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles. Nanodrug systems have been employed to improve the efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic profile of pharmaceutical substances. In particular, functionalized nanodrug systems can offer enhanced bioavailability of orally taken drugs, prolonged half-life of injected drugs (by reducing immunogenicity, and targeted delivery to specific tissues. Thus, nanodrug systems might lower the frequency of administration while providing maximized pharmacological effects and minimized systemic side effects, possibly leading to better therapeutic compliance and clinical outcomes. In spite of these attractive pharmacokinetic advantages, recent attention has been drawn to the toxic potential of nanodrugs since they often exhibit in vitro and in vivo cytotoxicity, oxidative stress, inflammation, and genotoxicity. A better understanding of the pharmacokinetic and safety characteristics of nanodrugs and the limitations of each delivery option is necessary for the further development of efficacious nanodrugs with high therapeutic potential and a wide safety margin. This review highlights the recent progress in nanodrug system development, with a focus on the pharmacokinetic advantages and safety challenges. Keywords: nanoparticles, nanotechnology, nanotoxicity, solubilization, targeted delivery

  4. Lecithin and PLGA-based self-assembled nanocomposite, Lecithmer: preparation, characterization, and pharmacokinetic/pharmacodynamic evaluation.

    Science.gov (United States)

    Varghese, Seby Elsy; Fariya, Mayur K; Rajawat, Gopal Singh; Steiniger, Frank; Fahr, Alfred; Nagarsenker, Mangal S

    2016-08-01

    The present study investigates the drug delivery potential of polymer lipid hybrid nanocomposites (Lecithmer®) composed of poly(D,L-lactide-co-glycolide (PLGA) and soya lecithin. Core-shell structure of Lecithmer was evident from cryo-TEM images. Daunorubicin (DNR) and lornoxicam (LNX)-incorporated Lecithmer nanocomposites were evaluated for anticancer and anti-inflammatory activity. DNR- and LNX-loaded Lecithmer had mean particle size of ∼335 and ∼282.7 nm, respectively. Lecithmer formulated with different cationic lipids resulted in lower particle size (∼120 nm) and positive zeta potential. Entrapment efficiency of DNR and LNX was 93.16 and 88.59 %, respectively. In vitro release of DNR from Lecithmer was slower compared to PLGA nanoparticles. DNR release from Lecithmer was significantly higher at pH 5.5 (80.96 %) as compared to pH 7.4 (55.95 %), providing advantage for selective tumor therapy. Similarly, sustained release of LNX (30 % in 10 h) was observed at pH 7.4. DNR in Lecithmer showed superior cytotoxicity on human erythroleukemic K562 cells. Pharmacokinetic study in Wistar rats with i.v. administered DNR-loaded Lecithmer showed higher volume of distribution, lower elimination rate constant, and longer half-life (81.68 L, 0.3535 h(-1), 1.96 h) as compared to DNR solution (57.46 L, 0.4237 h(-1), 1.635 h). Pharmacodynamic evaluation of orally administered LNX-loaded Lecithmer showed superior anti-inflammatory activity with maximum inhibition of 81.2 % vis-à-vis 53.57 % in case of LNX suspension. In light of these results, Lecithmer can be envisaged as a promising nanosystem for parenteral as well as oral drug delivery. PMID:27371394

  5. Clinical pharmacokinetics of melatonin

    DEFF Research Database (Denmark)

    Harpsøe, Nathja Groth; Andersen, Lars Peter Holst; Gögenur, Ismail;

    2015-01-01

    PURPOSE: The aim of the review was to provide an overview of studies investigating the pharmacokinetics of exogenous melatonin in humans and if possible, to provide recommendations for clinical use. METHODS: The review was conducted in accordance to PRISMA guidelines. A systematic literature search...... 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...... between 35 (0.005 mg, IV) 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...

  6. Model Based Definition

    Science.gov (United States)

    Rowe, Sidney E.

    2010-01-01

    In September 2007, the Engineering Directorate at the Marshall Space Flight Center (MSFC) created the Design System Focus Team (DSFT). MSFC was responsible for the in-house design and development of the Ares 1 Upper Stage and the Engineering Directorate was preparing to deploy a new electronic Configuration Management and Data Management System with the Design Data Management System (DDMS) based upon a Commercial Off The Shelf (COTS) Product Data Management (PDM) System. The DSFT was to establish standardized CAD practices and a new data life cycle for design data. Of special interest here, the design teams were to implement Model Based Definition (MBD) in support of the Upper Stage manufacturing contract. It is noted that this MBD does use partially dimensioned drawings for auxiliary information to the model. The design data lifecycle implemented several new release states to be used prior to formal release that allowed the models to move through a flow of progressive maturity. The DSFT identified some 17 Lessons Learned as outcomes of the standards development, pathfinder deployments and initial application to the Upper Stage design completion. Some of the high value examples are reviewed.

  7. Herb drug interaction:effect of Manix® on pharmacokinetic parameters of pefloxacin in rat model

    Institute of Scientific and Technical Information of China (English)

    Nduka Sunday Odunke; Okonta Eleje; Abba Chika Christiana; Ihekwereme Chibueze Peter; Ekwedigwe Uchenna; Okonta Matthew

    2014-01-01

    Objective: To evaluate the effect of Manix®, the commonly used polyherbal formulation on pefloxacin pharmacokinetic parameters.Methods:from hospitalized patients.Results:Microbiological assay was employed using clinical isolate of Escherichia coli samples Manix® altered the bioavailability parameters of pefloxacin as thus, maximal concentration (Cmax) of pefloxacin (0.91±0.31) µg/mL occurred at time to reach maximal concentration (tmax) 4.0 h while in the group that received Manix® alongside pefloxacin Cmax was (0.22±0.08) µg/mL at tmax 1.0 h respectively. The area under curve of pefloxacin alone was (7.83±5.14) µg/h/mL while with Manix® was (2.60±0.08) µg/h/mL. There was a significant difference between Cmax, tmax and area under curve between pefloxacin alone and pefloxacin after Manix® pre-treatment (P<0.05).Conclusions:The concurrent use of Manix® and pefloxacin has been found to compromise the therapeutic effectiveness of pefloxacin which could lead to poor clinical outcomes in patients.

  8. Azithromycin maintenance therapy in patients with cystic fibrosis : A dose advice based on a review of pharmacokinetics, efficacy, and side effects

    NARCIS (Netherlands)

    Wilms, Erik B.; Touw, Daniel J.; Heijerman, Harry G.M.; Van Der Ent, Cornelis K.

    2012-01-01

    Azithromycin maintenance therapy results in improvement of respiratory function in patients with cystic fibrosis (CF). In azithromycin maintenance therapy, several dosing schemes are applied. In this review, we combine current knowledge about azithromycin pharmacokinetics with the dosing schedules u

  9. A Review of Morphine and Morphine-6-Glucuronide's Pharmacokinetic-Pharmacodynamic Relationships in Experimental and Clinical Pain

    DEFF Research Database (Denmark)

    Sverrisdóttir, Eva; Lund, Trine Meldgaard; Olesen, Anne Estrup;

    2015-01-01

    Morphine is a widely used opioid for treatment of moderate to severe pain, but large interindividual variability in patient response and no clear guidance on how to optimise morphine dosage regimen complicates treatment strategy for clinicians. Population pharmacokinetic-pharmacodynamic models can...... provides a detailed overview of the published human population pharmacokinetic-pharmacodynamic studies for morphine analgesia in addition to basic drug disposition and pharmacological properties of morphine and its analgesic active metabolite, morphine-6-glucuronide, that may help identify future...... covariates. Furthermore, based on simulations from key pharmacokinetic-pharmacodynamic models, the contribution of morphine-6-glucuronide to the analgesic response in patients with renal insufficiency was investigated. Simulations were also used to examine the impact of effect-site equilibration half-life on...

  10. 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.

  11. Population pharmacokinetics of remifentanil in patients undergoing orthotopic liver transplantation

    Institute of Scientific and Technical Information of China (English)

    ZHANG Li-ping; YANG Lu; BI Shan-shan; LU Wei; ZHANG Xian-hua; ZHAI Suo-di; DUAN Li-ping

    2009-01-01

    Backgroud Little is known about the influence of liver transplantation on the pharmacokinetics of most anesthetic drugs. The goal of this study was to study the population pharmacokinetics of remifentanil in the different phases of orthotopic liver transplantation (OLT) and the influence of relevant factors.Methods Thirteen adult patients undergoing OLT were enrolled. A single bolus infusion of remifentanil 5 μg/kg was administered during the preanhepatic, anhepatic and neohepatic phases of OLT. Arterial blood samples of 1.5 ml were collected at 0 (baseline), 1, 2, 3, 5, 7, 10, 15, 20, 25, 30, 45, 60 and 90 minutes after drug administration. Remifentanil concentration was assayed by high-performance liquid chromatography/mass spectrometry/mass spectrometry (HPLC/MS/MS). Population pharmacokinetic modeling was performed using nonlinear mixed-effects modeling (NONMEM).Results The pharmacokinetics of remifentanil in patients undergoing OLT was best described by a two-compartment open model. The pharmacokinetic parameters were not influenced by age, gender, operative phase, blood temperature, rehydration volume, or blood loss volume during sampling. The volume of distribution in the central compartment (V1) and the volume of distribution in the peripheral compartment (V2) were influenced by body weight. Conclusions The population pharmacokinetics of remifentanil in patients undergoing OLT can be well described by a two-compartment open model. The functional status of the liver does not significantly affect the pharmacokinetics of remifentanil, but the body weight is an influential factor of V1 and V2.

  12. Comparison of Pharmacokinetics and Safety of Voriconazole Intravenous-to-Oral Switch in Immunocompromised Adolescents and Healthy Adults ▿

    OpenAIRE

    Driscoll, Timothy A.; Frangoul, Haydar; Nemecek, Eneida R.; Murphey, Donald K.; Yu, Lolie C.; Blumer, Jeffrey; Krance, Robert A; Baruch, Alice; Liu, Ping

    2011-01-01

    The current voriconazole dosing recommendation in adolescents is based on limited efficacy and pharmacokinetic data. To confirm the appropriateness of dosing adolescents like adults, a pharmacokinetic study was conducted in 26 immunocompromised adolescents aged 12 to

  13. Clinical Pharmacokinetic and Pharmacodynamic Profile of Idelalisib.

    Science.gov (United States)

    Ramanathan, Srinivasan; Jin, Feng; Sharma, Shringi; Kearney, Brian P

    2016-01-01

    Idelalisib is a potent and selective phosphatidylinositol 3-kinase-δ inhibitor, which is a first-in-class agent to be approved for the treatment of relapsed chronic lymphocytic leukaemia, follicular B cell non-Hodgkin's lymphoma and small lymphocytic lymphoma. In dose-ranging studies, idelalisib exposure increased in a less than dose-proportional manner, likely because of solubility-limited absorption. The approved starting dose of 150 mg twice daily was supported by extensive exposure-response evaluations, with dose reduction to 100 mg twice daily being allowed for specific toxicities. Idelalisib may be administered without regard to food on the basis of the absence of clinically relevant food effects, and was accordingly dosed in primary efficacy/safety studies. Idelalisib is metabolized primarily via aldehyde oxidase (AO) and, to a lesser extent, via cytochrome P450 (CYP) 3A. Coadministration with the strong CYP3A inhibitor ketoconazole 400 mg once daily resulted in a ~79 % increase in the idelalisib area under the plasma concentration-time curve (AUC). Administration with the potent inducer rifampin resulted in a 75 % decrease in idelalisib exposure (AUC) and, as such, coadministration with strong inducers should be avoided. GS-563117 is an inactive primary circulating metabolite of idelalisib formed mainly via AO. Unlike idelalisib, GS-563117 is a mechanism-based inhibitor of CYP3A. Accordingly, idelalisib 150 mg twice-daily dosing increases the midazolam AUC 5.4-fold. Clinically, idelalisib is not an inhibitor of the transporters P-glycoprotein, breast cancer resistance protein, organic anion-transporting polypeptide (OATP) 1B1 or OAPT1B3. In a population pharmacokinetic model, no meaningful impact on idelalisib pharmacokinetics was noted for any of the covariates tested. Idelalisib exposure was ~60 % higher with moderate/severe hepatic impairment; no relevant changes were observed with severe renal impairment. This article reviews a comprehensive

  14. 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 and...

  15. Nanodrugs: pharmacokinetics and safety.

    Science.gov (United States)

    Onoue, Satomi; Yamada, Shizuo; Chan, Hak-Kim

    2014-01-01

    To date, various nanodrug systems have been developed for different routes of administration, which include dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles. Nanodrug systems have been employed to improve the efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic profile of pharmaceutical substances. In particular, functionalized nanodrug systems can offer enhanced bioavailability of orally taken drugs, prolonged half-life of injected drugs (by reducing immunogenicity), and targeted delivery to specific tissues. Thus, nanodrug systems might lower the frequency of administration while providing maximized pharmacological effects and minimized systemic side effects, possibly leading to better therapeutic compliance and clinical outcomes. In spite of these attractive pharmacokinetic advantages, recent attention has been drawn to the toxic potential of nanodrugs since they often exhibit in vitro and in vivo cytotoxicity, oxidative stress, inflammation, and genotoxicity. A better understanding of the pharmacokinetic and safety characteristics of nanodrugs and the limitations of each delivery option is necessary for the further development of efficacious nanodrugs with high therapeutic potential and a wide safety margin. This review highlights the recent progress in nanodrug system development, with a focus on the pharmacokinetic advantages and safety challenges. PMID:24591825

  16. Pharmacokinetic profile of zafirlukast.

    NARCIS (Netherlands)

    Dekhuijzen, P.N.R.; Koopmans, P.P.

    2002-01-01

    Zafirlukast is a cysteinyl leukotriene type 1 receptor antagonist that causes bronchodilation and has anti-inflammatory properties. Clinical efficacy has been demonstrated when using oral doses of 20 to 40 mg twice daily. The pharmacokinetics of zafirlukast are best described by a two-compartment mo

  17. SYMBOLS IN PHARMACOKINETICS1

    OpenAIRE

    Rowland, Malcolm; Tucker, Geoffrey

    1982-01-01

    To encourage uniformity in the presentation of pharmacokinetic data, a general nomenclature has been developed. The system has wide application. Flexibility is achieved through the use of general variables, constants, qualifying terms and subscripts. Yet, through the use of implied terms, the symbols describing many common variables and constants are simple.

  18. Pharmacokinetics of labelled compounds with technetium-99m and samarium-153

    International Nuclear Information System (INIS)

    The purpose of this investigation was to establish the different pharmacokinetics parameters of the main radiopharmaceuticals labeled with technetium-99m and samarium-153. These parameters could be subsequently used as reference to compare other products with the same use. Mathematical models and a computerized pharmacokinetic program were used to this purpose. A biodistribution study in quadruplicate and/or quintuplicate was conducted for each radiopharmaceutical, data was was obtained in injection dose percentages. The biodistribution study involved the injection of a predetermined dose of the radiopharmaceutical into animals (rats or mice), which were subsequently put away at different time intervals, removing the relevant organs. Activity in each organ was read by means of a well-type NaI scintillation counter, data obtained in activity counts was transformed into injection dose percentages. Based on these percentages, the mathematical model was constructed and the pharmacokinetic parameters were obtained using the computerized program Expo 2 v. 1, which is written in C language and works in windows. Analyzing the results obtained, we can conclude that the use of the Expo 2 v. 1 program for a bi compartmental analysis allowed us to obtain reliable pharmacokinetic parameters which describe what happens in the organism when the radiopharmaceutical passes from the central compartment to the peripheral one and vice versa

  19. Pharmacokinetics of Acetaminophen in Hind Limbs Unloaded Mice: A Model System Simulating the Effects of Low Gravity on Astronauts in Space

    Science.gov (United States)

    Peterson, Amanda; Risin, Semyon A.; Ramesh, Govindarajan T.; Dasgupta, Amitava; Risin, Diana

    2008-01-01

    The pharmacokinetics (PK) of medications administered to astronauts could be altered by the conditions in Space. Low gravity and free floating (and associated hemodynamic changes) could affect the absorption, distribution, metabolism and excretion of the drugs. Knowledge of these alterations is essential for adjusting the dosage and the regimen of drug administration in astronauts. Acquiring of such knowledge has inherent difficulties due to limited opportunities for experimenting in Space. One of the approaches is to use model systems that simulate some of the Space conditions on Earth. In this study we used hind limbs unloaded mice (HLU) to investigate the possible changes in PK of acetaminophen, a widely used analgesic with high probability of use by astronauts. The HLU is recognized as an appropriate model for simulating the effects of low gravity on hemodynamic parameters. Mice were tail suspended (n = 24) for 24-96 hours prior to introduction of acetaminophen (150 - 300 mg/kg). The drug (in aqueous solution containing 10% ethyl alcohol by volume) was given orally by a gavage procedure and after the administration of acetaminophen mice were additionally suspended for 30 min, 1 and 2 hours. Control mice (n = 24) received the same dose of acetaminophen and were kept freely all the time. Blood specimens were obtained either from retroorbital venous sinuses or from heart. Acetaminophen concentration was measured in plasma by the fluorescent polarization immunoassay and the AxSYM analyzer (Abbott Laboratories). In control mice peak acetaminophen concentration was achieved at 30 min. By 1 hour the concentration decreased to less than 50% of the peak level and at 2 hours the drug was almost undetectable in the serum. HLU for 24 hours significantly altered the acetaminophen pharmacokinetic: at 30 min the acetaminophen concentrations were significantly (both statistically and medically significant) lower than in control mice. The concentrations also reduced less

  20. Prediction and monitoring of the response to chemoradiotherapy in oral squamous cell carcinomas using a pharmacokinetic analysis based on the dynamic contrast-enhanced MR imaging findings

    Energy Technology Data Exchange (ETDEWEB)

    Chikui, Toru; Kawazu, Toshiyuki; Yoshiura, Kazunori [Kyushu University, Department of Oral and Maxillofacial Radiology, Faculty of Dental Science, Fukuoka (Japan); Kawano, Shintaro [Kyushu University, Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Fukuoka (Japan); Hatakenaka, Masamitsu [Kyushu University, Department of Clinical Radiology, Graduate School of Medical Sciences, Fukuoka (Japan); Kyushu University, Radiology Center, Kyushu University Hospital, Fukuoka (Japan); Koga, Syouzou; Ohga, Masahiro [Kyushu University, Radiology Center, Kyushu University Hospital, Fukuoka (Japan); Matsuo, Yoshio; Sunami, Syunya [Kyushu University, Department of Clinical Radiology, Graduate School of Medical Sciences, Fukuoka (Japan); Sugiura, Tsuyoshi [Kyushu University, Department of Maxillofacial Surgery, Kyushu University Hospital, Fukuoka (Japan); Shioyama, Yoshiyuki [Kyushu University, Department of Heavy Particle Therapy and Radiation Oncology, Graduate School of Medical Sciences, Fukuoka (Japan); Obara, Makoto [Philips Electronics Japan, Ltd 2-13-37, Konan Minato-ku, Tokyo (Japan)

    2011-08-15

    To evaluate whether a pharmacokinetic analysis is useful for both predicting and monitoring the response to chemoradiotherapy (CRT) in oral cancer. Patients with oral squamous cell carcinoma treated with preoperative CRT and surgery were enrolled. They underwent dynamic contrast-enhanced MRI before (n = 23), and after CRT (n = 20). We estimated four parameters: arrival time of contrast medium (TA), exchange rate constant from the extracellular extravascular space (EES) to plasma (k{sub ep}), elimination of contrast medium from the central compartment (k{sub el}) and an amplitude scaling constant (AH) using the Brix model. The histological evaluation of the effects of CRT was performed according to Ohboshi and Shimosato's classification. We analysed the correlation between the parameters and the histological evaluation. The pre-CRT AH between the responders and non-responders was significantly different (P = 0.046), however, the three parameters (TA, K{sub ep}, K{sub el}) were not significantly different among the groups (P = 0.76, P = 0.60, P = 0.09). As AH decreased, the tumour response improved. The change in the AH between the pre- and post-CRT of responders was significantly higher than that of non-responders (P = 0.043). The AH, which is affected by the ratio of the EES, was an important parameter for predicting and monitoring the tumour response to CRT. (orig.)

  1. Methods for Addressing Uncertainty and Variability to Characterize Potential Health Risk From Trichloroethylene-Contaminated Ground Water Beale Air Force Base in California: Integration of Uncertainty and Variability in Pharmacokinetics and Dose-Response

    Energy Technology Data Exchange (ETDEWEB)

    Bogen, K.T.

    1999-09-29

    Traditional estimates of health risk are typically inflated, particularly if cancer is the dominant endpoint and there is fundamental uncertainty as to mechanism(s) of action. Risk is more realistically characterized if it accounts for joint uncertainty and interindividual variability after applying a unified probabilistic approach to the distributed parameters of all (linear as well as nonlinear) risk-extrapolation models involved. Such an approach was applied to characterize risks to potential future residents posed by trichloroethylene (TCE) in ground water at an inactive landfill site on Beale Air Force Base in California. Variability and uncertainty were addressed in exposure-route-specific estimates of applied dose, in pharmacokinetically based estimates of route-specific metabolized fractions of absorbed TCE, and in corresponding biologically effective doses estimated under a genotoxic/linear (MA{sub g}) vs. a cytotoxic/nonlinear (MA{sub c}) mechanistic assumption for TCE-induced cancer. Increased risk conditional on effective dose was estimated under MA{sub G} based on seven rodent-bioassay data sets, and under MA, based on mouse hepatotoxicity data. Mean and upper-bound estimates of combined risk calculated by the unified approach were <10{sup -6} and <10{sup -4}, respectively, while corresponding estimates based on traditional deterministic methods were >10{sup -5} and >10{sup -4}, respectively. It was estimated that no TCE-related harm is likely occur due any plausible residential exposure scenario involving the site. The unified approach illustrated is particularly suited to characterizing risks that involve uncertain and/or diverse mechanisms of action.

  2. Methods for Addressing Uncertainty and Variability to Characterize Potential Health Risk from Trichloroethylene-Contaminated Ground Water at Beale Air Force Base in California:Integration of Uncertainty and Variability in Pharmacokinetics and Dose-Response

    Energy Technology Data Exchange (ETDEWEB)

    Bogen, K T

    2001-05-24

    Traditional estimates of health risk are typically inflated, particularly if cancer is the dominant endpoint and there is fundamental uncertainty as to mechanism(s) of action. Risk is more realistically characterized if it accounts for joint uncertainty and interindividual variability within a systematic probabilistic framework to integrate the joint effects on risk of distributed parameters of all (linear as well as nonlinear) risk-extrapolation models involved. Such a framework was used to characterize risks to potential future residents posed by trichloroethylene (TCE) in ground water at an inactive landfill site on Beale Air Force Base in California. Variability and uncertainty were addressed in exposure-route-specific estimates of applied dose, in pharmacokinetically based estimates of route-specific metabolized fractions of absorbed TCE, and in corresponding biologically effective doses estimated under a genotoxic/linear (MA{sub G}) vs. a cytotoxic/nonlinear (MA{sub c}) mechanistic assumption for TCE-induced cancer. Increased risk conditional on effective dose was estimated under MA{sub G} based on seven rodent-bioassay data sets, and under MA{sub c} based on mouse hepatotoxicity data. Mean and upper-bound estimates of combined risk calculated by the unified approach were <10{sup -6} and 10{sup -4}, respectively, while corresponding estimates based on traditional deterministic methods were >10{sup -5} and 10{sup -4}, respectively. It was estimated that no TCE-related harm is likely to occur due to any plausible residential exposure scenario involving the site. The systematic probabilistic framework illustrated is particularly suited to characterizing risks that involve uncertain and/or diverse mechanisms of action.

  3. LSTM based Conversation Models

    OpenAIRE

    Luan, Yi; Ji, Yangfeng; Ostendorf, Mari

    2016-01-01

    In this paper, we present a conversational model that incorporates both context and participant role for two-party conversations. Different architectures are explored for integrating participant role and context information into a Long Short-term Memory (LSTM) language model. The conversational model can function as a language model or a language generation model. Experiments on the Ubuntu Dialog Corpus show that our model can capture multiple turn interaction between participants. The propos...

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

    Science.gov (United States)

    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

  5. Tools to evaluate pharmacokinetics data for establishing maximum residue limits for approved veterinary drugs: examples from JECFA's work.

    Science.gov (United States)

    Sanders, P; Henri, J; Laurentie, M

    2016-05-01

    Maximum residue limits (MRLs) for residues of veterinary drugs are the maximum concentrations of residues permitted in or on a food by national or regional legislation. In the process of MRLs recommendations by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), analysis of pharmacokinetic data describing the ADME process (absorption, distribution, metabolism and excretion) is a crucial step and requires the use of different pharmacokinetic tools. The results of animal metabolism studies are the prime determinants of the residue definition in food commodities. Substances labelled with radioactive isotopes are used so that the disposition of the residue can be followed as total residue and main metabolites concentrations. Residue depletion studies with radiolabelled parent drug will lead to the estimate of the time course of the total residue and to determine a marker residue. Depletion studies with an unlabelled drug provide more information on the time course of the marker residue in raw commodities after administration under approved practical conditions of use. By use of this information and after conversion with the total/residue marker ratio, MRLs are derived by comparison of the acceptable daily intake with the daily intakes calculated with different scenarios of dietary exposure. Progress in pharmacokinetic model such as physiologically based pharmacokinetics and population pharmacokinetics will drive the future research in this field to improved veterinary drug development. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27443212

  6. Pharmacokinetics, micro-SPECT/CT imaging and therapeutic efficacy of 188Re-DXR-liposome in C26 colon carcinoma ascites mice model

    International Nuclear Information System (INIS)

    The pharmacokinetics and internal radionuclide therapy of intraperitoneally administrated 188Re-N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomal doxorubicin (188Re-DXR-liposome) were investigated in the C26 murine colon carcinoma ascites mouse model. After intraperitoneal administration of the nanotargeted bimodality 188Re-DXR-liposome, the ascites and tumor accumulation of the radioactivity were observed, the levels of radioactivity within the ascites were maintained at relatively higher levels before 48 h and the levels of radioactivity in the tumor were maintained at steady levels after 4 h. The AUC(o→∞) of 188Re-DXR-liposome in blood, ascites and tumor was 9.3-, 4.2- and 4.7-fold larger than that of 188Re-BMEDA, respectively. The maximum tolerated dose of intraperitoneally administrated 188Re-DXR-liposome was determined in normal BALB/c mice. The survival, tumor and ascites inhibition of mice after 188Re-DXR-liposome (22.2 MBq of 188Re, 5 mg/kg of DXR) treatment were evaluated. Consequently, radiochemotherapeutics of 188Re-DXR-liposome attained better survival time, tumor and ascites inhibition (decreased by 49% and 91% at 4 days after treatment; P188Re-liposome or chemotherapeutics of Lipo-Dox did. Therefore, intraperitoneal administration of novel 188Re-DXR-liposome could provide a benefit and promising strategy for delivery of passive nanotargeted bimodality radiochemotherapeutics in oncology applications

  7. Pharmacokinetics, micro-SPECT/CT imaging and therapeutic efficacy of (188)Re-DXR-liposome in C26 colon carcinoma ascites mice model.

    Science.gov (United States)

    Chen, Liang-Cheng; Chang, Chih-Hsien; Yu, Chia-Yu; Chang, Ya-Jen; Wu, Yu-Hsien; Lee, Wan-Chi; Yeh, Chung-Hsin; Lee, Te-Wei; Ting, Gann

    2008-11-01

    The pharmacokinetics and internal radionuclide therapy of intraperitoneally administrated (188)Re-N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomal doxorubicin ((188)Re-DXR-liposome) were investigated in the C26 murine colon carcinoma ascites mouse model. After intraperitoneal administration of the nanotargeted bimodality (188)Re-DXR-liposome, the ascites and tumor accumulation of the radioactivity were observed, the levels of radioactivity within the ascites were maintained at relatively higher levels before 48 h and the levels of radioactivity in the tumor were maintained at steady levels after 4 h. The AUC((o-->infinity)) of (188)Re-DXR-liposome in blood, ascites and tumor was 9.3-, 4.2- and 4.7-fold larger than that of (188)Re-BMEDA, respectively. The maximum tolerated dose of intraperitoneally administrated (188)Re-DXR-liposome was determined in normal BALB/c mice. The survival, tumor and ascites inhibition of mice after (188)Re-DXR-liposome (22.2 MBq of (188)Re, 5 mg/kg of DXR) treatment were evaluated. Consequently, radiochemotherapeutics of (188)Re-DXR-liposome attained better survival time, tumor and ascites inhibition (decreased by 49% and 91% at 4 days after treatment; Ppassive nanotargeted bimodality radiochemotherapeutics in oncology applications. PMID:19026950

  8. Population stochastic modelling (PSM)--an R package for mixed-effects models based on stochastic differential equations.

    Science.gov (United States)

    Klim, Søren; Mortensen, Stig Bousgaard; Kristensen, Niels Rode; Overgaard, Rune Viig; Madsen, Henrik

    2009-06-01

    The extension from ordinary to stochastic differential equations (SDEs) in pharmacokinetic and pharmacodynamic (PK/PD) modelling is an emerging field and has been motivated in a number of articles [N.R. Kristensen, H. Madsen, S.H. Ingwersen, Using stochastic differential equations for PK/PD model development, J. Pharmacokinet. Pharmacodyn. 32 (February(1)) (2005) 109-141; C.W. Tornøe, R.V. Overgaard, H. Agersø, H.A. Nielsen, H. Madsen, E.N. Jonsson, Stochastic differential equations in NONMEM: implementation, application, and comparison with ordinary differential equations, Pharm. Res. 22 (August(8)) (2005) 1247-1258; R.V. Overgaard, N. Jonsson, C.W. Tornøe, H. Madsen, Non-linear mixed-effects models with stochastic differential equations: implementation of an estimation algorithm, J. Pharmacokinet. Pharmacodyn. 32 (February(1)) (2005) 85-107; U. Picchini, S. Ditlevsen, A. De Gaetano, Maximum likelihood estimation of a time-inhomogeneous stochastic differential model of glucose dynamics, Math. Med. Biol. 25 (June(2)) (2008) 141-155]. PK/PD models are traditionally based ordinary differential equations (ODEs) with an observation link that incorporates noise. This state-space formulation only allows for observation noise and not for system noise. Extending to SDEs allows for a Wiener noise component in the system equations. This additional noise component enables handling of autocorrelated residuals originating from natural variation or systematic model error. Autocorrelated residuals are often partly ignored in PK/PD modelling although violating the hypothesis for many standard statistical tests. This article presents a package for the statistical program R that is able to handle SDEs in a mixed-effects setting. The estimation method implemented is the FOCE(1) approximation to the population likelihood which is generated from the individual likelihoods that are approximated using the Extended Kalman Filter's one-step predictions. PMID:19268387

  9. Pharmacokinetic evaluation of pemetrexed

    DEFF Research Database (Denmark)

    Sørensen, Jens Benn

    2011-01-01

    currently published pharmacokinetic data of pemetrexed reviewing a number of different scenarios and patient populations. All the articles reviewed in this manuscript are from peer-reviewed English-spoken literature without any limitations to the time of publication. EXPERT OPINION: Pemetrexed's clearance...... 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...... or targeted agents. It is the author's opinion that pemetrexed is already a valuable cytotoxic agent which has proved useful in several malignancies. However, future trials might expand on the combined use of pemetrexed with other targeted agents that could be beneficial to other selected patients...

  10. Pharmacokinetic evaluation of pemetrexed

    DEFF Research Database (Denmark)

    Sørensen, Jens Benn

    2011-01-01

    currently published pharmacokinetic data of pemetrexed reviewing a number of different scenarios and patient populations. All the articles reviewed in this manuscript are from peer-reviewed English-spoken literature without any limitations to the time of publication. EXPERT OPINION: Pemetrexed's clearance...... 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...... or targeted agents. It is the author's opinion that pemetrexed is already a valuable cytotoxic agent which has proved useful in several malignancies. However, future trials might expand on the combined use of pemetrexed with other targeted agents that could be beneficial to other selected patients...

  11. Pharmacokinetic consequences of spaceflight

    Science.gov (United States)

    Putcha, L.; Cintron, N. M.

    1991-01-01

    Spaceflight induces a wide range of physiological and biochemical changes, including disruption of gastrointestinal (GI) function, fluid and electrolyte balance, circulatory dynamics, and organ blood flow, as well as hormonal and metabolic perturbations. Any of these changes can influence the pharmacokinetics and pharmacodynamics of in-flight medication. That spaceflight may alter bioavailability was proposed when drugs prescribed to alleviate space motion sickness (SMS) had little therapeutic effect. Characterization of the pharmacokinetic and/or pharmacodynamic behavior of operationally critical medications is crucial for their effective use in flight; as a first step, we sought to determine whether drugs administered in space actually reach the site of action at concentrations sufficient to elicit the therapeutic response.

  12. Pharmacokinetics and Bioequivalence Evaluation of Cyclobenzaprine Tablets

    Directory of Open Access Journals (Sweden)

    Tatiane Maria de Lima Souza Brioschi

    2013-01-01

    Full Text Available The purpose of this study was to investigate cyclobenzaprine pharmacokinetics and to evaluate bioequivalence between two different tablet formulations containing the drug. An open, randomized, crossover, single-dose, two-period, and two-sequence design was employed. Tablets were administered to 23 healthy subjects after an overnight fasting and blood samples were collected up to 240 hours after drug administration. Plasma cyclobenzaprine was quantified by means of an LC-MS/MS method. Pharmacokinetic parameters related to absorption, distribution, and elimination were calculated. Cyclobenzaprine plasma profiles for the reference and test products were similar, as well as absorption pharmacokinetic parameters AUC (reference: 199.4 ng∗h/mL; test: 201.6 ng∗h/mL, (reference: 7.0 ng/mL; test: 7.2 ng/mL, and (reference: 4.5 h; test: 4.6 h. Bioequivalence was evaluated by means of 90% confidence intervals for the ratio of AUC (93%–111% and (93%–112% values for test and reference products, which were within the 80%–125% interval proposed by FDA. Cyclobenzaprine pharmacokinetics can be described by a multicompartment open model with an average rapid elimination half-life ( of 3.1 hours and an average terminal elimination half-life ( of 31.9 hours.

  13. Pharmacokinetics and molecular detoxication.

    OpenAIRE

    Cashman, J R; Perotti, B Y; Berkman, C E; J. Lin

    1996-01-01

    This paper presents a comprehensive overview of the pharmacokinetic parameters used from in vivo and in vitro studies that are important in order to understand the major conceptual approaches of toxicokinetics and the disposition of environmental chemicals. In vitro biochemical information concerning the detoxication of environmental chemicals is also presented. The discussion leads to a more complete appreciation for the use of in vitro measurements for in vivo correlations. The concept of i...

  14. Pharmacokinetics of Cannabinoids

    OpenAIRE

    McGilveray, Iain J

    2005-01-01

    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 ...

  15. Pharmacokinetics of fexofenadine

    DEFF Research Database (Denmark)

    Lappin, Graham; Shishikura, Yoko; Jochemsen, Roeline;

    2010-01-01

    . Urine was collected and analysed for total (14)C. Good concordance between the microdose and therapeutic dose pharmacokinetics was observed. Microdose: CL 13L/h, CL(R) 4.1L/h, V(ss) 54L, t(1/2) 16h; therapeutic dose: CL 16L/h, CL(R) 6.2L/h, V(ss) 64L, t(1/2) 12h. The absolute oral bioavailability of...

  16. Nanodrugs: pharmacokinetics and safety

    OpenAIRE

    Onoue S; Yamada S; Chan HK

    2014-01-01

    Satomi Onoue,1 Shizuo Yamada,1 Hak-Kim Chan2 1Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; 2Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia Abstract: To date, various nanodrug systems have been developed for different routes of administration, which include dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nan...

  17. Clinical pharmacokinetics of dapsone.

    Science.gov (United States)

    Zuidema, J; Hilbers-Modderman, E S; Merkus, F W

    1986-01-01

    Dapsone (DDS) has for about 4 decades been the most important antileprosy drug. Concentrations of dapsone and its monoacetyl metabolite, MADDS, can be determined in biological media by high-performance liquid chromatography. After oral administration, the drug is slowly absorbed, the maximum concentration in plasma being reached at about 4 hours, with an absorption half-life of about 1.1 hours. However, the extent of absorption has not been adequately determined. The elimination half-life of dapsone is about 30 hours. The drug shows linear pharmacokinetics within the therapeutic range and the time-course after oral administration fits a 2-compartment model. The concentration-time profile of dapsone after parenteral administration is reviewed. Of clinical importance is the development of a new long acting injection, which permits monthly supervised administration as recommended by the World Health Organization. Following dapsone injection in gluteal subcutaneous adipose tissue, a sufficiently sustained absorption for this purpose has been reported. Dapsone is about 70 to 90% protein bound and its monoacetylated metabolite (MADDS) is almost completely protein bound. The volume of distribution of dapsone is estimated to be 1.5 L/kg. It is distributed in most tissues, but M. leprae living in the Schwann cells of the nerves might be unaffected. Dapsone crosses the placenta and is excreted in breast milk and saliva. Dapsone is extensively metabolised. Dapsone, some MADDS and their hydroxylated metabolites are found in urine, partly conjugated as N-glucuronides and N-sulphates. The acetylation ratio (MADDS:dapsone) shows a genetically determined bimodal distribution and allows the definition of 'slow' and 'rapid' acetylators. As enterohepatic circulation occurs, the elimination half-life of dapsone is markedly decreased after oral administration of activated charcoal. This permits successful treatment in cases of intoxication. The daily dose of dapsone in leprosy is 50 to

  18. Michaelis-Menten Kinetics under Spatially Constrained Conditions: Application to Mibefradil Pharmacokinetics

    OpenAIRE

    Kosmidis, Kosmas; Karalis, Vangelis; Argyrakis, Panos; Macheras, Panos

    2004-01-01

    Two different approaches were used to study the kinetics of the enzymatic reaction under heterogeneous conditions to interpret the unusual nonlinear pharmacokinetics of mibefradil. Firstly, a detailed model based on the kinetic differential equations is proposed to study the enzymatic reaction under spatial constraints and in vivo conditions. Secondly, Monte Carlo simulations of the enzyme reaction in a two-dimensional square lattice, placing special emphasis on the input and output of the su...

  19. Physiologically Based Pharmacokinetic (PBPK) Modeling of Interstrain Variability in Trichloroethylene Metabolism in the Mouse

    Science.gov (United States)

    Background: Quantitative estimation of toxicokinetic variability in the human population is a persistent challenge in risk assessment of environmental chemicals. Traditionally, inter-individual differences in the population are accounted for by default assumptions or, in rare cas...

  20. Physiologically Based Pharmacokinetic Models: Integration of In Silico Approaches with Micro Cell Culture Analogues

    OpenAIRE

    Chen, A.; Yarmush, M L; Maguire, T.

    2012-01-01

    There is a large emphasis within the pharmaceutical industry to provide tools that will allow early research and development groups to better predict dose ranges for and metabolic responses of candidate molecules in a high throughput manner, prior to entering clinical trials. These tools incorporate approaches ranging from PBPK, QSAR, and molecular dynamics simulations in the in silico realm, to micro cell culture analogue (CCAs)s in the in vitro realm. This paper will serve to review these a...

  1. Development of a physiologically based pharmacokinetic model for flunixin in cattle (Bos taurus)

    Science.gov (United States)

    Violative residues of flunixin in tissues from bob veal calves and cull dairy cows has been attributed to noncompliance with the FDA-approved route of administration and withdrawal time, however, the effect of administration route and physiological differences among animals on tissue residue depleti...

  2. Pharmacokinetics of ambroxol and clenbuterol tablets in healthy Chinese volunteers

    OpenAIRE

    Yang, Yong-Ge; Song, Li-Xue; Jiang, Nan; Xu, Xue-Ting; Di, Xiao-Hui; Zhang, Mei

    2015-01-01

    Objective: To investigate the pharmacokinetics of Ambroxol and Clenbuterol Tablets in Chinese healthy volunteers after a single or multiple dosages oral administration. Methods: A total of 9 healthy adult subjects were given Ambroxol and Clenbuterol Tablets in a single dosage or multiple dosages respectively. LC/MS/MS were used for the determination of Ambroxol and Clenbuterol of in plasma. The important pharmacokinetic parameters were calculated by DAS 2.0 software (compartment model). Resul...

  3. Metabolism and pharmacokinetics of aztreonam in healthy subjects.

    OpenAIRE

    Swabb, E A; Singhvi, S M; Leitz, M A; Frantz, M; Sugerman, A

    1983-01-01

    The metabolism and pharmacokinetics of aztreonam (SQ 26,776) were studied in four healthy male volunteers, each of whom received single 500-mg intravenous and intramuscular doses of 14C-labeled drug according to a two-way crossover design. Serial samples of serum, urine, and feces were assayed for aztreonam and metabolites. Serum pharmacokinetics of aztreonam administered intravenously were described by an open, linear, two-compartment kinetic model. Kinetics of intramuscular aztreonam follow...

  4. The pharmacokinetics of oral and intravenous nalbuphine in healthy volunteers.

    OpenAIRE

    Aitkenhead, A R; Lin, E S; Achola, K J

    1988-01-01

    The pharmacokinetics of nalbuphine were studied in 10 healthy volunteers on two separate occasions following administration by either the intravenous (20 mg) or oral (60 mg) route. After administration, serum concentrations of nalbuphine were measured for 12 h using a high pressure liquid chromatography assay, and pharmacokinetic parameters were derived using a three compartment model. After i.v. administration, elimination half-life was 222 (111-460) min (mean and range) and total body clear...

  5. Model-Based Reasoning

    Science.gov (United States)

    Ifenthaler, Dirk; Seel, Norbert M.

    2013-01-01

    In this paper, there will be a particular focus on mental models and their application to inductive reasoning within the realm of instruction. A basic assumption of this study is the observation that the construction of mental models and related reasoning is a slowly developing capability of cognitive systems that emerges effectively with proper…

  6. Model-based software design

    Science.gov (United States)

    Iscoe, Neil; Liu, Zheng-Yang; Feng, Guohui; Yenne, Britt; Vansickle, Larry; Ballantyne, Michael

    1992-01-01

    Domain-specific knowledge is required to create specifications, generate code, and understand existing systems. Our approach to automating software design is based on instantiating an application domain model with industry-specific knowledge and then using that model to achieve the operational goals of specification elicitation and verification, reverse engineering, and code generation. Although many different specification models can be created from any particular domain model, each specification model is consistent and correct with respect to the domain model.

  7. Towards optimal design of anti-malarial pharmacokinetic studies.

    OpenAIRE

    White Nicholas J; Price Ric N; Jamsen Kris M; Simpson Julie A; Lindegardh Niklas; Tarning Joel; Duffull Stephen B

    2009-01-01

    Abstract Background Characterization of anti-malarial drug concentration profiles is necessary to optimize dosing, and thereby optimize cure rates and reduce both toxicity and the emergence of resistance. Population pharmacokinetic studies determine the drug concentration time profiles in the target patient populations, including children who have limited sampling options. Currently, population pharmacokinetic studies of anti-malarial drugs are designed based on logistical, financial and ethi...

  8. Model-based Software Engineering

    DEFF Research Database (Denmark)

    Kindler, Ekkart

    2010-01-01

    The vision of model-based software engineering is to make models the main focus of software development and to automatically generate software from these models. Part of that idea works already today. But, there are still difficulties when it comes to behaviour. Actually, there is no lack in models...

  9. Principles of models based engineering

    Energy Technology Data Exchange (ETDEWEB)

    Dolin, R.M.; Hefele, J.

    1996-11-01

    This report describes a Models Based Engineering (MBE) philosophy and implementation strategy that has been developed at Los Alamos National Laboratory`s Center for Advanced Engineering Technology. A major theme in this discussion is that models based engineering is an information management technology enabling the development of information driven engineering. Unlike other information management technologies, models based engineering encompasses the breadth of engineering information, from design intent through product definition to consumer application.

  10. Model Construct Based Enterprise Model Architecture and Its Modeling Approach

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    In order to support enterprise integration, a kind of model construct based enterprise model architecture and its modeling approach are studied in this paper. First, the structural makeup and internal relationships of enterprise model architecture are discussed. Then, the concept of reusable model construct (MC) which belongs to the control view and can help to derive other views is proposed. The modeling approach based on model construct consists of three steps, reference model architecture synthesis, enterprise model customization, system design and implementation. According to MC based modeling approach a case study with the background of one-kind-product machinery manufacturing enterprises is illustrated. It is shown that proposal model construct based enterprise model architecture and modeling approach are practical and efficient.

  11. Nevirapine Exposure with WHO Pediatric Weight Band Dosing: Enhanced Therapeutic Concentrations Predicted Based on Extensive International Pharmacokinetic Experience

    NARCIS (Netherlands)

    Nikanjam, M.; Kabamba, D.; Cressey, T.R.; Burger, D.M.; Aweeka, F.T.; Acosta, E.P.; Spector, S.A.; Capparelli, E.V.

    2012-01-01

    Nevirapine (NVP) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) used worldwide as part of combination antiretroviral therapy in infants and children to treat HIV infection. Dosing based on either weight or body surface area has been approved by the U.S. Food and Drug Administration (FDA)

  12. Relationship of quantitative structure and pharmacokinetics in fluoroquinolone antibacterials

    Institute of Scientific and Technical Information of China (English)

    Die Cheng; Wei-Ren Xu; Chang-Xiao Liu

    2007-01-01

    AIM: To study the relationship between quantitative structure and pharmacokinetics (QSPkR) of fluoroquinolone antibacterials.METHODS: The pharmacokinetic (PK) parameters of oral fluoroquinolones were collected from the literature. These pharmacokinetic data were averaged, 19 compounds were used as the training set, and 3 served as the test set. Genetic function approximation (GFA)module of Cerius2 software was used in QSPkR analysis.RESULTS: A small volume and large polarizability and surface area of substituents at C-7 contribute to a large area under the curve (AUC) for fluoroquinolones. Large polarizability and small volume of substituents at N-1 contribute to a long half life elimination.CONCLUSION: QSPkR models can contribute to some fluoroquinolones antibacterials with excellent pharmacokinetic properties.

  13. Morbid Obesity Alters Both Pharmacokinetics and Pharmacodynamics of Propofol: Dosing Recommendation for Anesthesia Induction.

    Science.gov (United States)

    Dong, Dong; Peng, Xuemei; Liu, Jie; Qian, Hao; Li, Jiayang; Wu, Baojian

    2016-10-01

    The prevalence of obesity has markedly increased worldwide. Obese patients pose significant challenges to anesthesiologists with regard to accurate dosing of anesthetics due to potentially altered pharmacokinetics (PK). Here we determined the PK and pharmacodynamics (PD) of propofol for anesthesia induction in morbidly obese (MO) subjects (body mass index >35 kg/m(2)) at two dosing regimens: dosing based on total body weight and lean body weight (LBW), respectively. The propofol pharmacokinetic profile was well fitted with a two-compartment model. Both elimination clearance (223%-243% of controls, who had a body mass index 0.05) between MO subjects and controls. Morbid obesity led to a significant decrease (37.9%-38.6%; P obesity significantly altered both PK and PD of propofol. LBW was a better weight-based dosing scalar for anesthesia induction with propofol in MO subjects. PMID:27481855

  14. Pharmacokinetics, micro-SPECT/CT imaging and therapeutic efficacy of {sup 188}Re-DXR-liposome in C26 colon carcinoma ascites mice model

    Energy Technology Data Exchange (ETDEWEB)

    Chen, L.-C.; Chang, C.-H.; Yu, C.-Y.; Chang, Y.-J.; Wu, Y.-H.; Lee, W.-C.; Yeh, C.-H.; Lee, T.-W. [Institute of Nuclear Energy Research, Taoyuan, Taiwan (China); Ting Gann [National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan (China)], E-mail: gann.ting@msa.hinet.net

    2008-11-15

    The pharmacokinetics and internal radionuclide therapy of intraperitoneally administrated {sup 188}Re-N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomal doxorubicin ({sup 188}Re-DXR-liposome) were investigated in the C26 murine colon carcinoma ascites mouse model. After intraperitoneal administration of the nanotargeted bimodality {sup 188}Re-DXR-liposome, the ascites and tumor accumulation of the radioactivity were observed, the levels of radioactivity within the ascites were maintained at relatively higher levels before 48 h and the levels of radioactivity in the tumor were maintained at steady levels after 4 h. The AUC{sub (o{yields}{infinity})} of {sup 188}Re-DXR-liposome in blood, ascites and tumor was 9.3-, 4.2- and 4.7-fold larger than that of {sup 188}Re-BMEDA, respectively. The maximum tolerated dose of intraperitoneally administrated {sup 188}Re-DXR-liposome was determined in normal BALB/c mice. The survival, tumor and ascites inhibition of mice after {sup 188}Re-DXR-liposome (22.2 MBq of {sup 188}Re, 5 mg/kg of DXR) treatment were evaluated. Consequently, radiochemotherapeutics of {sup 188}Re-DXR-liposome attained better survival time, tumor and ascites inhibition (decreased by 49% and 91% at 4 days after treatment; P<.05) in mice than radiotherapeutics of {sup 188}Re-liposome or chemotherapeutics of Lipo-Dox did. Therefore, intraperitoneal administration of novel {sup 188}Re-DXR-liposome could provide a benefit and promising strategy for delivery of passive nanotargeted bimodality radiochemotherapeutics in oncology applications.

  15. Theranostic system for drug delivery and pharmacokinetic imaging based on nanosecond pulsed light-induced photomechanical and photoacoustic effects

    Science.gov (United States)

    Tsunoi, Yasuyuki; Sato, Shunichi; Kawauchi, Satoko; Akutsu, Yusuke; Miyagawa, Yoshihiro; Araki, Koji; Shiotani, Akihiro; Terakawa, Mitsuhiro

    2015-11-01

    For efficient and side effects-free pharmacological treatment, we here propose a theranostic system that enables transvascular drug delivery by photomechanical waves (PMWs) and photoacoustic (PA) imaging of the drug distribution; both functions are based on nanosecond laser pulses and can therefore be integrated in one system. Through optical fibers arranged around an ultrasound sensor, low-energy and high-energy nanosecond light pulses were transmitted respectively for PA imaging and PMW-based drug delivery by temporal switching. With the system, we delivered a test drug (Evans blue) to tumors in mice and visualized distributions of both the blood vessels and drug in the tissue in vivo, showing the validity of the system.

  16. Theranostic system for drug delivery and pharmacokinetic imaging based on nanosecond pulsed light-induced photomechanical and photoacoustic effects

    International Nuclear Information System (INIS)

    For efficient and side effects-free pharmacological treatment, we here propose a theranostic system that enables transvascular drug delivery by photomechanical waves (PMWs) and photoacoustic (PA) imaging of the drug distribution; both functions are based on nanosecond laser pulses and can therefore be integrated in one system. Through optical fibers arranged around an ultrasound sensor, low-energy and high-energy nanosecond light pulses were transmitted respectively for PA imaging and PMW-based drug delivery by temporal switching. With the system, we delivered a test drug (Evans blue) to tumors in mice and visualized distributions of both the blood vessels and drug in the tissue in vivo, showing the validity of the system. (author)

  17. Population pharmacokinetics of olprinone in healthy male volunteers

    Directory of Open Access Journals (Sweden)

    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

  18. Michaelis-Menten Kinetics under Spatially Constrained Conditions: Application to Mibefradil Pharmacokinetics

    Science.gov (United States)

    Kosmidis, Kosmas; Karalis, Vangelis; Argyrakis, Panos; Macheras, Panos

    2004-01-01

    Two different approaches were used to study the kinetics of the enzymatic reaction under heterogeneous conditions to interpret the unusual nonlinear pharmacokinetics of mibefradil. Firstly, a detailed model based on the kinetic differential equations is proposed to study the enzymatic reaction under spatial constraints and in vivo conditions. Secondly, Monte Carlo simulations of the enzyme reaction in a two-dimensional square lattice, placing special emphasis on the input and output of the substrate were applied to mimic in vivo conditions. Both the mathematical model and the Monte Carlo simulations for the enzymatic reaction reproduced the classical Michaelis-Menten (MM) kinetics in homogeneous media and unusual kinetics in fractal media. Based on these findings, a time-dependent version of the classic MM equation was developed for the rate of change of the substrate concentration in disordered media and was successfully used to describe the experimental plasma concentration-time data of mibefradil and derive estimates for the model parameters. The unusual nonlinear pharmacokinetics of mibefradil originates from the heterogeneous conditions in the reaction space of the enzymatic reaction. The modified MM equation can describe the pharmacokinetics of mibefradil as it is able to capture the heterogeneity of the enzymatic reaction in disordered media. PMID:15345531

  19. Estimation of internal radiation dose in human based on animal data. Application of methodology in drug metabolism and pharmacokinetics

    International Nuclear Information System (INIS)

    Before conducting human study on radiolabeled drug, internal radiation dose is evaluated based on the animal data. Generally, however, species difference in the elimination process of radioactivity, mostly in the hepatic metabolism, is ignored. The methodology of correction was described for drugs that are eliminated mostly by hepatic metabolism. We showed the validity of using the method where the hepatic clearance in animal and human are constructed by the hepatic blood flow, protein unbound fraction and metabolic rate in vitro, and the internal radiation exposure calculated is corrected by the animal/human ratio of the hepatic clearance. (author)

  20. Clinical pharmacokinetics of molsidomine.

    Science.gov (United States)

    Rosenkranz, B; Winkelmann, B R; Parnham, M J

    1996-05-01

    Molsidomine is a prodrug for the formation of nitric oxide (NO). Its pharmacokinetics are characterised by rapid absorption and hydrolysis, taking a short time to achieve maximal systemic concentrations of both the parent compound and its active metabolite, SIN-1. The time to peak plasma drug concentration (tmax) is 1 to 2 hours. The bioavailability of the parent compound after oral administration in tablet form is 44 to 59%, but further metabolism to release NO and form polar metabolites is rapid; the half-life (t-1/2) of SIN-1 is 1 to 2 hours. Urinary excretion accounts for more than 90% of the part of the administered dose of molsidomine which is not excreted unchanged. Protein binding of the parent compound is very low (3 to 11%) and its volume of distribution (Vd) corresponds to the range of bodyweight. Single-dose studies (1, 2 and 4 mg) have revealed linear pharmacokinetics, and multiple dose studies in healthy individuals (2 mg 3 times daily for 7 days) and coronary artery disease (CAD) patients (4 mg 4 times daily for 4 weeks) do not show any accumulation of the drug. A study in young and elderly individuals indicated that the first-pass effect is decreased and t-1/2 prolonged with age, resulting in an increased area under the concentration-time curve (AUC) of molsidomine and SIN-1. In patients with liver disease and congestive heart failure similar changes were observed, but much less so in patients with CAD. Clearance was also impaired in patients with liver disease, but the pharmacokinetics of molsidomine were not markedly altered by impaired renal function. In general, due to a large therapeutic dose range, dosage adjustments are not required on the basis of clinical experience. In certain patients a lower starting dose may be recommended, such as in those with impaired liver or kidney function, in congestive heart failure or in the presence of concomitant treatment with other vasoactive compounds. A linear dose-effect relationship is observed with

  1. Influence of rifampin on fleroxacin pharmacokinetics.

    OpenAIRE

    Schrenzel, J.; Dayer, P; Leemann, T; Weidekamm, E; Portmann, R; Lew, D P

    1993-01-01

    Staphylococcus aureus infections have been successfully treated in animal models with the combination of fleroxacin and rifampin. We studied the influence of rifampin, a potent cytochrome P-450 inducer, on the pharmacokinetics and biotransformation of fleroxacin in 14 healthy young male volunteers. Subjects were given 400 mg of fleroxacin orally once a day for 3 days to reach steady state. After a wash-out period of 2 days, the same subjects received 600 mg of rifampin orally once daily for 7...

  2. Pharmacokinetics of dexamethasone in broiler chickens

    OpenAIRE

    Watteyn, Anneleen; Wyns, Heidi; Plessers, Elke; De Baere, Siegrid; De Backer, Patrick; Croubels, Siska

    2012-01-01

    Dexamethasone (DEX) is a synthetic derivate of cortisol and is one of the most potent glucocorticoids in man and animal. It is well known as an anti-inflammatory drug in many species. In poultry, however, data on the use of DEX are scarce. DEX would be a possible candidate-drug to influence mediators like cytokines and acute phase proteins in a lipopolysaccharide (LPS) inflammation model. First of all, it is important to determine the pharmacokinetics to investigate the immunomodulating p...

  3. Pharmacokinetic, residue and irritation aspects of chloramphenicol sodium succinate and a chloramphenicol base formulation following intramuscular administration to ruminants.

    Science.gov (United States)

    Nouws, J F; Vree, T B; Holtkamp, J; Baakman, M; Driessens, F; Guelen, P J

    1986-07-01

    The disposition of chloramphenicol (CAP) and of its glucuronide metabolite in plasma and milk was studied following a single intramuscular injection of a chloramphenicol base formulation (Amicol Forte; product A) and of chloramphenicol sodium succinate (product B) to dairy cows. The dose applied of both formulations was equivalent to 50 mg CAP base/kg body weight. The HPLC determined CAP concentrations were microbiologically active. Product A revealed 30% higher plasma CAP peak concentrations (13.0 vs 9.0 micrograms/ml) and 36% larger areas under the plasma concentration-time curves than product B, whereas their absorption and elimination half-lives were of the same order of magnitude. In the onset phase (during 4 h p.i.) unhydrolysed CAP sodium succinate could be detected in plasma and the glucuronide fraction was 26% of the parent drug. After 25 h p.i. the glucuronide fraction equalled that of the parent drug. The maximum CAP concentration in milk was for product B equal to, and for product A 80% of, the CAP plasma concentration. In milk no chloramphenicol glucuronide metabolites could be detected. HPLC methods for detecting ultra-trace CAP concentrations in edible tissues were developed by the employment of extraction with or without a clean-up procedure. Seven days after i.m. administration of product A and B to calves, the CAP residue concentrations in the kidney, liver, and muscle were less than 2 nanogram/g tissue. Traces of CAP residues could be still found at the injection site and in the urine. Chloramphenicol sodium succinate (product B) caused extensive tissue irritation at the injection site, while in the case of product A the irritation was limited.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3750804

  4. Population pharmacokinetics of a single intramuscular administration of tulathromycin in adult desert tortoises (Gopherus agassizii).

    Science.gov (United States)

    Kinney, M E; Lamberski, N; Wack, R; Foster, R; Neely, M; Tell, L; Gehring, R

    2014-10-01

    Tulathromycin, a long acting macrolide antibiotic, has demonstrated efficacy against respiratory pathogens including Mycoplasma bovis and M. hyopneumoniae. A pharmacokinetic study was performed to evaluate the clinical applicability of tulathromycin in desert tortoises following a single intramuscular dose of 5 mg/kg. A single blood sample was collected from 110 different desert tortoises at 0.25, 0.5, 1, 4, 8, 24, 48, 72, 120, and 240 h following drug administration. Plasma concentrations of the parent form of tulathromycin were measured using liquid chromatography/mass spectrometry. As each tortoise was only bled once, pharmacokinetic parameters were initially estimated using a naïve pooled data approach. Given the variability in the data, population-based compartmental modeling was also performed. Using nonparametric population compartmental modeling, a two-compartment model with first-order absorption and elimination best fit the data. An observed Cmax of 36.2 ± 29.7 μg/mL was detected at 0.25 h (observed Tmax ). The elimination half-life (T½el ) was long (77.1 h) resulting in detectable plasma concentrations 240 h postadministration. This study represents a preliminary step in evaluating the utility of tulathromycin in chelonian species and demonstrates that population data modeling offers advantages for estimating pharmacokinetic parameters where sparse data sampling occurs and there is substantial variability in the data. PMID:24611596

  5. Graph Model Based Indoor Tracking

    DEFF Research Database (Denmark)

    Jensen, Christian Søndergaard; Lu, Hua; Yang, Bin

    2009-01-01

    The tracking of the locations of moving objects in large indoor spaces is important, as it enables a range of applications related to, e.g., security and indoor navigation and guidance. This paper presents a graph model based approach to indoor tracking that offers a uniform data management...... infrastructure for different symbolic positioning technologies, e.g., Bluetooth and RFID. More specifically, the paper proposes a model of indoor space that comprises a base graph and mappings that represent the topology of indoor space at different levels. The resulting model can be used for one or several...... indoor positioning technologies. Focusing on RFID-based positioning, an RFID specific reader deployment graph model is built from the base graph model. This model is then used in several algorithms for constructing and refining trajectories from raw RFID readings. Empirical studies with implementations...

  6. The use of the Levenberg-Marquardt curve-fitting algorithm in pharmacokinetic modelling of DCE-MRI data

    International Nuclear Information System (INIS)

    The use of curve-fitting and compartmental modelling for calculating physiological parameters from measured data has increased in popularity in recent years. Finding the 'best fit' of a model to data involves the minimization of a merit function. An example of a merit function is the sum of the squares of the differences between the data points and the model estimated points. This is facilitated by curve-fitting algorithms. Two curve-fitting methods, Levenberg-Marquardt and MINPACK-1, are investigated with respect to the search start points that they require and the accuracy of the returned fits. We have simulated one million dynamic contrast enhanced MRI curves using a range of parameters and investigated the use of single and multiple search starting points. We found that both algorithms, when used with a single starting point, return unreliable fits. When multiple start points are used, we found that both algorithms returned reliable parameters. However the MINPACK-1 method generally outperformed the Levenberg-Marquardt method. We conclude that the use of a single starting point when fitting compartmental modelling data such as this produces unsafe results and we recommend the use of multiple start points in order to find the global minima. (note)

  7. Pharmacokinetic-Pharmacodynamic Modelling of the Analgesic and Antihyperalgesic Effects of Morphine after Intravenous Infusion in Human Volunteers

    DEFF Research Database (Denmark)

    Ravn, Pernille; Foster, David J. R.; Kreilgaard, Mads;

    2014-01-01

    Using a modelling approach, this study aimed to (i) examine whether the pharmacodynamics of the analgesic and antihyperalgesic effects of morphine differ; (ii) investigate the influence of demographic, pain sensitivity and genetic (OPRM1) variables on between-subject variability of morphine pharm...

  8. Cluster Based Text Classification Model

    DEFF Research Database (Denmark)

    Nizamani, Sarwat; Memon, Nasrullah; Wiil, Uffe Kock

    2011-01-01

    We propose a cluster based classification model for suspicious email detection and other text classification tasks. The text classification tasks comprise many training examples that require a complex classification model. Using clusters for classification makes the model simpler and increases the...... classifier is trained on each cluster having reduced dimensionality and less number of examples. The experimental results show that the proposed model outperforms the existing classification models for the task of suspicious email detection and topic categorization on the Reuters-21578 and 20 Newsgroups...... datasets. Our model also outperforms A Decision Cluster Classification (ADCC) and the Decision Cluster Forest Classification (DCFC) models on the Reuters-21578 dataset....

  9. Influence of liver cirrhosis on sertraline pharmacokinetics

    OpenAIRE

    Démolis, Jean-Louis; ANGEBAUD, PASCAL; GRANGÉ, JEAN-DIDIER; Coates, Peter; Funck-Brentano, Christian; Jaillon, Patrice

    1996-01-01

    Sertraline is a serotonin reuptake inhibitor. The enhancement of serotoninergic transmission is associated with antidepressant activity. In order to determine the pharmacokinetics of sertraline in patients with chronic stable hepatic insufficiency, 10 patients were matched (age, weight, sex) with 10 healthy subjects in an open study. Each participant received a single capsule containing the equivalent of 100 mg sertraline base. Blood samples were taken during 264 h after administration for me...

  10. Pharmacokinetics of pivmecillinam.

    Science.gov (United States)

    Parsons, R L; Hossack, G A; Paddock, G M

    1977-06-01

    1 The plasma concentration/time curves of ampicillin and mecillinam in normal subjects were measured after oral administration of ampicillin (500 mg) and pivmecillinam (400 and 600 mg). 2 Similar plasma concentration/time curves of ampicillin and mecillinam in the starved normal subjects followed oral administration of ampicillin (500 mg) and pivmecillinam (600 mg). 3 The plasma concentration/time curve of mecillinam was measured in the same normal subjects after oral administration of pivmecillinam (400 mg) with a reproducible standardized Lundh test meal. 4 There was no statistically significant difference in the plasma concentration/time curve of mecillinam after pivmecillinam/400 mg) and the meal compared with the plasma concentration/time curve after oral pivmecillinam (400 mg) was given to the same subjects when starved. After administration of pivmecillinam (400 mg) with meal, Tasc was significantly delayed beyond the value obtained when the subjects were starved. 5 The pharmacokinetics of pivmecillinam in coeliac disease are normal. This finding contrasts with previous studies on the pharmacokinetics of another pivaloyloxymethylpenicillin ester, pivampicillin, in this condition. PMID:197981

  11. Development and characterization of self-assembling lecithin-based mixed polymeric micelles containing quercetin in cancer treatment and an in vivo pharmacokinetic study

    Directory of Open Access Journals (Sweden)

    Chen LC

    2016-04-01

    Full Text Available Ling-Chun Chen,1,* Ying-Chen Chen,1,* Chia-Yu Su,1 Chung-Shu Hong,1 Hsiu-O Ho,1 Ming-Thau Sheu1,2 1School of Pharmacy, College of Pharmacy, 2Clinical Research Center and Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan *These authors contributed equally to this work Abstract: Quercetin (Que is known to have biological benefits including an anticancer effect, but low water solubility limits its clinical application. The aim of this study was to develop a lecithin-based mixed polymeric micelle (LMPM delivery system to improve the solubility and bioavailability of Que. The optimal Que-LMPM, composed of Que, lecithin, Pluronic® P123, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy[poly(ethylene glycol-2000] in a proportion of 3:1:17.5:2.5 (w/w, was prepared by a thin-film method. The average size, polydispersion index, encapsulating efficiency, and drug loading of Que-LMPM were 61.60±5.02 nm, 0.589±0.198, 96.87%±9.04%, and 12.18%±1.11%, respectively. The solubility of Que in the Que-LMPM system increased to 5.81 mg/mL, compared to that of free Que in water of 0.17–7.7 µg/mL. The Que-LMPM system presented a sustained-release property in vitro. The in vitro cytotoxicity assay showed that the 50% inhibitory concentration values toward MCF-7 breast cancer cells for free Que, blank LMPMs, and Que-LMPMs were >200, >200, and 110 µM, respectively, indicating the nontoxicity of the LMPM carrier, but the LMPM formulation enhanced the cytotoxicity of Que against MCF-7 cells. A cellular uptake assay also confirmed the intake of Que-LMPM by MCF-7 cells. An in vivo pharmacokinetic study demonstrated that Que-LMPMs had higher area under the concentration–time curve and a longer half-life, leading to better bioavailability compared to a free Que injection. Due to their nanosize, core–shell structure, and solubilization potential, LMPMs were successfully developed as

  12. PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel.

    Science.gov (United States)

    Zhang, Yong; Huo, Meirong; Zhou, Jianping; Xie, Shaofei

    2010-09-01

    This study presents PKSolver, a freely available menu-driven add-in program for Microsoft Excel written in Visual Basic for Applications (VBA), for solving basic problems in pharmacokinetic (PK) and pharmacodynamic (PD) data analysis. The program provides a range of modules for PK and PD analysis including noncompartmental analysis (NCA), compartmental analysis (CA), and pharmacodynamic modeling. Two special built-in modules, multiple absorption sites (MAS) and enterohepatic circulation (EHC), were developed for fitting the double-peak concentration-time profile based on the classical one-compartment model. In addition, twenty frequently used pharmacokinetic functions were encoded as a macro and can be directly accessed in an Excel spreadsheet. To evaluate the program, a detailed comparison of modeling PK data using PKSolver and professional PK/PD software package WinNonlin and Scientist was performed. The results showed that the parameters estimated with PKSolver were satisfactory. In conclusion, the PKSolver simplified the PK and PD data analysis process and its output could be generated in Microsoft Word in the form of an integrated report. The program provides pharmacokinetic researchers with a fast and easy-to-use tool for routine and basic PK and PD data analysis with a more user-friendly interface. PMID:20176408

  13. Pharmacokinetics and biodistribution of recently-developed siRNA nanomedicines.

    Science.gov (United States)

    Park, Jinho; Park, Joonyoung; Pei, Yihua; Xu, Jun; Yeo, Yoon

    2016-09-01

    Small interfering RNA (siRNA) is a promising drug candidate, expected to have broad therapeutic potentials toward various diseases including viral infections and cancer. With recent advances in bioconjugate chemistry and carrier technology, several siRNA-based drugs have advanced to clinical trials. However, most cases address local applications or diseases in the filtering organs, reflecting remaining challenges in systemic delivery of siRNA. The difficulty in siRNA delivery is in large part due to poor circulation stability and unfavorable pharmacokinetics and biodistribution profiles of siRNA. This review describes the pharmacokinetics and biodistribution of siRNA nanomedicines, focusing on those reported in the past 5years, and their pharmacological effects in selected disease models such as hepatocellular carcinoma, liver infections, and respiratory diseases. The examples discussed here will provide an insight into the current status of the art and unmet needs in siRNA delivery. PMID:26686832

  14. Base Flow Model Validation Project

    Data.gov (United States)

    National Aeronautics and Space Administration — The program focuses on turbulence modeling enhancements for predicting high-speed rocket base flows. A key component of the effort is the collection of...

  15. The development of a quantitative and qualitative method based on UHPLC-QTOF MS/MS for evaluation paclitaxel-tetrandrine interaction and its application to a pharmacokinetic study.

    Science.gov (United States)

    Li, Dan; Cao, Zhonglian; Liao, Xueling; Yang, Ping; Liu, Li

    2016-11-01

    Paclitaxel is a broad-spectrum anti-cancer drug by targeting microtubulin. However, multidrug resistant (MDR) makes its clinical application more difficult and results in failure of chemotherapy. Tetrandrine as a potential multidrug resistant modulator could be combined with other anti-cancer drugs. In this study, ultra-performance liquid chromatography (UHPLC) combined with quadrupole time-of-flight mass spectrometry (QTOF) was applied to simultaneously qualitative and quantitative analysis of paclitaxel for the pharmacokinetic studies while combined with tetrandrine. This method was developed based on non-target screening mode IDA (Information Dependent Acquisition). As a result, the validated range was 0.25-64ng/ml (30µl plasma) for paclitaxel. Totally 33 metabolites of paclitaxel and tetrandine were identified in vivo and in vitro. The main metabolites of PTX were dose-dependent decreased with different amounts of tetrandine co-administration no matter in vivo and in vitro, the exposure of PTX increased in pharmacokinetic study. The verified method is sensitive accurate and effective for the simultaneous determination of paclitaxel and its metabolites in blood, urine and live microsome incubation samples and it was successfully applied to evaluate the pharmacokinetics and drug-drug interaction between paclitaxel and tetrandine. Furthermore, a biosensor technology, surface plasmon resonance (SPR) analysis was applied to preliminary evaluate the competitive protein binding of multiple components. The SPR analysis indicated that the affinity between 6-hydroxy-paclitaxel and micotubulin is similar to that between paclitaxel and micotubulin, and tetrandrine also does not form a competitive combination with paclitaxel. For human, 6-hydroxy-paclitaxel is the one of main metabolites of paclitaxel, so the results suggested that tetrandine has an influence on the metabolite of paclitaxel, but tetrandine and the main metabolites of PTX probably do not affect PTX

  16. Pharmacokinetic modeling of penciclovir and BRL42359 in the plasma and tears of healthy cats to optimize dosage recommendations for oral administration of famciclovir.

    Science.gov (United States)

    Sebbag, Lionel; Thomasy, Sara M; Woodward, Andrew P; Knych, Heather K; Maggs, David J

    2016-08-01

    OBJECTIVES To determine, following oral administration of famciclovir, pharmacokinetic (PK) parameters for 2 of its metabolites (penciclovir and BRL42359) in plasma and tears of healthy cats so that famciclovir dosage recommendations for the treatment of herpetic disease can be optimized. ANIMALS 7 male domestic shorthair cats. PROCEDURES In a crossover study, each of 3 doses of famciclovir (30, 40, or 90 mg/kg) was administered every 8 or 12 hours for 3 days. Six cats were randomly assigned to each dosage regimen. Plasma and tear samples were obtained at predetermined times after famciclovir administration. Pharmacokinetic parameters were determined for BRL42359 and penciclovir by compartmental and noncompartmental methods. Pharmacokinetic-pharmacodynamic (PK-PD) indices were determined for penciclovir and compared among all dosage regimens. RESULTS Compared with penciclovir concentrations, BRL42359 concentrations were 5- to 11-fold greater in plasma and 4- to 7-fold greater in tears. Pharmacokinetic parameters and PK-PD indices for the 90 mg/kg regimens were superior to those for the 30 and 40 mg/kg regimens, regardless of dosing frequency. Penciclovir concentrations in tears ranged from 18% to 25% of those in plasma. Administration of 30 or 40 mg/kg every 8 hours achieved penciclovir concentrations likely to be therapeutic in plasma but not in tears. Penciclovir concentrations likely to be therapeutic in tears were achieved only with the two 90 mg/kg regimens. CONCLUSIONS AND CLINICAL RELEVANCE In cats, famciclovir absorption is variable and its metabolism saturable. Conversion of BRL42359 to penciclovir is rate limiting. The recommended dosage of famciclovir is 90 mg/kg every 12 hours for cats infected with feline herpesvirus. PMID:27463546

  17. Ex Vivo Pharmacodynamics of Amoxicillin-Clavulanate against β-Lactamase-Producing Escherichia coli in a Yucatan Miniature Pig Model That Mimics Human Pharmacokinetics

    OpenAIRE

    Bronner, Stéphane; Murbach, Valérie; Peter, Jean-Daniel; Levêque, Dominique; Elkhaïli, Hassan; Salmon, Yves; Dhoyen, Nathalie; Monteil, Henri; Woodnutt, Gary; Jehl, François

    2002-01-01

    The objective of the present study was to investigate the potential bactericidal activity of amoxicillin-clavulanate against β-lactamase-producing Escherichia coli strains and to elucidate the extent to which enzyme production affects the activity. Six adult Yucatan miniature pigs received a single intravenous dose of 1.1 g of amoxicillin-clavulanate as an intravenous infusion over 30 min. The pharmacokinetic parameters were determined for the serum samples and compared to the published data ...

  18. Modeling Guru: Knowledge Base for NASA Modelers

    Science.gov (United States)

    Seablom, M. S.; Wojcik, G. S.; van Aartsen, B. H.

    2009-05-01

    Modeling Guru is an on-line knowledge-sharing resource for anyone involved with or interested in NASA's scientific models or High End Computing (HEC) systems. Developed and maintained by the NASA's Software Integration and Visualization Office (SIVO) and the NASA Center for Computational Sciences (NCCS), Modeling Guru's combined forums and knowledge base for research and collaboration is becoming a repository for the accumulated expertise of NASA's scientific modeling and HEC communities. All NASA modelers and associates are encouraged to participate and provide knowledge about the models and systems so that other users may benefit from their experience. Modeling Guru is divided into a hierarchy of communities, each with its own set forums and knowledge base documents. Current modeling communities include those for space science, land and atmospheric dynamics, atmospheric chemistry, and oceanography. In addition, there are communities focused on NCCS systems, HEC tools and libraries, and programming and scripting languages. Anyone may view most of the content on Modeling Guru (available at http://modelingguru.nasa.gov/), but you must log in to post messages and subscribe to community postings. The site offers a full range of "Web 2.0" features, including discussion forums, "wiki" document generation, document uploading, RSS feeds, search tools, blogs, email notification, and "breadcrumb" links. A discussion (a.k.a. forum "thread") is used to post comments, solicit feedback, or ask questions. If marked as a question, SIVO will monitor the thread, and normally respond within a day. Discussions can include embedded images, tables, and formatting through the use of the Rich Text Editor. Also, the user can add "Tags" to their thread to facilitate later searches. The "knowledge base" is comprised of documents that are used to capture and share expertise with others. The default "wiki" document lets users edit within the browser so others can easily collaborate on the

  19. Pharmacokinetics-Pharmacodynamics of a Novel β-Lactamase Inhibitor, CB-618, in Combination with Meropenem in an In Vitro Infection Model.

    Science.gov (United States)

    VanScoy, Brian D; Trang, Michael; McCauley, Jennifer; Conde, Haley; Bhavnani, Sujata M; Friedrich, Lawrence V; Alexander, Dylan C; Ambrose, Paul G

    2016-07-01

    The usefulness of β-lactam antimicrobial agents is threatened as never before by β-lactamase-producing bacteria. For this reason, there has been renewed interest in the development of broad-spectrum β-lactamase inhibitors. Herein we describe the results of dose fractionation and dose-ranging studies carried out using a one-compartment in vitro infection model to determine the exposure measure for CB-618, a novel β-lactamase inhibitor, most predictive of the efficacy when given in combination with meropenem. The challenge panel included Enterobacteriaceae clinical isolates, which collectively produced a wide range of β-lactamase enzymes (KPC-2, KPC-3, FOX-5, OXA-48, SHV-11, SHV-27, and TEM-1). Human concentration-time profiles were simulated for each drug, and samples were collected for drug concentration and bacterial density determinations. Using data from dose fractionation studies and a challenge Klebsiella pneumoniae isolate (CB-618-potentiated meropenem MIC = 1 mg/liter), relationships between change from baseline in log10 CFU/ml at 24 h and each of CB-618 area under the concentration-time curve over 24 h (AUC0-24), maximum concentration (Cmax), and percentage of the dosing interval that CB-618 concentrations remained above a given threshold were evaluated in combination with meropenem at 2 g every 8 h (q8h). The exposure measures most closely associated with CB-618 efficacy in combination with meropenem were the CB-618 AUC0-24 (r(2) = 0.835) and Cmax (r(2) = 0.826). Using the CB-618 AUC0-24 indexed to the CB-618-potentiated meropenem MIC value, the relationship between change from baseline in log10 CFU/ml at 24 h and CB-618 AUC0-24/MIC ratio in combination with meropenem was evaluated using the pooled data from five challenge isolates; the CB-618 AUC0-24/MIC ratio associated with net bacterial stasis and the 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 27.3, 86.1, and 444.8, respectively. These data provide a pharmacokinetics

  20. Single-dose safety and pharmacokinetic evaluation of fluorocoxib A: pilot study of novel cyclooxygenase-2-targeted optical imaging agent in a canine model

    Science.gov (United States)

    Cekanova, Maria; Uddin, Md. Jashim; Legendre, Alfred M.; Galyon, Gina; Bartges, Joseph W.; Callens, Amanda; Martin-Jimenez, Tomas; Marnett, Lawrence J.

    2012-11-01

    We evaluated preclinical single-dose safety, pharmacokinetic properties, and specific uptake of the new optical imaging agent fluorocoxib A in dogs. Fluorocoxib A, N-[(5-carboxy-X-rhodaminyl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, selectively binds and inhibits the cyclooxygenase-2 (COX-2) enzyme, which is overexpressed in many cancers. Safety pilot studies were performed in research dogs following intravenous (i.v.) administration of 0.1 and 1 mg/kg fluorocoxib A. Blood and urine samples collected three days after administration of each dose of fluorocoxib A revealed no evidence of toxicity, and no clinically relevant adverse events were noted on physical examination of exposed dogs over that time period. Pharmacokinetic parameters were assessed in additional research dogs from plasma collected at several time points after i.v. administration of fluorocoxib A using high-performance liquid chromatography analysis. The pharmacokinetic studies using 1 mg/kg showed a peak of fluorocoxib A (92±28 ng/ml) in plasma collected at 0.5 h. Tumor specific uptake of fluorocoxib A was demonstrated using a dog diagnosed with colorectal cancer expressing COX-2. Our data support the safe single-dose administration and in vivo efficacy of fluorocoxib A, suggesting a high potential for successful translation to clinical use as an imaging agent for improved tumor detection in humans.

  1. Event-Based Activity Modeling

    DEFF Research Database (Denmark)

    Bækgaard, Lars

    2004-01-01

    We present and discuss a modeling approach that supports event-based modeling of information and activity in information systems. Interacting human actors and IT-actors may carry out such activity. We use events to create meaningful relations between information structures and the related...

  2. Clinical pharmacokinetics of anticonvulsants.

    Science.gov (United States)

    Hvidberg, E F; Dam, M

    1976-01-01

    Anticonvulsant therapy was among the first areas to benefit from clinical pharmacokinetic studies. The most important advantage is that the frequent interindividual variation in the plasma level/dose ratio for these drugs can be circumvented by plasma level monitoring. For several anticonvulsants the brain concentration is shown to parallel the plasma concentration. Phenytoin (diphenylhydantoin) is stil the most important anticonvulsant and the one for which kinetics have been thoroughly investigated in man. These investigations have revealed several reasons for the wellknown difficulties in using this drug clinically. The absorption rate and fraction are very much dependent on the pharmaceutical preparation, and changes of brand may alter the plasma level of phenytoin in spite of unaltered dose. The elimination capacity is saturable causing dose dependent kinetics, which again means disproportional changes in plasma level with changes in dose. Great individual variations exist in the rate of metabolism, and several pharmacokinetic drug interactions are known. As an optimum therapeutic plasma concentration range has been established monitoring plasma levels must be strongly advocated. Interpretation of plasma levels in uraemic patients must take into account decreased protein binding of the drug. Carbamazepine is probably as effective as phenytoin. The elimination is a first order process, but the rate of metabolism increases after a few weeks' treatment. An active metabolite (epoxide) may be the cause of some side-effects. Combined treatment with other anticonvulsant drugs decreases the half-life and more frequent dosing may be necessary. An optimum therapeutic concentration range has been suggested and plasma monitoring is advocated, along with that of the active metabolite, the epoxide. Phenobarbitone is still much used but its kinetics have been investigated to a lesser extent. The main problem is the variability in the rate of elimination. In children the half

  3. Pharmacokinetics of cefixime

    International Nuclear Information System (INIS)

    The serum protein binding of cefixime, was concentration-dependent. Below 30 mcg/mL, free-fractions (fu) of cefixime in dog serum were approximately 8%. As cefixime concentrations increased, concomitant increases in free-fraction were observed. At 328 mcg/mL almost half of the cefixime in serum was not bound. To examine the effect of this concentration-dependent binding on cefixime's pharmacokinetics, four dogs were administered 50 mg/kg of the carbon 14-labeled drug by the oral and intravenous routes. The absolute bioavailability of cefixime was 48.0 +/- 17% (mean +/- SD). Absorption of radioactivity was 51.9 +/- 18%. Cefixime's elimination was a function of its free-fraction in serum and reabsorption of filtered drug by the kidney

  4. Pharmacokinetics of cefixime

    Energy Technology Data Exchange (ETDEWEB)

    Tonelli, A.P.

    1987-01-01

    The serum protein binding of cefixime, was concentration-dependent. Below 30 mcg/mL, free-fractions (fu) of cefixime in dog serum were approximately 8%. As cefixime concentrations increased, concomitant increases in free-fraction were observed. At 328 mcg/mL almost half of the cefixime in serum was not bound. To examine the effect of this concentration-dependent binding on cefixime's pharmacokinetics, four dogs were administered 50 mg/kg of the carbon 14-labeled drug by the oral and intravenous routes. The absolute bioavailability of cefixime was 48.0 +/- 17% (mean +/- SD). Absorption of radioactivity was 51.9 +/- 18%. Cefixime's elimination was a function of its free-fraction in serum and reabsorption of filtered drug by the kidney.

  5. Pharmacokinetic profile of tert-butylaminoethanethiol

    Directory of Open Access Journals (Sweden)

    M. H. Guerra Andrade

    1990-09-01

    Full Text Available A preliminary study of the pharmacokinetic parameters of t-Butylaminoethanethiol (TBAESH was performed after administration of a single dose (35 mg/kg either orally or intravenously. Plasma or blood samples were treated with dithiothreitol, perchloric acid and, after filtration, submitted to further purification with anionic resin. In the final step the drug was retained on a cationic resin column, eluted with NaCl lM and detected according to the method of Ellman (1958. The results suggested a pharmacokinetic behavior related to a one open compartment model with the following values for the total drug: area under the intravenous curve (AUC i.v.: 443(+ ou - 24.0; AUC oral: 85.5(+ ou - 14.5 ug min.ml(elevado a -1; elimination rate constant: 0.069(+ ou - 0.0055 min(elevado a -1, biological half-life: 10.0(+ ou - 0.80 min; distribution volume 1.15(+ ou - 0.15 ml/g; biodisponibility: 0.19(+ ou - 0.02. From a pharmacokinetic standpoint, TBAESH seems to have no advantage over the analogous disulfide compound.

  6. [Pharmacokinetics--pharmacodynamics of modafinil in mice].

    Science.gov (United States)

    Ma, Zhang-Qing; Hong, Zong-Yuan; Wang, Wu-San; Tao, Fang

    2012-01-01

    To guide the reasonable clinical application of modafinil (MOD), pharmacokinetics and pharmacodynamics of MOD in mice and the correlation between them were investigated. Male mice (Kunming strain) were given a single oral dose of MOD (120 mg x kg(-1)). The plasma concentration of MOD was measured by HPLC and the pharmacokinetic parameters were calculated with DAS 3.0 software. For another batch of male Kunming strain mice, their locomotor activities were recorded by an infrared ray passive sensor after a same oral dose of MOD, and the synchronization and correlation between the changes of MOD plasma concentration and the locomotor activity induced by MOD were compared and analyzed. The results showed that the plasma concentration-time curve of MOD was fitted to two-compartment open model with a first order absorption. The main pharmacokinetic parameters t1/2alpha, t1/2beta, t(max), C(max) and AUC(0-inifinity) were 0.42 h, 3.10 h, 1.00 h, 41.34 mg x L(-1) and 142.22 mg x L(-1) x h, respectively. MOD significantly increased locomotor activity and the effect lasted for about 4 h. The changes of MOD plasma concentration and the locomotor activity induced by MOD were synchronous. In conclusion, there is a significant correlation between the effect of MOD and its plasma concentration after administration of 120 mg x kg(-1) in mice. PMID:22493813

  7. CLINICAL PHARMACOKINETIC STUDIES OF MIFEPRISTONE

    Institute of Scientific and Technical Information of China (English)

    XUNing; WUXi-Rui

    1989-01-01

    In ordcr to cxaminc thc pharmacokinetic charactcristics of mifcpristonc, manufactured by the Roussel-Uclaf Company, in Chincsee healthy volunteers and early pregnant womcn, the following two studies wcre carried out.

  8. Pharmacokinetics of clomipramine during pregnancy

    NARCIS (Netherlands)

    ter Horst, P. G. J.; Proost, J. H.; Smit, J. P.; Vries, M. T.; Jong-van den Berg, de L. T. W.; 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 rati

  9. 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

    PURPOSE: 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 t

  10. Clinical pharmacokinetics in infants and children.

    Science.gov (United States)

    Rane, A; Wilson, J T

    1976-01-01

    Wide variations in drug dose recommendations for children of the same or different ages reflect the inadequacy of data on pharmacokinetics and pharmacodynamics in children. Selected aspects of available literature on pharmacokinetics of drugs used in older infants and children has been reviewed with special attention to calculation of an age-appropriate dose. During the neonatal period and early infancy the elimination of many drugs that are excreted in the urine in unchanged form is restricted by the immaturity of glomerular filtration and renal tubular secretion. On the other hand, in late infancy and/or in childhood, a similar or greater rate of elimination from plasma than in adults has been observed for many drugs, notably digoxin, phenobarbitone, phenytoin, carbamazepine, ethosuximide, diazoxide, clindamycin and propoxyphene. Consistent with this, it has been shown that some drugs exhibit a lower plasma level/dose ratio in infancy and early childhood as compared with the adult. This is true for phenobarbitone, phenytoin and ethosuximide. Some age groups of children remain uninvestigated with regard to pharmacokinetics, even for the drugs reviewed. Therefore, pediatric therapy remains empirically based for many drugs. PMID:1017153

  11. Current clinical evidence on topiramate pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Jakovljević Mihajlo

    2009-01-01

    Full Text Available Topiramate is biochemically classified as a fructopyranose sulphamate. Discovered as early as 1979, during middle 1980's it was approved in many countries for the treatment of epilepsies and migraine prevention. More recently, in the experimental stage, possible new indications have been disclosed: treatment of obesity, bipolar disorder, also cessation of smoking, neuropathic pain, cerebral pseudotumour, bulimia, periventricular leucomalatia in preterm infants and alcohol addiction. Most epileptologists consider it to be the first choice antiepileptic drug in severe pharmacoresistant epilepsies. A substantial corpus of evidence in paediatric population has been accumulated that confirms its efficiency in the treatment of generalised tonic-clonic seizures, Lenox-Gestaut syndrome, partial, absence and combined seizures. Having a unique monosaccharide chemical structure among other anticonvulsant drugs, characterizes it with special pharmacokinetic features. This substance exhibits a low interindividual variability in plasma levels and hence it features predictable pharmacokinetics. A steady state plasma concentration of topiramate increases linearly with higher dosages. Serum protein binding is approximately 15%, and biologic half-life in healthy volunteers is considered to range from 20 to 30 hours. Mean expected distribution volume rates from 0.55-0.8 l/kg, and accordingly, the drug shows a low and saturable binding capacity toward erythrocytes. It has not been present at the market for a sufficiently long time that would enable us to speak about a significant accumulation of data on its metabolism based on post-registration 4th stage clinical trials. For this purpose, we have done a literature review in order to summarise so far reported experience on topiramate pharmacokinetics in patients and healthy adults. Deeper understanding of its pharmacokinetic profile could enable a better technological design of the produced drug and the choice of

  12. Estimation of the binding modes with important human cytochrome P450 enzymes, drug interaction potential, pharmacokinetics, and hepatotoxicity of ginger components using molecular docking, computational, and pharmacokinetic modeling studies

    Directory of Open Access Journals (Sweden)

    Qiu JX

    2015-02-01

    2, 2C9, 2C19, 2D6, and 3A4 mainly through hydrogen bond formation, to a lesser extent, via π–π stacking. The pharmacokinetic simulation studies showed that the [I]/[Ki] value for CYP2C9, 2C19, and 3A4 ranged from 0.0002 to 19.6 and the R value ranged from 1.0002 to 20.6 and that ginger might exhibit a high risk of drug interaction via inhibition of the activity of human CYP2C9 and CYP3A4, but a low risk of drug interaction toward CYP2C19-mediated drug metabolism. Furthermore, it has been evaluated that the 12 ginger components possessed a favorable ADMET profiles with regard to the solubility, absorption, permeability across the blood–brain barrier, interactions with CYP2D6, hepatotoxicity, and plasma protein binding. The validation results showed that there was no remarkable effect of ginger on the metabolism of warfarin in humans, whereas concurrent use of ginger and nifedipine exhibited a synergistic effect on platelet aggregation in humans. Moreover, ginger components showed a rapid half-life and no to low toxicity in humans. Taken together, this study shows that ginger components may regulate the activity and expression of various human CYPs, probably resulting in alterations in drug clearance and response. More studies are warranted to identify and confirm potential ginger–drug interactions and explore possible interactions of ginger with human CYPs and other functionally important proteins, to reduce and avoid side effects induced by unfavorable ginger–drug interactions.Keywords: CYP, drug metabolism, ginger, drug interaction, docking

  13. Modelling Gesture Based Ubiquitous Applications

    CERN Document Server

    Zacharia, Kurien; Varghese, Surekha Mariam

    2011-01-01

    A cost effective, gesture based modelling technique called Virtual Interactive Prototyping (VIP) is described in this paper. Prototyping is implemented by projecting a virtual model of the equipment to be prototyped. Users can interact with the virtual model like the original working equipment. For capturing and tracking the user interactions with the model image and sound processing techniques are used. VIP is a flexible and interactive prototyping method that has much application in ubiquitous computing environments. Different commercial as well as socio-economic applications and extension to interactive advertising of VIP are also discussed.

  14. Population pharmacokinetics of ciclosporin in Chinese children with aplastic anemia: effects of weight, renal function and stanozolol administration

    OpenAIRE

    Ni, Shao-qing; Zhao, Wei; Wang, Jue; Zeng, Su; Chen, Shu-Qing; Jacqz-Aigrain, Evelyne; Zhao, Zheng-Yan

    2013-01-01

    Aim: To develop a population pharmacokinetic model for the immunosuppressant ciclosporin in Chinese children with aplastic anemia and to identify covariates influencing ciclosporin pharmacokinetics. Methods: A total of 102 children with either acquired or congenital aplastic anemia aged 8.8±3.6 years (range 0.9–17.6 years) were included. Therapeutic drug monitoring (TDM) data for ciclosporin were collected. The population pharmacokinetic model of ciclosporin was described using the nonlinear ...

  15. Sketch-based geologic modeling

    Science.gov (United States)

    Rood, M. P.; Jackson, M.; Hampson, G.; Brazil, E. V.; de Carvalho, F.; Coda, C.; Sousa, M. C.; Zhang, Z.; Geiger, S.

    2015-12-01

    Two-dimensional (2D) maps and cross-sections, and 3D conceptual models, are fundamental tools for understanding, communicating and modeling geology. Yet geologists lack dedicated and intuitive tools that allow rapid creation of such figures and models. Standard drawing packages produce only 2D figures that are not suitable for quantitative analysis. Geologic modeling packages can produce 3D models and are widely used in the groundwater and petroleum communities, but are often slow and non-intuitive to use, requiring the creation of a grid early in the modeling workflow and the use of geostatistical methods to populate the grid blocks with geologic information. We present an alternative approach to rapidly create figures and models using sketch-based interface and modelling (SBIM). We leverage methods widely adopted in other industries to prototype complex geometries and designs. The SBIM tool contains built-in geologic rules that constrain how sketched lines and surfaces interact. These rules are based on the logic of superposition and cross-cutting relationships that follow from rock-forming processes, including deposition, deformation, intrusion and modification by diagenesis or metamorphism. The approach allows rapid creation of multiple, geologically realistic, figures and models in 2D and 3D using a simple, intuitive interface. The user can sketch in plan- or cross-section view. Geologic rules are used to extrapolate sketched lines in real time to create 3D surfaces. Quantitative analysis can be carried our directly on the models. Alternatively, they can be output as simple figures or imported directly into other modeling tools. The software runs on a tablet PC and can be used in a variety of settings including the office, classroom and field. The speed and ease of use of SBIM enables multiple interpretations to be developed from limited data, uncertainty to be readily appraised, and figures and models to be rapidly updated to incorporate new data or concepts.

  16. Improving the pharmacokinetic and CYP inhibition profiles of azaxanthene-based glucocorticoid receptor modulators-identification of (S)-5-(2-(9-fluoro-2-(4-(2-hydroxypropan-2-yl)phenyl)-5H-chromeno[2,3-b]pyridin-5-yl)-2-methylpropanamido)-N-(tetrahydro-2H-pyran-4-yl)-1,3,4-thiadiazole-2-carboxamide (BMS-341).

    Science.gov (United States)

    Yang, Michael G; Dhar, T G Murali; Xiao, Zili; Xiao, Hai-Yun; Duan, James J-W; Jiang, Bin; Galella, Michael A; Cunningham, Mark; Wang, Jinhong; Habte, Sium; Shuster, David; McIntyre, Kim W; Carman, Julie; Holloway, Deborah A; Somerville, John E; Nadler, Steven G; Salter-Cid, Luisa; Barrish, Joel C; Weinstein, David S

    2015-05-28

    An empirical approach to improve the microsomal stability and CYP inhibition profile of lead compounds 1a and 1b led to the identification of 5 (BMS-341) as a dissociated glucocorticoid receptor modulator. Compound 5 showed significant improvements in pharmacokinetic properties and, unlike compounds 1a-b, displayed a linear, dose-dependent pharmacokinetic profile in rats. When tested in a chronic model of adjuvant-induced arthritis in rat, the ED50 of 5 (0.9 mg/kg) was superior to that of both 1a and 1b (8 and 17 mg/kg, respectively). PMID:25905990

  17. Comparative pharmacokinetic study of dosage forms with morpholinium 2-[5-(pyridin-4-yl)-1,2,4-triazol-3-ylthio] acetate

    OpenAIRE

    Bushueva, I. V.; Gladyshev, V. V.; Panasenko, О. I.; Knish, E. G.

    2014-01-01

    Using mathematical models of income distribution and excretion of drugs greatly enhances the interpretation of the results of biopharmaceutical research. Pharmacokinetic modeling makes it possible to quantify the biological assessment of pharmaceutical factors, opens the possibility of a science-based regulation of the kinetics of substances introduced through targeted changesof pharmaceutical factors. Results of the study of kinetic models are used to solve some practical problems associated...

  18. Developmental pharmacokinetics of gentamicin in preterm and term neonates

    DEFF Research Database (Denmark)

    Nielsen, Elisabet I; Sandström, Marie; Honoré, Per Hartvig;

    2009-01-01

    BACKGROUND AND OBJECTIVE: Preterm and term newborn infants show wide interindividual variability (IIV) in pharmacokinetic parameters of gentamicin. More extensive knowledge and use of predictive covariates could lead to faster attainment of therapeutic concentrations and a reduced need for...... concentration monitoring. This study was performed to characterize the population pharmacokinetics of gentamicin in preterm and term neonates and to identify and quantify relationships between patient characteristics and IIV. A secondary aim was to evaluate cystatin C as a marker for gentamicin clearance in...... this patient population. METHODS: Data were collected in a prospective study performed in the Neonatal Intensive Care Unit at the University Children's Hospital, Uppsala, Sweden. Population pharmacokinetic modelling was performed using nonlinear mixed-effects modelling (NONMEM) software. Bodyweight was...

  19. HMM-based Trust Model

    DEFF Research Database (Denmark)

    ElSalamouny, Ehab; Nielsen, Mogens; Sassone, Vladimiro

    2010-01-01

    Probabilistic trust has been adopted as an approach to taking security sensitive decisions in modern global computing environments. Existing probabilistic trust frameworks either assume fixed behaviour for the principals or incorporate the notion of ‘decay' as an ad hoc approach to cope with thei...... the major limitation of existing Beta trust model. We show the consistency of the HMM-based trust model and contrast it against the well known Beta trust model with the decay principle in terms of the estimation precision....

  20. Population Pharmacokinetics and Pharmacodynamic Modeling of Abacavir (1592U89) from a Dose-Ranging, Double-Blind, Randomized Monotherapy Trial with Human Immunodeficiency Virus-Infected Subjects

    OpenAIRE

    Weller, Stephen; Radomski, Kristine M.; Lou, Yu; Stein, Daniel S.

    2000-01-01

    Abacavir (formerly 1592U89) is a carbocyclic nucleoside analog with potent anti-human immunodeficiency virus (anti-HIV) activity when administered alone or in combination with other antiretroviral agents. The population pharmacokinetics and pharmacodynamics of abacavir were investigated in 41 HIV type 1 (HIV-1)-infected, antiretroviral naive adults with baseline CD4+ cell counts of ≥100/mm3 and plasma HIV-1 RNA levels of >30,000 copies/ml. Data for analysis were obtained from patients who rec...

  1. The effect of liposome encapsulation on the pharmacokinetics of recombinant secretory leukocyte protease inhibitor (rSLPI) therapy after local delivery to a guinea pig asthma model.

    LENUS (Irish Health Repository)

    Gibbons, Aileen

    2011-09-01

    Inhaled recombinant Secretory Leukocyte Protease Inhibitor (rSLPI) has shown potential for treatment of inflammatory lung conditions. Rapid inactivation of rSLPI by cathepsin L (Cat L) and rapid clearance from the lungs have limited clinical efficacy. Encapsulation of rSLPI within 1,2-Dioleoyl-sn-Glycero-3-[Phospho-L-Serine]:Cholesterol liposomes (DOPS-rSLPI) protects rSLPI against Cat L inactivation in vitro. We aimed to determine the effect of liposomes on rSLPI pharmacokinetics and activity in vitro and after local delivery to the airways in vivo.

  2. Pharmacokinetic study of sulbactomax.

    Science.gov (United States)

    Payasi, Anurag; Chaudhary, Manu; Gupta, Ankush; Dwivedi, Vivek Kumar; Bhatnagar, Anuj

    2010-08-01

    We have evaluated pharmacokinetics of a fixed dose combination (FDC) of ceftriaxone and sulbactam (2:1) or sulbactomax in eight healthy volunteers. A 1.5 g dose of sulbactomax, 1 g dose of ceftriaxone and 0.5 g sulbactam were given intravenously in a balanced two-ways cross-over study. Serially collected plasma sample was analyzed for ceftriaxone and sulbactam by high performance liquid chromatography (HPLC). The mean peaks of ceftriaxone and sulbactam concentrations in plasma were 152.06+/-6.65 microg/ml and 21.32+/-1.80 microg/ml, respectively and plasma half-lives for ceftriaxone and sulbactam were 5.2+/-0.35 hr and 0.94+/-0.038 hr, respectively. The AUC0-24 for ceftriaxone and sulbactam was 760.16+/-27.68 microg.hr/ml and 20.74+/-2.34 microg.hr/ml, respectively, with elimination rate constant of 0.133+/-0.009 hr(-1) and 0.732+/-0.029 hr(-1), respectively. The kinetics of ceftriaxone and sulbactum did not change in combination as compared to the alone treatment. Also, concentration of the ceftriaxone after 24 hr is higher than the minimum inhibitory concentration (MIC) of the most of the gram positive and gram negative bacteria indicating that one dose in a day is sufficient to treat the disease caused by these organisms. PMID:20686332

  3. Mechanistic investigation of biopharmaceutic and pharmacokinetic characteristics of surface engineering of satranidazole nanocrystals.

    Science.gov (United States)

    Dhat, Shalaka; Pund, Swati; Kokare, Chandrakant; Sharma, Pankaj; Shrivastava, Birendra

    2016-03-01

    The designing of surface engineered nanocrystals for improved stability and bioavailability is a multivariate process depending on several critical formulation and process variables. The present investigation deals with formulation of stable nanocrystals of poorly soluble satranidazole (SAT) for improving dissolution rate and pharmacokinetic profiling. SAT has low polar surface area, high dose and dosing frequency. Based on goniometric and stability studies of formulations prepared with various stabilizers, a unique combination of Span 20 and HPMC E-5 was selected for detailed investigation. Lyophilization of SAT nanosuspension was explored with nine different cryoprotectants in varying amounts to obtain easily redispersible nanocrystals (SAT-NC). The mean particle size and zeta potential of SAT-NC were found to be 208.8nm and -41.3mV respectively. DSC and XRPD confirmed the crystalline state of SAT. In vitro release studies of SAT-NC showed almost complete dissolution within 20min in water. Extravascular, one compartment pharmacokinetic modeling of in vivo plasma concentration versus time studies in male Wistar rats revealed twofold increase in Cmax, and AUC0-∞. Method of residuals was employed to calculate rate of absorption Ka and lag time. Nanosizing with appropriate stabilizers and programmed processing conditions successfully produced SAT-NC with improved pharmaceutic and pharmacokinetic characteristics. PMID:26748382

  4. Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval--A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity.

    Directory of Open Access Journals (Sweden)

    Jörg Täubel

    Full Text Available E-52862 is a Sigma-1 receptor antagonist (S1RA currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects.Thirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK samples on Day 1 (dosing day.In this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90% CI: -4.04, 6.93 ms for 500 mg; -0.39 ms (90% CI: -3.91, 3.13 ms for 600 mg and 1.32 ms (90% CI: -1.89, 4.53 ms for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis.The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9 one hour and -7.2 (90% CI: -9.4, -5.0 three hours after a standardised meal.EU Clinical Trials Register EudraCT 2010 020343 13.

  5. A model-based display

    International Nuclear Information System (INIS)

    A model-based display is identified, discussed, and illustrated. The model used in the display is based upon the Rankine Cycle, a heat engine cycle. Plant process data from the loss of main and auxiliary feedwater event at the Davis-Besse Plant on June 9, l985 is used to illustrate the display. The model used in the display fuses individual process variables into process functions. It also serves as a medium to communicate status of the process to human users. The human users may evaluate the goals of operation from the displayed process functions. Because of these display features, the user's cognitive workload is minimized. The opinions expressed herein are the author's personal ones and do not necessarily reflect criteria, requirements, and guidelines of the U.S. Nuclear Regulatory Commission

  6. Model-Based Optimization of Clinical Trial Designs

    OpenAIRE

    Vong, Camille

    2014-01-01

    General attrition rates in drug development pipeline have been recognized as a necessity to shift gears towards new methodologies that allow earlier and correct decisions, and the optimal use of all information accrued throughout the process. The quantitative science of pharmacometrics using pharmacokinetic-pharmacodynamic models was identified as one of the strategies core to this renaissance. Coupled with Optimal Design (OD), they constitute together an attractive toolkit to usher more rapi...

  7. Model-based sensor diagnosis

    International Nuclear Information System (INIS)

    Running a nuclear power plant involves monitoring data provided by the installation's sensors. Operators and computerized systems then use these data to establish a diagnostic of the plant. However, the instrumentation system is complex, and is not immune to faults and failures. This paper presents a system for detecting sensor failures using a topological description of the installation and a set of component models. This model of the plant implicitly contains relations between sensor data. These relations must always be checked if all the components are functioning correctly. The failure detection task thus consists of checking these constraints. The constraints are extracted in two stages. Firstly, a qualitative model of their existence is built using structural analysis. Secondly, the models are formally handled according to the results of the structural analysis, in order to establish the constraints on the sensor data. This work constitutes an initial step in extending model-based diagnosis, as the information on which it is based is suspect. This work will be followed by surveillance of the detection system. When the instrumentation is assumed to be sound, the unverified constraints indicate errors on the plant model. (authors). 8 refs., 4 figs

  8. Management of antipsychotic treatment discontinuation and interruptions using model-based simulations

    Directory of Open Access Journals (Sweden)

    Samtani MN

    2012-07-01

    Full Text Available Mahesh N Samtani,1 John J Sheehan,2 Dong-Jing Fu,2 Bart Remmerie,3 Jennifer Kern Sliwa,2 Larry Alphs21Janssen Research and Development, Raritan, NJ, USA; 2Janssen Scientific Affairs, Titusville, NJ, USA; 3Janssen Research and Development, Division of Janssen Pharmaceutica, Beerse, BelgiumBackground: Medication nonadherence is a well described and prevalent clinical occurrence in schizophrenia. These pharmacokinetic model-based simulations analyze predicted antipsychotic plasma concentrations in nonadherence and treatment interruption scenarios and with treatment reinitiation.Methods: Starting from steady state, pharmacokinetic model-based simulations of active moiety plasma concentrations of oral, immediate-release risperidone 3 mg/day, risperidone long-acting injection 37.5 mg/14 days, oral paliperidone extended-release 6 mg/day, and paliperidone palmitate 117 mg (75 mg equivalents/28 days were assessed under three treatment discontinuation/interruption scenarios, ie, complete discontinuation, one week of interruption, and four weeks of interruption. In the treatment interruption scenarios, pharmacokinetic simulations were performed using medication-specific reinitiation strategies.Results: Following complete treatment discontinuation, plasma concentrations persisted longest with paliperidone palmitate, followed by risperidone long-acting injection, while oral formulations exhibited the most rapid decrease. One week of oral paliperidone or risperidone interruption resulted in near complete elimination from the systemic circulation within that timeframe, reflecting the rapid elimination rate of the active moiety. After 1 and 4 weeks of interruption, minimum plasma concentrations were higher with paliperidone palmitate than risperidone long-acting injection over the simulated period. Four weeks of treatment interruption followed by reinitiation resulted in plasma levels returning to predicted therapeutic levels within 1 week.Conclusion: Due to

  9. FIRST REPORTS OF CLINICAL PHARMACOKINETICS IN NIGERIA

    OpenAIRE

    Michael, O.S.

    2015-01-01

    The German Friedrich Hartmut Dost (1910-1985) introduced the word Pharmacokinetics. Clinical pharmacokinetics is the direct application of knowledge regarding a drug's pharmacokinetics to a therapeutic situation in an individual or a population. It is the basis of therapeutic drug monitoring with the ultimate goal of keeping drugs safe. This branch of pharmacology has become the most relevant to the sub-specialty of clinical pharmacology. First reports of Clinical Pharmacokinetics in Nigeria ...

  10. Bioavailability of Organic Solvents in soils: Input into Biologically Based Dose-Response Models for Human Risk Assessments

    Energy Technology Data Exchange (ETDEWEB)

    Wester, Ronald C.

    1999-06-01

    The purpose of this study was to develop methods to expose rats and humans percutaneously and to use PBPK modeling to assess the percutaneous permeability of volatile compounds from aqueous or soil exposures. To estimate dermal absorption under realistic environmental exposure conditions, a patch system was developed that allowed for the volatilization of the compounds from the soil without contamination of inhaled or exhaled breath. The end product for this research will be a tested framework for the rapid screening of real and potential exposures while simultaneously developing physiologically based pharmacokinetic (PBPK) models to comprehensively evaluate and compare exposures to volatile chemicals from either contaminated soil or water.

  11. Model-based requirements engineering

    CERN Document Server

    Holt, Jon

    2012-01-01

    This book provides a hands-on introduction to model-based requirementsengineering and management by describing a set of views that form the basisfor the approach. These views take into account each individual requirement interms of its description, but then also provide each requirement with meaning byputting it into the correct 'context'. A requirement that has been put into a contextis known as a 'use case' and may be based upon either stakeholders or levelsof hierarchy in a system. Each use case must then be analysed and validated bydefining a combination of scenarios and formal mathematica

  12. Model-based tomographic reconstruction

    Science.gov (United States)

    Chambers, David H.; Lehman, Sean K.; Goodman, Dennis M.

    2012-06-26

    A model-based approach to estimating wall positions for a building is developed and tested using simulated data. It borrows two techniques from geophysical inversion problems, layer stripping and stacking, and combines them with a model-based estimation algorithm that minimizes the mean-square error between the predicted signal and the data. The technique is designed to process multiple looks from an ultra wideband radar array. The processed signal is time-gated and each section processed to detect the presence of a wall and estimate its position, thickness, and material parameters. The floor plan of a building is determined by moving the array around the outside of the building. In this paper we describe how the stacking and layer stripping algorithms are combined and show the results from a simple numerical example of three parallel walls.

  13. Pharmacokinetics of doxycycline in dogs.

    OpenAIRE

    Wilson, R C; Kemp, D T; Kitzman, J V; Goetsch, D D

    1988-01-01

    Six adult dogs were given doxycycline hyclate at a dosage of 5 mg/kg of body weight intravenously so that pharmacokinetic parameters could be evaluated. Serum doxycycline concentrations were determined over a 48 h period using a modified agar well bioassay. Compartmental pharmacokinetic evaluation of the serum concentration time data indicated that doxycycline has a half-life of 10.36 h, a body clearance of 1.68 +/- 0.44 mL/min/kg, and a volume of distribution at steady state of 1.468 +/- 0.2...

  14. Simultaneous multi-component quantitation of Chinese herbal injection Yin-zhi-huang in rat plasma by using a single-tube extraction procedure for mass spectrometry-based pharmacokinetic measurement.

    Science.gov (United States)

    Zeng, Le; Wang, Meiling; Yuan, Yu; Guo, Bin; Zhou, Jing; Tan, Zhen; Ye, Meiling; Ding, Li; Chen, Bo

    2014-09-15

    Ying-zhi-huang injection (YZH-I) is an injectable multi-herbal prescription derived from the ancient Chinese remedy "Yin-chen-hao-tang", which is widely used in the clinic for the treatment of jaundice and chronic liver diseases. To date, little information is available on the pharmacokinetic properties of this poly-herbal formulation. Herein, we reported a simple, rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantitative multiple reaction monitoring (MRM) of eight major ingredients of YZH-I (including baicalin, baicalein, wogonoside, geniposide, geniposidic acid, chlorogenic acid, neochlorogenic acid, and caffeic acid) in rat plasma. A fast single-tube multi-impurity precipitation extraction ("SMIPE") procedure was introduced for straightforward plasma preparation, based on one-pot deproteinization precipitation with acidified methanol extraction and in-situ multifunction impurity removal by a solid sorbent mixture (anh. magnesium sulfate plus octadecylsilane). Particularly, the addition of ascorbic acid in methanol (10 mg/mL) was found to exhibit a pronounced protective effect and significantly increase extraction effectiveness of the herbal phenolic components. Some pretreatment variables (protein precipitating solvent, acidifying agent and sorbent) were optimized with acceptable matrix effect (-18 to 7.7%), extraction recovery (65-88%) and process efficiency (62-91%) for the SMIPE-based LC-MRM multi-analyte quantitation using matrix-matched calibration (5-1000 ng/mL) without using internal standard. Mean accuracies were obtained in the range of 83-114% at three different fortification levels, with intra- and inter-day variations within 13%. This validated method was successfully applied to the simultaneous measurement and