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  1. 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.

  2. 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...

  3. 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...

  4. 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

  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. 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 ...

  8. 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.

  9. 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...

  10. 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...

  11. 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

  12. 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.

  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. 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

  15. 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...

  16. 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...

  17. 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.

  18. 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...

  19. 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”.

  20. 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.

  1. 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...

  2. Human physiologically based pharmacokinetic model for propofol

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    Schnider Thomas W

    2005-04-01

    Full Text Available Abstract Background Propofol is widely used for both short-term anesthesia and long-term sedation. It has unusual pharmacokinetics because of its high lipid solubility. The standard approach to describing the pharmacokinetics is by a multi-compartmental model. This paper presents the first detailed human physiologically based pharmacokinetic (PBPK model for propofol. Methods PKQuest, a freely distributed software routine http://www.pkquest.com, was used for all the calculations. The "standard human" PBPK parameters developed in previous applications is used. It is assumed that the blood and tissue binding is determined by simple partition into the tissue lipid, which is characterized by two previously determined set of parameters: 1 the value of the propofol oil/water partition coefficient; 2 the lipid fraction in the blood and tissues. The model was fit to the individual experimental data of Schnider et. al., Anesthesiology, 1998; 88:1170 in which an initial bolus dose was followed 60 minutes later by a one hour constant infusion. Results The PBPK model provides a good description of the experimental data over a large range of input dosage, subject age and fat fraction. Only one adjustable parameter (the liver clearance is required to describe the constant infusion phase for each individual subject. In order to fit the bolus injection phase, for 10 or the 24 subjects it was necessary to assume that a fraction of the bolus dose was sequestered and then slowly released from the lungs (characterized by two additional parameters. The average weighted residual error (WRE of the PBPK model fit to the both the bolus and infusion phases was 15%; similar to the WRE for just the constant infusion phase obtained by Schnider et. al. using a 6-parameter NONMEM compartmental model. Conclusion A PBPK model using standard human parameters and a simple description of tissue binding provides a good description of human propofol kinetics. The major advantage of a

  3. 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...

  4. 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...

  5. Bayesian Uncertainty Analysis of PBPK Model Predictions for Permethrin in Rats

    Science.gov (United States)

    Uncertainty analysis of human physiologically-based pharmacokinetic (PBPK) model predictions can pose a significant challenge due to data limitations. As a result of these limitations, human models are often derived from extrapolated animal PBPK models, for which there is usuall...

  6. A Workflow for Global Sensitivity Analysis of PBPK Models

    OpenAIRE

    McNally, Kevin; Cotton, Richard; Loizou, George D.

    2011-01-01

    Physiologically based pharmacokinetic (PBPK) models have a potentially significant role in the development of a reliable predictive toxicity testing strategy. The structure of PBPK models are ideal frameworks into which disparate in vitro and in vivo data can be integrated and utilized to translate information generated, using alternative to animal measures of toxicity and human biological monitoring data, into plausible corresponding exposures. However, these models invariably include the de...

  7. 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...

  8. 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...

  9. 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.

  10. Maximum Recommended Dosage of Lithium for Pregnant Women Based on a PBPK Model for Lithium Absorption

    Directory of Open Access Journals (Sweden)

    Scott Horton

    2012-01-01

    Full Text Available Treatment of bipolar disorder with lithium therapy during pregnancy is a medical challenge. Bipolar disorder is more prevalent in women and its onset is often concurrent with peak reproductive age. Treatment typically involves administration of the element lithium, which has been classified as a class D drug (legal to use during pregnancy, but may cause birth defects and is one of only thirty known teratogenic drugs. There is no clear recommendation in the literature on the maximum acceptable dosage regimen for pregnant, bipolar women. We recommend a maximum dosage regimen based on a physiologically based pharmacokinetic (PBPK model. The model simulates the concentration of lithium in the organs and tissues of a pregnant woman and her fetus. First, we modeled time-dependent lithium concentration profiles resulting from lithium therapy known to have caused birth defects. Next, we identified maximum and average fetal lithium concentrations during treatment. Then, we developed a lithium therapy regimen to maximize the concentration of lithium in the mother’s brain, while maintaining the fetal concentration low enough to reduce the risk of birth defects. This maximum dosage regimen suggested by the model was 400 mg lithium three times per day.

  11. 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

  12. 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...

  13. Dynamical coupling of PBPK/PD and AUC-based toxicity models for arsenic in tilapia Oreochromis mossambicus from blackfoot disease area in Taiwan

    Energy Technology Data Exchange (ETDEWEB)

    Liao, C.-M. [Ecotoxicological Modeling Center, Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, Taiwan 10617 (China)]. E-mail: cmliao@ntu.edu.tw; Liang, H.-M. [Ecotoxicological Modeling Center, Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, Taiwan 10617 (China); Chen, B.-C. [Department of Post-Modern Agriculture, Mingdao University, Changhua, Taiwan 52345 (China); Singh Sher [Center of Genomics Medicine, School of Medicine, National Taiwan University, Taipei, Taiwan 10617 (China); Tsai, J.-W. [Ecotoxicological Modeling Center, Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, Taiwan 10617 (China); Chou, Y.-H. [Ecotoxicological Modeling Center, Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, Taiwan 10617 (China); Lin, W.-T. [Environment Change Research Center, Academia Sinica, Nankang, Taipei, Taiwan 11517 (China)

    2005-05-01

    A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models were developed for arsenic (As) in tilapia Oreochromis mossambicus from blackfoot disease area in Taiwan. The PBPK/PD model structure consisted of muscle, gill, gut wall, alimentary canal, and liver, which were interconnected by blood circulation. We integrate the target organ concentrations and dynamic response describing uptake, metabolism, and disposition of As and the associated area-under-curve (AUC)-based toxicological dynamics following an acute exposure. The model validations were compared against the field observations from real tilapia farms and previously published uptake/depuration experimental data, indicating that predicted and measured As concentrations in major organs of tilapia were in good agreement. The model was utilized to reasonably simulate and construct a dose-dependent dynamic response between mortality effect and equilibrium target organ concentrations. Model simulations suggest that tilapia gills may serve as a surrogate sensitive biomarker of short-term exposure to As. This integrated As PBPK/PD/AUC model quantitatively estimates target organ concentration and dynamic response in tilapia and is a strong framework for future waterborne metal model development and for refining a biologically-based risk assessment for exposure of aquatic species to waterborne metals under a variety of scenarios. - Integrated toxicity models can identify dynamic responses of fish to arsenic.

  14. 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

  15. 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.

  16. 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

  17. 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

  18. 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).

  19. 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...

  20. P16.33AN IN SILICO ESTIMATION OF THE PHARMACOKINETIC PROFILE AND THE DISPOSITION OF GD-DTPA IN BRAIN TUMOR LESIONS OF DIFFERENT VASCULATURE THROUGH PBPK MODELS

    Science.gov (United States)

    Spanakis, M.; Oraiopoulou, M.E.; Tzamali, E.; Sakkalis, V.; Maris, T.G.; Papadaki, E.; Karantanas, A.; Marias, K.

    2014-01-01

    Brain tumor lesions (BTL), i.e. high grade gliomas, are known to have a prominence of vasculature, which is promoted through hypoxia mechanisms and differential expression of vascular endothelial growth factor (VEGF). Imaging techniques such as dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) with intra-venous (i.v.) administration of a Gd-based contrast agent (GBCA) are successfully used for the diagnosis and characterization of the BTLs. Tracer kinetics plays an important role in DCE-MRI by assessing the vessel leakage through estimation of the transfer and disposition of GBCAs in a lesion. Physiologically-based pharmacokinetic modeling (PBPK) represents a well-documented approach to estimate in silico the disposition of pharmacologic agents in the body. In this work, we sought to i)present a whole-body PBPK approach in order to estimate the PK profile of Gd-DTPA (Gadopentetic acid, Magnevist®) and ii)evaluate the impact of vascular fraction of tracer's extravascular-extracellular disposition in a simulated BTL. PK profile was assessed through the application of Simcyp® simulator platform and the generation of whole-body PBPK model. BTL was introduced as an additional compartment (∼5% of total brain weight) with tissue characteristics matching those of a brain tumor. In silico clinical trials (ISCTs) were designed by integrating literature data for a virtual population of patients with cancer for Simcyp® and Gd-DTPA properties. The ISCTs were generated for a representative individual and concentrations were estimated for 15 minutes following i.v. bolus injection of Gd-DTPA (0.1 mmol/kg). Given the simulated BTL's size, all parameters were kept constant except for capillary fraction in order to evaluate the impact of vasculature. RESULTS: from the whole-body PBPK simulations estimate the maximum plasma concentration of Gd-DTPA to be 3.0 mM whereas the intracranial blood concentration to be 1.7 mM. Regarding the simulated BTL, concentrations

  1. Short Communication: Is Ethanol-Based Hand Sanitizer Involved in Acute Pancreatitis after Excessive Disinfection?—An Evaluation with the Use of PBPK Model

    Science.gov (United States)

    Huynh-Delerme, Céline; Artigou, Catherine; Bodin, Laurent; Tardif, Robert; Charest-Tardif, Ginette; Verdier, Cécile; Sater, Nessryne; Ould-Elhkim, Mostafa; Desmares, Catherine

    2012-01-01

    An occupational physician reported to the French Health Products Safety Agency (Afssaps) a case of adverse effect of acute pancreatitis (AP) in a teaching nurse, after multiple demonstrations with ethanol-based hand sanitizers (EBHSs) used in a classroom with defective mechanical ventilation. It was suggested by the occupational physician that the exposure to ethanol may have produced a significant blood ethanol concentration and subsequently the AP. In order to verify if the confinement situation due to defective mechanical ventilation could increase the systemic exposure to ethanol via inhalation route, a physiologically based pharmacokinetic (PBPK) modeling was used to predict ethanol blood levels. Under the worst case scenario, the simulation by PBPK modeling showed that the maximum blood ethanol concentration which can be predicted of 5.9 mg/l is of the same order of magnitude to endogenous ethanol concentration (mean = 1.1 mg/L; median = 0.4 mg/L; range = 0–35 mg/L) in nondrinker humans (Al-Awadhi et al., 2004). The present study does not support the likelihood that EBHS leads to an increase in systemic ethanol concentration high enough to provoke an acute pancreatitis. PMID:22577377

  2. Short Communication: Is Ethanol-Based Hand Sanitizer Involved in Acute Pancreatitis after Excessive Disinfection?—An Evaluation with the Use of PBPK Model

    Directory of Open Access Journals (Sweden)

    Céline Huynh-Delerme

    2012-01-01

    Full Text Available An occupational physician reported to the French Health Products Safety Agency (Afssaps a case of adverse effect of acute pancreatitis (AP in a teaching nurse, after multiple demonstrations with ethanol-based hand sanitizers (EBHSs used in a classroom with defective mechanical ventilation. It was suggested by the occupational physician that the exposure to ethanol may have produced a significant blood ethanol concentration and subsequently the AP. In order to verify if the confinement situation due to defective mechanical ventilation could increase the systemic exposure to ethanol via inhalation route, a physiologically based pharmacokinetic (PBPK modeling was used to predict ethanol blood levels. Under the worst case scenario, the simulation by PBPK modeling showed that the maximum blood ethanol concentration which can be predicted of 5.9 mg/l is of the same order of magnitude to endogenous ethanol concentration (mean = 1.1 mg/L; median = 0.4 mg/L; range = 0–35 mg/L in nondrinker humans (Al-Awadhi et al., 2004. The present study does not support the likelihood that EBHS leads to an increase in systemic ethanol concentration high enough to provoke an acute pancreatitis.

  3. 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

  4. A Workflow for Global Sensitivity Analysis of PBPK Models

    OpenAIRE

    GeorgeDLoizou

    2011-01-01

    Physiologically based pharmacokinetic models have a potentially significant role in the development of a reliable predictive toxicity testing strategy. The structure of PBPK models are ideal frameworks into which disparate in vitro and in vivo data can be integrated and utilised to translate information generated, using alternative to animal measures of toxicity and human biological monitoring data, into plausible corresponding exposures. However, these models invariably include the descripti...

  5. 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

  6. 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

  7. 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

  8. 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...

  9. 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...

  10. 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.

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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...

  16. 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.

  17. 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

  18. 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

  19. 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

  20. 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

  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. 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

  3. 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...

  4. 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...

  5. 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 ...

  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. 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

  8. 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

  9. 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)

  10. 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...

  11. 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

  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. PBPK model of methotrexate in cerebrospinal fluid ventricles using a combined microdialysis and MRI acquisition.

    Science.gov (United States)

    Brandhonneur, Nolwenn; Noury, Fanny; Bruyère, Arnaud; Saint-Jalmes, Hervé; Le Corre, Pascal

    2016-07-01

    The objective of the study was to evaluate the distribution of methotrexate (MTX) in cerebrospinal fluid (CSF) lateral ventricles and in cisterna magna after 3rd intraventricular CSF administration in a rabbit model. MTX or gadolinium chelate (Gd-DOTA) was administered in the 3rd ventricle with a local microdialysis to study the pharmacokinetics at the site of administration and with a simultaneous magnetic resonance imaging (MRI) acquisition in the 3rd ventricle, the lateral ventricles and in the cisterna magna. A specific CSF Physiologically Based Pharmacokinetic (PBPK) model was then extrapolated for MTX from Gd-DOTA data. The relative contribution of elimination and distribution processes to the overall disposition of MTX and Gd-DOTA in the 3rd ventricle was similar (i.e., around 60% for CLE and 40% for CLI) suggesting that Gd-DOTA was a suitable surrogate marker for MTX disposition in ventricular CSF. The PBPK predictions for MTX both in CSF of the 3rd ventricle and in plasma were in accordance with the in vivo results. The present study showed that the combination of local CSF microdialysis with MRI acquisition of the brain ventricles and a PBPK model could be a useful methodology to estimate the drug diffusion within CSF ventricles after direct brain CSF administration. Such a methodology would be of interest to clinicians for a rationale determination and optimization of drug dosing parameters in the treatment of leptomeningeal metastases. PMID:27142258

  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. 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

  16. 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.

  17. 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)

  18. 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

  19. 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

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. A Workflow for Global Sensitivity Analysis of PBPK Models

    Directory of Open Access Journals (Sweden)

    Kevin eMcNally

    2011-06-01

    Full Text Available Physiologically based pharmacokinetic models have a potentially significant role in the development of a reliable predictive toxicity testing strategy. The structure of PBPK models are ideal frameworks into which disparate in vitro and in vivo data can be integrated and utilised to translate information generated, using alternative to animal measures of toxicity and human biological monitoring data, into plausible corresponding exposures. However, these models invariably include the description of well known non-linear biological processes such as, enzyme saturation and interactions between parameters such as, organ mass and body mass. Therefore, an appropriate sensitivity analysis technique is required which can quantify the influences associated with individual parameters, interactions between parameters and any non-linear processes. In this report we have defined a workflow for sensitivity analysis of PBPK models that is computationally feasible, accounts for interactions between parameters, and can be displayed in the form of a bar chart and cumulative sum line (Lowry plot, which we believe is intuitive and appropriate for toxicologists, risk assessors and regulators.

  5. 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...

  6. Use of a PBPK model with dose-dependent elimination rates predicts higher peak dioxin exposures than previously estimated

    Energy Technology Data Exchange (ETDEWEB)

    Emond, C. [NRC, NAS, WA, DC (United States); Michalek, J.E. [Air Force Research Lab., Brooks City-Base, TX (United States); Birnbaum, L.S.; DeVito, M.J. [PKB, ETD, ORD, NHEERL U.S. EPA, RTP, NC (United States)

    2004-09-15

    Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with increased risk for cancer, diabetes and reproductive toxicities in numerous epidemiological studies. Several of these studies base exposure estimates on measurements of blood levels years after the accidental or occupational exposures. Peak exposures have been estimated in these studies assuming a mono or biphasic elimination rate for TCDD, with estimates of half-life ranging from 5 to 12 years. Recent clinical studies suggest that the elimination rate of TCDD is dose dependent. To address this question a physiologically based pharmacokinetic (PBPK) model can be used to predict the concentration of TCDD with a dose-dependent elimination rate. The aims of this study were to validate a dose-dependent elimination rate by using a PBPK model and to adequately predict the concentration of TCDD shortly after the exposure.

  7. 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

  8. 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

  9. 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

  10. PBPK modeling/Monte Carlo simulation of methylene chloride kinetic changes in mice in relation to age and acute, subchronic, and chronic inhalation exposure.

    OpenAIRE

    Thomas, R S; Yang, R S; Morgan, D G; Moorman, M P; Kermani, H R; Sloane, R A; O'Connor, R W; Adkins, B; Gargas, M L; Andersen, M E

    1996-01-01

    During a 2-year chronic inhalation study on methylene chloride (2000 or 0 ppm; 6 hr/day, 5 days/week), gas-uptake pharmacokinetic studies and tissue partition coefficient determinations were conducted on female B6C3F1, mice after 1 day, 1 month, 1 year, and 2 years of exposure. Using physiologically based pharmacokinetic (PBPK) modeling coupled with Monte Carlo simulation and bootstrap resampling for data analyses, a significant induction in the mixed function oxidase (MFO) rate constant (Vma...

  11. 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.

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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 ...

  17. 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

  18. 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

  19. 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.

  20. A PBPK Model to Predict Disposition of CYP3A-Metabolized Drugs in Pregnant Women: Verification and Discerning the Site of CYP3A Induction.

    Science.gov (United States)

    Ke, A B; Nallani, S C; Zhao, P; Rostami-Hodjegan, A; Unadkat, J D

    2012-01-01

    Besides logistical and ethical concerns, evaluation of safety and efficacy of medications in pregnant women is complicated by marked changes in pharmacokinetics (PK) of drugs. For example, CYP3A activity is induced during the third trimester (T3). We explored whether a previously published physiologically based pharmacokinetic (PBPK) model could quantitatively predict PK profiles of CYP3A-metabolized drugs during T3, and discern the site of CYP3A induction (i.e., liver, intestine, or both). The model accounted for gestational age-dependent changes in maternal physiological function and hepatic CYP3A activity. For model verification, mean plasma area under the curve (AUC), peak plasma concentration (Cmax), and trough plasma concentration (Cmin) of midazolam (MDZ), nifedipine (NIF), and indinavir (IDV) were predicted and compared with published studies. The PBPK model successfully predicted MDZ, NIF, and IDV disposition during T3. A sensitivity analysis suggested that CYP3A induction in T3 is most likely hepatic and not intestinal. Our PBPK model is a useful tool to evaluate different dosing regimens during T3 for drugs cleared primarily via CYP3A metabolism.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e3; doi:10.1038/psp.2012.2; advance online publication 26 September 2012. PMID:23835883

  1. 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

  2. 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

  3. 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

  4. 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...

  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. 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.

  7. 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

  8. More Power to OATP1B1: An Evaluation of Sample Size in Pharmacogenetic Studies Using a Rosuvastatin PBPK Model for Intestinal, Hepatic, and Renal Transporter-Mediated Clearances.

    Science.gov (United States)

    Emami Riedmaier, Ariane; Burt, Howard; Abduljalil, Khaled; Neuhoff, Sibylle

    2016-07-01

    Rosuvastatin is a substrate of choice in clinical studies of organic anion-transporting polypeptide (OATP)1B1- and OATP1B3-associated drug interactions; thus, understanding the effect of OATP1B1 polymorphisms on the pharmacokinetics of rosuvastatin is crucial. Here, physiologically based pharmacokinetic (PBPK) modeling was coupled with a power calculation algorithm to evaluate the influence of sample size on the ability to detect an effect (80% power) of OATP1B1 phenotype on pharmacokinetics of rosuvastatin. Intestinal, hepatic, and renal transporters were mechanistically incorporated into a rosuvastatin PBPK model using permeability-limited models for intestine, liver, and kidney, respectively, nested within a full PBPK model. Simulated plasma rosuvastatin concentrations in healthy volunteers were in agreement with previously reported clinical data. Power calculations were used to determine the influence of sample size on study power while accounting for OATP1B1 haplotype frequency and abundance in addition to its correlation with OATP1B3 abundance. It was determined that 10 poor-transporter and 45 intermediate-transporter individuals are required to achieve 80% power to discriminate the AUC0-48h of rosuvastatin from that of the extensive-transporter phenotype. This number was reduced to 7 poor-transporter and 40 intermediate-transporter individuals when the reported correlation between OATP1B1 and 1B3 abundance was taken into account. The current study represents the first example in which PBPK modeling in conjunction with power analysis has been used to investigate sample size in clinical studies of OATP1B1 polymorphisms. This approach highlights the influence of interindividual variability and correlation of transporter abundance on study power and should allow more informed decision making in pharmacogenomic study design. PMID:27385171

  9. AOP Knowledge Base/Wiki Tool Set

    Science.gov (United States)

    Utilizing ToxCast Data and Lifestage Physiologically-Based Pharmacokinetic (PBPK) models to Drive Adverse Outcome Pathways (AOPs)-Based Margin of Exposures (ABME) to Chemicals. Hisham A. El-Masri1, Nicole C. Klienstreur2, Linda Adams1, Tamara Tal1, Stephanie Padilla1, Kristin Is...

  10. Inhalation exposure or body burden? Better way of estimating risk--An application of PBPK model.

    Science.gov (United States)

    Majumdar, Dipanjali; Dutta, Chirasree; Sen, Subha

    2016-01-01

    We aim to establish a new way for estimating the risk from internal dose or body burden due to exposure of benzene in human subject utilizing physiologically based pharmacokinetic (PBPK) model. We also intend to verify its applicability on human subjects exposed to different levels of benzene. We estimated personal inhalation exposure of benzene for two occupational groups namely petrol pump workers and car drivers with respect to a control group, only environmentally exposed. Benzene in personal air was pre-concentrated on charcoal followed by chemical desorption and analysis by gas chromatography equipped with flame ionization detector (GC-FID). We selected urinary trans,trans-muconic acid (t,t-MA) as biomarker of benzene exposure and measured its concentration using solid phase extraction followed by high performance liquid chromatography (HPLC). Our estimated inhalation exposure of benzene was 137.5, 97.9 and 38.7 μg/m(3) for petrol pump workers, car drivers and environmentally exposed control groups respectively which resulted in urinary t,t-MA levels of 145.4±55.3, 112.6±63.5 and 60.0±34.9 μg g(-1) of creatinine, for the groups in the same order. We deduced a derivation for estimation of body burden from urinary metabolite concentration using PBPK model. Estimation of the internal dose or body burden of benzene in human subject has been made for the first time by the measurement of t,t-MA as a urinary metabolite using physiologically based pharmacokinetic (PBPK) model as a tool. The weight adjusted total body burden of benzene was estimated to be 17.6, 11.1 and 5.0 μg kg(-1) of body weight for petrol pump workers, drivers and the environmentally exposed control group, respectively using this method. We computed the carcinogenic risk using both the estimated internal benzene body burden and external exposure values using conventional method. Our study result shows that internal dose or body burden is not proportional to level of exposure rather have a

  11. 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.

  12. Application of a catenary PBPK model to predict the disposition of "catch and release" anti-PCSK9 antibodies.

    Science.gov (United States)

    Glassman, Patrick M; Balthasar, Joseph P

    2016-05-30

    The development of 'catch and release', or pH-sensitive, monoclonal antibodies (mAb) has become of interest to groups seeking to reduce the influence of target-mediated elimination on pharmacokinetics and pharmacodynamics. In this work, a catenary physiologically-based pharmacokinetic (PBPK) model is described to predict the pharmacokinetic benefit conferred by engineering mAbs for 'catch and release' binding. Our previously published PBPK model was adapted for consideration of the production and elimination of proprotein convertase subtilisin/kexin type 9 (PCSK9) in mice, and the model was then applied to predict the pharmacokinetics of anti-PCSK9 mAb with pH-stable (J10) and pH-sensitive binding (J17). The model was able to generate reasonable predictions of both J10 and J17 plasma pharmacokinetics. For J10, mean (±standard deviation) predicted vs. observed areas under the plasma concentration curve (AUCinf) were: 217 (77.1) vs. 103nMday (1mg/kg), 1.14×10(3) (858) vs. 769nMday (3mg/kg), and 6.60×10(3) (5.58×10(3)) vs. 2.86×10(3)nMday (10mg/kg), and for J17 the values were: 838 (161) vs. 818nMday (1mg/kg), 2.30×10(3) (441) vs. 2.57×10(3)nMday (3mg/kg), and 8.42×10(3) (1.50×10(3)) vs. 9.17×10(3)nMday (10mg/kg). Further simulations with the model predicted that target turnover and the magnitude of change in the complex dissociation rate constant between pH 7.4 and pH 6.0 are key determinants of the improvements in pharmacokinetics associated with 'catch and release' mAbs. The model described here may be useful for prediction of the pharmacokinetics of 'catch and release' mAbs directed against other targets. PMID:27041125

  13. A non-invasive approach to study lifetime exposure and bioaccumulation of PCBs in protected marine mammals: PBPK modeling in harbor porpoises

    International Nuclear Information System (INIS)

    In the last decade, physiologically based pharmacokinetic (PBPK) models have increasingly been developed to explain the kinetics of environmental pollutants in wildlife. For marine mammals specifically, these models provide a new, non-destructive tool that enables the integration of biomonitoring activities and in vitro studies. The goals of the present study were firstly to develop PBPK models for several environmental relevant PCB congeners in harbor porpoises (Phocoena phocoena), a species that is sensitive to pollution because of its limited metabolic capacity for pollutant transformation. These models were tested using tissue data of porpoises from the Black Sea. Secondly, the predictive power of the models was investigated for time trends in the PCB concentrations in North Sea harbor porpoises between 1990 and 2008. Thirdly, attempts were made to assess metabolic capacities of harbor porpoises for the investigated PCBs. In general, results show that parameter values from other species (rodents, humans) are not always suitable in marine mammal models, most probably due to differences in physiology and exposure. The PCB 149 levels decrease the fastest in male harbor porpoises from the North Sea in a time period of 18 years, whereas the PCB 101 levels decrease the slowest. According to the models, metabolic breakdown of PCB 118 is probably of lesser importance compared to other elimination pathways. For PCB 101 and 149 however, the presence of their metabolites can be attributed to bioaccumulation of metabolites from the prey and to metabolic breakdown of the parent compounds in the harbor porpoises. - Highlights: → PBPK modeling was used to study the kinetics of several PCBs in a marine mammal. → Harbor porpoises are sensitive to pollution and therefore ideal model organisms. → Black Sea data were used for parameterization. → North Sea data for assessing temporal trends (1990-2008). → PBPK modeling is a non-invasive and non-destructive tool.

  14. Development of an integrated multi-species and multi-dose route PBPK model for volatile methyl siloxanes - D4 and D5.

    Science.gov (United States)

    McMullin, Tami S; Yang, Yuching; Campbell, Jerry; Clewell, Harvey J; Plotzke, Kathy; Andersen, Melvin E

    2016-02-01

    There are currently seven published physiologically based pharmacokinetic (PBPK) models describing aspects of the pharmacokinetics of octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) for various exposure routes in rat and human. Each model addressed the biological and physico-chemical properties of D4 and D5 (highly lipophilic coupled with low blood: air partition coefficient and high liver clearance) that result in unique kinetic behaviors as well differences between D4 and D5. However, the proliferation of these models resulted in challenges for various risk assessment applications when needing to determine the optimum model for estimating dose metrics. To enhance the utility of these PBPK models for risk assessment, we integrated the suite of structures into one coherent model capable of simulating the entire set of existing data equally well as older more limited scope models. In this paper, we describe the steps required to develop this integrated model, the choice of physiological, partitioning and biochemical parameters for the model, and the concordance of the model behavior across key data sets. This integrated model is sufficiently robust to derive relevant dose metrics following individual or combined dermal and inhalation exposures of workers, consumer or the general population to D4 and D5 for route-to-route, interspecies and high to low dose extrapolations for risk assessment. PMID:26724268

  15. Towards a Best Practice Approach in PBPK Modeling: Case Example of Developing a Unified Efavirenz Model Accounting for Induction of CYPs 3A4 and 2B6.

    Science.gov (United States)

    Ke, A; Barter, Z; Rowland-Yeo, K; Almond, L

    2016-07-01

    In this study, we present efavirenz physiologically based pharmacokinetic (PBPK) model development as an example of our best practice approach that uses a stepwise approach to verify the different components of the model. First, a PBPK model for efavirenz incorporating in vitro and clinical pharmacokinetic (PK) data was developed to predict exposure following multiple dosing (600 mg q.d.). Alfentanil i.v. and p.o. drug-drug interaction (DDI) studies were utilized to evaluate and refine the CYP3A4 induction component in the liver and gut. Next, independent DDI studies with substrates of CYP3A4 (maraviroc, atazanavir, and clarithromycin) and CYP2B6 (bupropion) verified the induction components of the model (area under the curve [AUC] ratios within 1.0-1.7-fold of observed). Finally, the model was refined to incorporate the fractional contribution of enzymes, including CYP2B6, propagating autoinduction into the model (Racc 1.7 vs. 1.7 observed). This validated mechanistic model can now be applied in clinical pharmacology studies to prospectively assess both the victim and perpetrator DDI potential of efavirenz. PMID:27435752

  16. 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.

  17. 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

  18. 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.

  19. 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

  20. Utilizing in vitro and PBPK tools to link ADME characteristics to plasma profiles: case example nifedipine immediate release formulation.

    Science.gov (United States)

    Wagner, Christian; Thelen, Kirstin; Willmann, Stefan; Selen, Arzu; Dressman, Jennifer B

    2013-09-01

    One of the most prominent food-drug interactions is the inhibition of intestinal cytochrome P450 (CYP) 3A enzymes by grapefruit juice ingredients, and, as many drugs are metabolized via CYP 3A, this interaction can be of clinical importance. Calcium channel-blocking agents of the dihydropyridine type, such as felodipine and nifedipine, are subject to extensive intestinal first pass metabolism via CYP 3A, thus resulting in significantly enhanced in vivo exposure of the drug when administered together with grapefruit juice. Physiologically based pharmacokinetic (PBPK) modeling was used to simulate pharmacokinetics of a nifedipine immediate release formulation following concomitant grapefruit juice ingestion, that is, after inhibition of small intestinal CYP 3A enzymes. For this purpose, detailed data about CYP 3A levels were collected from the literature and implemented into commercial PBPK software. As literature reports show that grapefruit juice (i) leads to a marked delay in gastric emptying, and (ii) rapidly lowers the levels of intestinal CYP 3A enzymes, inhibition of intestinal first pass metabolism following ingestion of grapefruit juice was simulated by altering the intestinal CYP 3A enzyme levels and simultaneously decelerating the gastric emptying rate. To estimate the in vivo dispersion and dissolution behavior of the formulation, dissolution tests in several media simulating both the fasted and fed state stomach and small intestine were conducted, and the results from the in vitro dissolution tests were used as input function to describe the in vivo dissolution of the drug. Plasma concentration-time profiles of the nifedipine immediate release formulation both with and without simultaneous CYP 3A inhibition were simulated, and the results were compared with data gathered from the literature. Using this approach, nifedipine plasma profiles could be simulated well both with and without enzyme inhibition. A reduction in small intestinal CYP 3A levels by 60

  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. 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。

  3. 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.

  4. 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

  5. THE IMPORTANCE OF OBTAINING INFORMATION ON THE SPECIFIC CONTENT OF TISSUE ENZYMES METABOLIZING ORGANOPHOSPHORUS PESTICIDES, PRIOR TO DETERMINE VMAX, KM VALUES FOR USE IN PBPK MODELS

    Science.gov (United States)

    Physiological pharmacokinetic/pharmacodynamic models require Vmax, Km values for the metabolism of OPs by tissue enzymes. Current literature values cannot be easily used in OP PBPK models (i.e., parathion and chlorpyrifos) because standard methodologies were not used in their ...

  6. THE IMPORTANCE OF OBTAINING INFORMATION ON THE SPECIFIC CONTENT OF TISSUE ENZYMES METABOLIZING ORGANOPHOSPHORUS PESTICIDES, PRIOR TO DETERMINING VMAX, KM VALUES FOR USE IN PBPK MODELS

    Science.gov (United States)

    Physiological pharmacokinetic\\pharmacodynamic models require Vmax, Km values for the metabolism of OPs by tissue enzymes. Current literature values cannot be easily used in OP PBPK models (i.e., parathion and chlorpyrifos) because standard methodologies were not used in their ...

  7. 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

  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

    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.

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. Prednisone has no effect on the pharmacokinetics of CYP3A4 metabolized drugs - midazolam and odanacatib.

    Science.gov (United States)

    Marcantonio, Eugene E; Ballard, Jeanine; Gibson, Christopher R; Kassahun, Kelem; Palamanda, Jairam; Tang, Cuyue; Evers, Raymond; Liu, Chengcheng; Zajic, Stefan; Mahon, Chantal; Mostoller, Kate; Hreniuk, David; Mehta, Anish; Morris, Denise; Wagner, John A; Stoch, S Aubrey

    2014-11-01

    We evaluated the effect of prednisone on midazolam and odanacatib pharmacokinetics. In this open-label, 2-period crossover study in healthy male subjects, midazolam 2 mg was administered (Day -1) followed by odanacatib 50 mg (Day 1) during Part 1. In Period 2, prednisone 10 mg once daily (qd) was administered on Days 1-28; odanacatib was co-administered on Day 14 and midazolam 2 mg was co-administered on Days 1 and 28. Subjects were administered midazolam 2 mg on Days 42 and 56. Safety and tolerability were assessed throughout the study. A physiologically-based pharmacokinetic (PBPK) model was also built. There were 15 subjects enrolled; mean age was 31 years. The odanacatib AUC(0- ∞) GMR (90% CI) [odanacatib + prednisone (Day 14, Period 2)/odanacatib alone (Day 1, Period 1] was 1.06 (0.96, 1.17). AUC(0-∞) GMR (90%CI) [midazolam + prednisone (Day 28, Period 2)/midazolam alone (Day -1, Period 1] was 1.08 (0.93,1.26). There were no serious AEs or AEs leading to discontinuation. PBPK modeling showed that prednisone does not cause significant effects on the exposure of sensitive CYP3A4 substrates in vivo at therapeutic doses. Co-administration of prednisone 10 mg qd had no effect on pharmacokinetics of either odanacatib 10 mg or midazolam 2 mg. PMID:24895078

  14. 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

  15. 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

  16. Species Extrapolation of Life-Stage Physiologically-Based Pharmacokinetic (PBPK) Models to Investigate the Developmental Toxicology of Ethanol Using In vitro to In vivo (IVIVE) Methods

    Science.gov (United States)

    To provide useful alternatives to in vivo animal studies, in vitro assays for dose-response assessments of xenobiotic chemicals must use concentrations in media and target tissues that are within biologically-plausible limits. Determining these concentrations is a complex matter,...

  17. Inhibition of the Sodium-Iodide Symporter by Perchlorate: An Evaluation of Lifestage Sensitivity Using Physiologically Based Pharmacokinetic (PBPK) Modeling (Final Report)

    Science.gov (United States)

    EPA originally released this document in draft form as supporting material for the Preliminary Regulatory Determination on Perchlorate (FR Notice) in October 2008. The document has since been revised in response to comments from independent external peer review. A copy of the PBP...

  18. INHIBITION OF THE SODIUM-IODIDE SYMPORTER BY PERCHLORATE: AN EVALUATION OF LIFESTAGE SENSITIVITY USING PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING (EXTERNAL REVIEW DRAFT)

    Science.gov (United States)

    EPA first released this document in draft form as supporting material for the Preliminary Regulatory Determination on Perchlorate (FR Notice) in October 2008. The document has since been revised. The final report is available in response to comments from independent external pee...

  19. 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

  20. 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

  1. 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...

  2. 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.

  3. 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

  4. Short Communication: Is Ethanol-Based Hand Sanitizer Involved in Acute Pancreatitis after Excessive Disinfection?—An Evaluation with the Use of PBPK Model

    OpenAIRE

    Céline Huynh-Delerme; Catherine Artigou; Laurent Bodin; Robert Tardif; Ginette Charest-Tardif; Cécile Verdier; Nessryne Sater; Mostafa Ould-Elhkim; Catherine Desmares

    2012-01-01

    An occupational physician reported to the French Health Products Safety Agency (Afssaps) a case of adverse effect of acute pancreatitis (AP) in a teaching nurse, after multiple demonstrations with ethanol-based hand sanitizers (EBHSs) used in a classroom with defective mechanical ventilation. It was suggested by the occupational physician that the exposure to ethanol may have produced a significant blood ethanol concentration and subsequently the AP. In order to verify if the confinement situ...

  5. 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

  6. 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

  7. 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...

  8. 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

  9. 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

  10. 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

  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. 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.

  13. 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

  14. Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models

    Energy Technology Data Exchange (ETDEWEB)

    Bogen, K T

    2007-05-11

    A relatively simple, quantitative approach is proposed to address a specific, important gap in the appr approach recommended by the USEPA Guidelines for Cancer Risk Assessment to oach address uncertainty in carcinogenic mode of action of certain chemicals when risk is extrapolated from bioassay data. These Guidelines recognize that some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained using separate 'linear' (genotoxic) vs. 'nonlinear' (nongenotoxic) approaches to low low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient t to parameterize a biologically based model that reliably o extrapolates risk to low levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach - similar to that used in reference dose procedures for classic toxicity endpoints - can address MOA uncertainty in a way that avoids explicit modeling of low low-dose risk as a function of administere administered or internal dose. Even when a 'nonlinear' toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was i illustrated llustrated for a likely DMOA rodent carcinogen naphthalene, specifically to the issue of risk extrapolation from bioassay data on naphthalene naphthalene-induced nasal tumors in rats. Bioassay data, supplemental toxicokinetic data, and related physiologically based p

  15. 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

  16. 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

  17. 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

  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. 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

  20. 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

  1. DETERMINATION OF AGE AND GENDER DIFFERENCES IN BIOCHEMICAL PROCESSES AFFECTING THE DISPOSITION OF 2-BUTOXYETHANOL AND ITS METABOLITES IN MICE AND RATS TO IMPROVE PBPK MODELING

    Energy Technology Data Exchange (ETDEWEB)

    Corley, Rick A.; Grant, Donna M.; Farris, Elizabeth; Weitz, Karl K.; Soelberg, Jolen J.; Thrall, K D.; Poet, Torka S.

    2005-03-28

    2-Butoxyethanol (BE) is the most widely used glycol ether solvent. BE's major metabolite, butoxyacetic acid (BAA), causes hemolysis with significant species differences in sensitivity. Several PBPK models have been developed over the past two decades to describe the disposition of BE and BAA in male rats and humans to refine health risk assessments. More recent efforts by Lee et al. (1998) to describe the kinetics of BE and BAA in the National Toxicology Program (NTP) chronic inhalation studies required the use of several assumptions to extrapolate model parameters from earlier PBPK models developed for young male rats to include female F344 and both sexes of B6C3F1 mice and the effects of aging. To replace these assumptions, studies were conducted to determine the impact of age, gender and species on the metabolism of BE, and the tissue partitioning, renal acid transport and plasma protein binding of BAA. In the current study, the Lee et al. PBPK model was updated and expanded to include the further metabolism of BAA and the salivary excretion of BE and BAA which may contribute to the forestomach irritation observed in mice in the NTP study. The revised model predicted that peak blood concentrations of BAA achieved following 6-hr inhalation exposures are greatest in young adult female rats at concentrations up to 300 ppm. This is not the case predicted for old (>18 months) animals, where peak blood concentrations of BAA in male and female mice were similar to or greater than female rats. The revised model serves as a quantitative tool for integrating an extensive pharmacokinetic and mechanistic database into a format that can readily be used to compare internal dosimetry across dose, route of exposure and species.

  2. 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

  3. 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.

  4. 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.

  5. 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...

  6. 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.

  7. 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 ...

  8. 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.

  9. 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...

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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...

  16. 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...

  17. 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...

  18. 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

  19. 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.

  20. 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…

  1. 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...

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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.

  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. 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.

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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)

  14. 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.

  15. 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

  16. 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

  17. 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...

  18. 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.

  19. 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 ...

  20. 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

  1. 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...

  2. 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...

  3. Comparative chlorpyrifos pharmacokinetics via multiple routes of exposure and vehicles of administration in the adult rat

    International Nuclear Information System (INIS)

    Chlorpyrifos (CPF) is a commonly used organophosphorus pesticide. A number of toxicity and mechanistic studies have been conducted in animals, where CPF has been administered via a variety of different exposure routes and dosing vehicles. This study compared chlorpyrifos (CPF) pharmacokinetics using oral, intravenous (IV), and subcutaneous (SC) exposure routes and corn oil, saline/Tween 20, and dimethyl sulfoxide (DMSO) as dosing vehicles. Two groups of rats were co-administered target doses (5 mg/kg) of CPF and isotopically labeled CPF (L-CPF). One group was exposed by both oral (CPF) and IV (L-CPF) routes using saline/Tween 20 vehicle; whereas, the second group was exposed by the SC route using two vehicles, corn oil (CPF) and DMSO (L-CPF). A third group was only administered CPF by the oral route in corn oil. For all treatments, blood and urine time course samples were collected and analyzed for 3,5,6-trichloro-2-pyridinol (TCPy), and isotopically labeled 3,5,6-trichloro-2-pyridinol (L-TCPy). Peak TCPy/L-TCPy concentrations in blood (20.2 μmol/l), TCPy/L-TCPy blood AUC (94.9 μmol/l h), and percent of dose excreted in urine (100%) were all highest in rats dosed orally with CPF in saline/Tween 20 and second highest in rats dosed orally with CPF in corn oil. Peak TCPy concentrations in blood were more rapidly obtained after oral administration of CPF in saline/Tween 20 compared to all other dosing scenarios (>1.5 h). These results indicate that orally administered CPF is more extensively metabolized than systemic exposures of CPF (SC and IV), and vehicle of administration also has an effect on absorption rates. Thus, equivalent doses via different routes and/or vehicles of administration could potentially lead to different body burdens of CPF, different rates of bioactivation to CPF-oxon, and different toxic responses. Simulations using a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for CPF are consistent with these possibilities

  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. 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.

  6. 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

  7. 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.

  8. 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...

  9. 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....

  10. 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

  11. 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.

  12. PBPK and population modelling to interpret urine cadmium concentrations of the French population

    International Nuclear Information System (INIS)

    As cadmium accumulates mainly in kidney, urinary concentrations are considered as relevant data to assess the risk related to cadmium. The French Nutrition and Health Survey (ENNS) recorded the concentration of cadmium in the urine of the French population. However, as with all biomonitoring data, it needs to be linked to external exposure for it to be interpreted in term of sources of exposure and for risk management purposes. The objective of this work is thus to interpret the cadmium biomonitoring data of the French population in terms of dietary and cigarette smoke exposures. Dietary and smoking habits recorded in the ENNS study were combined with contamination levels in food and cigarettes to assess individual exposures. A PBPK model was used in a Bayesian population model to link this external exposure with the measured urinary concentrations. In this model, the level of the past exposure was corrected thanks to a scaling function which account for a trend in the French dietary exposure. It resulted in a modelling which was able to explain the current urinary concentrations measured in the French population through current and past exposure levels. Risk related to cadmium exposure in the general French population was then assessed from external and internal critical values corresponding to kidney effects. The model was also applied to predict the possible urinary concentrations of the French population in 2030 assuming there will be no more changes in the exposures levels. This scenario leads to significantly lower concentrations and consequently lower related risk. - Highlights: • Interpretation of urine cadmium concentrations in France • PBPK and Bayesian population modelling of cadmium exposure • Assessment of the historic time-trend of the cadmium exposure in France • Risk assessment from current and future external and internal exposure

  13. PBPK and population modelling to interpret urine cadmium concentrations of the French population

    Energy Technology Data Exchange (ETDEWEB)

    Béchaux, Camille, E-mail: Camille.bechaux@anses.fr [ANSES, French Agency for Food, Environmental and Occupational Health Safety, 27-31 Avenue du Général Leclerc, 94701 Maisons-Alfort (France); Bodin, Laurent [ANSES, French Agency for Food, Environmental and Occupational Health Safety, 27-31 Avenue du Général Leclerc, 94701 Maisons-Alfort (France); Clémençon, Stéphan [Telecom ParisTech, 46 rue Barrault, 75634 Paris Cedex 13 (France); Crépet, Amélie [ANSES, French Agency for Food, Environmental and Occupational Health Safety, 27-31 Avenue du Général Leclerc, 94701 Maisons-Alfort (France)

    2014-09-15

    As cadmium accumulates mainly in kidney, urinary concentrations are considered as relevant data to assess the risk related to cadmium. The French Nutrition and Health Survey (ENNS) recorded the concentration of cadmium in the urine of the French population. However, as with all biomonitoring data, it needs to be linked to external exposure for it to be interpreted in term of sources of exposure and for risk management purposes. The objective of this work is thus to interpret the cadmium biomonitoring data of the French population in terms of dietary and cigarette smoke exposures. Dietary and smoking habits recorded in the ENNS study were combined with contamination levels in food and cigarettes to assess individual exposures. A PBPK model was used in a Bayesian population model to link this external exposure with the measured urinary concentrations. In this model, the level of the past exposure was corrected thanks to a scaling function which account for a trend in the French dietary exposure. It resulted in a modelling which was able to explain the current urinary concentrations measured in the French population through current and past exposure levels. Risk related to cadmium exposure in the general French population was then assessed from external and internal critical values corresponding to kidney effects. The model was also applied to predict the possible urinary concentrations of the French population in 2030 assuming there will be no more changes in the exposures levels. This scenario leads to significantly lower concentrations and consequently lower related risk. - Highlights: • Interpretation of urine cadmium concentrations in France • PBPK and Bayesian population modelling of cadmium exposure • Assessment of the historic time-trend of the cadmium exposure in France • Risk assessment from current and future external and internal exposure.

  14. Life-Stage PBPK Models for Multiple Routes of Ethanol Exposure in the Rat

    Science.gov (United States)

    Ethanol is commonly blended with gasoline (10% ethanol) in the US, and higher ethanol concentrations are being considered. While the pharmacokinetics and toxicity of orally-ingested ethanol are widely reported, comparable work is limited for inhalation exposure (IE), particularly...

  15. 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.

  16. 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

  17. 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

  18. 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...

  19. 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

  20. Kinetics, Mechanisms and Stereoselective Metabolism of 1,2,4-Triazole Fungicides and the Implications for Human Health and Ecological Risk Assessment

    Science.gov (United States)

    A major uncertainty in risk assessment is determining the exposure of a chemical stressor to a target organism; a confounding issue is the transformation of the chemical inside the target organism. Increasingly, physiologically based pharmacokinetic (PBPK) models are becoming the...

  1. Human health and the environment: Predicting plasma protein binding and metabolic clearance rates of environmentally relevant chemicals.

    Science.gov (United States)

    In silico methods provide a rapid, inexpensive means of screening a wide array of environmentally relevant pollutants, pesticides, fungicides and consumer products for further toxicity testing. Physiologically based pharmacokinetic (PBPK) models bridge the gap between in vitro as...

  2. 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

  3. 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

  4. 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...

  5. 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

  6. 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

  7. 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.

  8. An assessment of dioxin exposure across gestation and lactation using a PBPK model and new data from Seveso.

    Science.gov (United States)

    Emond, C; DeVito, M; Warner, M; Eskenazi, B; Mocarelli, P; Birnbaum, L S

    2016-01-01

    On July 10, 1976, an explosion at a chemical plant in Seveso, Italy, released up to 30kg of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-the most potent dioxin congener. Twenty years later, the Seveso Women's Health Study (SWHS) initiated a follow-up assessment of a cohort of female Seveso residents. Researchers collected serial blood, measured for TCDD levels, and recorded information about the women's medical history after the explosion. The study's aims were to: 1) modify the human PBPK model for TCDD (Emond et al. 2004; Emond et al. 2005; NCEA-USEPA, 2010) to include repetitive gestation and lactation; 2) simulate TCDD blood concentrations during different life stages including pregnancy and lactation, under different exposure scenarios; and 3) use this PBPK model to compare the influence of gestation and lactation on elimination of TCDD. After optimization of the model, it was assessed using data from the SWHS cohort. The 23 women in Subcohort A, were 4-39years old and in Subcohort B, the 18 women were 3-17years old when the explosion occurred. The model accurately predicted the blood concentrations during the 20years post-exposure, including periods of pregnancy and lactation. The model was also used to analyze the contribution of gestation and lactation to the mother's elimination of TCDD. The results suggest that gestation and lactation do not significantly impact TCDD blood elimination. Future efforts will focus on using additional data to evaluate the PBPK model and improving the mathematical descriptions of lactation and multiple gestations. PMID:27045706

  9. 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

  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 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...

  12. 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.

  13. 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

  14. 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...

  15. 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 ...

  16. 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...

  17. 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...

  18. 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.)

  19. 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.)

  20. 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...

  1. 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)

  2. 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.

  3. 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)

  4. 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...

  5. 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)

  6. 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

  7. 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

  8. 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...

  9. 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

  10. 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, ...

  11. 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...

  12. 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...

  13. Maximum Recommended Dosage of Lithium for Pregnant Women Based on a PBPK Model for Lithium Absorption

    OpenAIRE

    Scott Horton; Amalie Tuerk; Daniel Cook; Jiadi Cook; Prasad Dhurjati

    2012-01-01

    Treatment of bipolar disorder with lithium therapy during pregnancy is a medical challenge. Bipolar disorder is more prevalent in women and its onset is often concurrent with peak reproductive age. Treatment typically involves administration of the element lithium, which has been classified as a class D drug (legal to use during pregnancy, but may cause birth defects) and is one of only thirty known teratogenic drugs. There is no clear recommendation in the literature on the maximum acceptabl...

  14. 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

  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. 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

  17. 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

  18. 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.

  19. 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.

  20. 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

  1. 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

  2. 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.

  3. 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

  4. 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

  5. Concurrent determination of bisphenol A pharmacokinetics in maternal and fetal rhesus monkeys

    International Nuclear Information System (INIS)

    Bisphenol A (BPA) is an important industrial chemical used as the monomer for polycarbonate plastic and in epoxy resins for food can liners. Worldwide biomonitoring studies consistently find a high prevalence of BPA conjugates in urine (> 90%) in amounts consistent with aggregate exposure at levels below 1 μg/kg bw/d. The current study used LC/MS/MS to measure concurrently the pharmacokinetics of aglycone (active) and conjugated (inactive) deuterated BPA (d6) in maternal and fetal rhesus monkey serum, amniotic fluid, and placenta following intravenous injection in the dam (100 μg/kg bw). Internal exposures of the fetus to aglycone d6-BPA (serum AUC) were attenuated by maternal, placental, and fetal Phase II metabolism to less than half that in the dam. Levels of aglycone and conjugated d6-BPA measured in whole placenta were consistent with a role in metabolic detoxification. The monotonic elimination of aglycone d6-BPA from the fetal compartment accompanied by persistent conjugate levels provides further evidence arguing against the hypothesis that BPA conjugates are selectively deconjugated by either the placenta or fetus. These results also provide benchmarks to guide the interpretation of human cord blood, amniotic fluid, and placenta sampling and measurement strategies as a basis for estimating fetal exposures to BPA. This study in a non-human primate model provides additional pharmacokinetic data for use in PBPK modeling of perinatal exposures to BPA from food contact, medical devices, and other environmental sources. - Highlights: ► Maternal, placental, and fetal Phase II metabolism attenuate fetal exposure to BPA. ► Serum AUC for aglycone BPA in fetal monkeys is less than half of that in the dam. ► BPA profiles in monkey fetus rule out selective deconjugation and accumulation. ► BPA levels in monkey placenta are similar to other metabolically active tissues. ► Some published human cord blood data for BPA are inconsistent with these measurements

  6. Concurrent determination of bisphenol A pharmacokinetics in maternal and fetal rhesus monkeys

    Energy Technology Data Exchange (ETDEWEB)

    Patterson, Tucker A. [Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Twaddle, Nathan C. [Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Roegge, Cindy S. [Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Callicott, Ralph J. [U.S. Food and Drug Administration and Priority One Services Corp, Jefferson, AR 72079 (United States); Fisher, Jeffrey W. [Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Doerge, Daniel R., E-mail: daniel.doerge@fda.hhs.gov [Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States)

    2013-02-15

    Bisphenol A (BPA) is an important industrial chemical used as the monomer for polycarbonate plastic and in epoxy resins for food can liners. Worldwide biomonitoring studies consistently find a high prevalence of BPA conjugates in urine (> 90%) in amounts consistent with aggregate exposure at levels below 1 μg/kg bw/d. The current study used LC/MS/MS to measure concurrently the pharmacokinetics of aglycone (active) and conjugated (inactive) deuterated BPA (d6) in maternal and fetal rhesus monkey serum, amniotic fluid, and placenta following intravenous injection in the dam (100 μg/kg bw). Internal exposures of the fetus to aglycone d6-BPA (serum AUC) were attenuated by maternal, placental, and fetal Phase II metabolism to less than half that in the dam. Levels of aglycone and conjugated d6-BPA measured in whole placenta were consistent with a role in metabolic detoxification. The monotonic elimination of aglycone d6-BPA from the fetal compartment accompanied by persistent conjugate levels provides further evidence arguing against the hypothesis that BPA conjugates are selectively deconjugated by either the placenta or fetus. These results also provide benchmarks to guide the interpretation of human cord blood, amniotic fluid, and placenta sampling and measurement strategies as a basis for estimating fetal exposures to BPA. This study in a non-human primate model provides additional pharmacokinetic data for use in PBPK modeling of perinatal exposures to BPA from food contact, medical devices, and other environmental sources. - Highlights: ► Maternal, placental, and fetal Phase II metabolism attenuate fetal exposure to BPA. ► Serum AUC for aglycone BPA in fetal monkeys is less than half of that in the dam. ► BPA profiles in monkey fetus rule out selective deconjugation and accumulation. ► BPA levels in monkey placenta are similar to other metabolically active tissues. ► Some published human cord blood data for BPA are inconsistent with these measurements.

  7. 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

  8. 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

  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. [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

  11. 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

  12. 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...

  13. 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

  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 pharmacokinetic investigation of the chemical constituents in rats following an intravenous administration of YZH-I. PMID:25129410

  15. The pharmacokinetics of meloxicam in vultures.

    Science.gov (United States)

    Naidoo, V; Wolter, K; Cromarty, A D; Bartels, P; Bekker, L; McGaw, L; Taggart, M A; Cuthbert, R; Swan, G E

    2008-04-01

    Vulture populations across the Asian subcontinent have declined dramatically in the last 15 years and are now on the verge of extinction. Although the cause of the population decline was initially unknown, the decrease has recently been conclusively linked to the use of the nonsteroidal anti-inflammatory drug diclofenac in cattle that inadvertently ended up in the vulture food chain. With the vulture numbers continuing to decline by up to 48% a year, the Indian, Nepali and Pakistan governments have recently banned the manufacture and importation of veterinary diclofenac. They have also suggested meloxicam as an alternate anti-inflammatory for use in cattle. This recommendation was based on extensive acute safety studies in the African White-backed vulture (Gyps africanus), which evaluated worst case scenarios of maximum intake based on a once in three day feeding pattern. However, the possible cumulative pharmacokinetic and pharmacodynamic effects in vultures receiving multiple daily doses of meloxicam over time were not assessed. At present very little pharmacokinetic or pharmacodynamic information is available to add further support for the safety of meloxicam in this animal species. This article discusses the oral and intramuscular pharmacokinetics of meloxicam in Cape Griffon vultures (Gyps coprotheres). Therapeutic drug monitoring was also undertaken in White-backed, Egyptian (Neophron pernopterus) and one Lappet Faced vulture (Torgos tracheliotos). In all these species, meloxicam was characterized by a short half-life of elimination. The rapid metabolism of meloxicam in combination with a short duration of effect in the studied species Gyps vultures shown in this study makes it unlikely that the drug could accumulate. This confirms the safety of repeated exposure to meloxicam in vultures of this genus. PMID:18307504

  16. 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...

  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. Abdominal irradiation modulates 5-Fluorouracil pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Shueng Pei-Wei

    2010-03-01

    Full Text Available Abstract Background Concurrent chemoradiation with 5-fluorouracil (5-FU is widely accepted for treatment of abdominal malignancy. Nonetheless, the interactions between radiation and 5-FU remain unclear. We evaluated the influence of abdominal irradiation on the pharmacokinetics of 5-FU in rats. Methods The radiation dose distributions of cholangiocarcinoma patients were determined for the low dose areas, which are generously deposited around the intrahepatic target volume. Then, corresponding single-fraction radiation was delivered to the whole abdomen of Sprague-Dawley rats from a linear accelerator after computerized tomography-based planning. 5-FU at 100 mg/kg was intravenously infused 24 hours after radiation. A high-performance liquid chromatography system equipped with a UV detector was used to measure 5-FU in the blood. Ultrafiltration was used to measure protein-unbound 5-FU. Results Radiation at 2 Gy, simulating the daily human treatment dose, reduced the area under the plasma concentration vs. time curve (AUC of 5-FU by 31.7% compared to non-irradiated controls. This was accompanied by a reduction in mean residence time and incremental total plasma clearance values, and volume of distribution at steady state. Intriguingly, low dose radiation at 0.5 Gy, representing a dose deposited in the generous, off-target area in clinical practice, resulted in a similar pharmacokinetic profile, with a 21.4% reduction in the AUC. This effect was independent of protein binding capacity. Conclusions Abdominal irradiation appears to significantly modulate the systemic pharmacokinetics of 5-FU at both the dose level for target treatment and off-target areas. This unexpected and unwanted influence is worthy of further investigation and might need to be considered in clinical practice.

  19. 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

  20. Reassessment of stiripentol pharmacokinetics in healthy adult volunteers.

    Science.gov (United States)

    Peigné, Sophie; Rey, Elisabeth; Le Guern, Marie-Emmanuelle; Dulac, Olivier; Chiron, Catherine; Pons, Gerard; Jullien, Vincent

    2014-07-01

    Because children who have been receiving stiripentol for the treatment of Dravet syndrome for more than 10 years are now becoming young adults, it is important to accurately characterize stiripentol pharmacokinetics in this age range. A double-blind placebo-controlled dose ranging study was therefore conducted to investigate the pharmacokinetics and tolerability of stiripentol in 12 healthy volunteers. Each subject received 3 single doses of stiripentol (500, 1000, and 2000 mg) separated by a wash-out period of 1 week. Pharmacokinetics of stiripentol was analyzed for each dose by non-compartmental analysis. Median area under the curve (AUC), terminal elimination half-life (t1/2,z) and maximal concentration (Cmax) were calculated for between-dose comparison. Safety was evaluated based on both clinical and biological criteria. Oppositely to previous results, there was no concentration rebounds in the elimination phase, which could be the consequence of the food intake. A more than proportional increase in the AUC was observed, associated with a significant increase in the t1/2,z, for increasing doses (median AUC of 8.3, 31 and 88 mgh/L, and median t1/2,z of 2, 7.7 and 10h for the 500, 1000, and 2000 mg doses respectively), which confirmed the Michaelis-Menten pharmacokinetics of Stiripentol. However, dose-normalized Cmax did not significantly vary between doses. Median Michaelis-Menten parameters were 117 mg/h for Vmax and 1.9 mg/L for Km. No safety concern was observed during the study. The present study allowed a better characterization of the disposition phase of stiripentol and confirmed its non-linear pharmacokinetic behaviour. Further pharmacokinetic/pharmacodynamic studies would be useful to determine the optimal dose of stiripentol for the treatment of Dravet patients in adulthood. PMID:24725808

  1. Revised assessment of cancer risk to dichloromethane: part I Bayesian PBPK and dose-response modeling in mice.

    OpenAIRE

    Marino, Dale J.; Clewell, Harvey J.; Gentry, P. Robinan; Covington, Tammie R.; Hack, C. Eric; David, Raymond M.; Morgott, David A.

    2006-01-01

    KEYWORDS - CLASSIFICATION: analysis;Animals;Bayes Theorem;chemically induced;Carcinogens;Dose-Response Relationship,Drug;Environment;Inhalation Exposure;metabolism;methods;Markov Chains;mechanisms of carcinogenesis;Methylene Chloride;Mice;Models,Biological;Monte Carlo Method;Neoplasms;pharmacokinetics;Risk Assessment;Safety.

  2. 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

  3. 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.)

  4. 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

  5. Pharmacokinetics of mitragynine in man

    Directory of Open Access Journals (Sweden)

    Trakulsrichai S

    2015-04-01

    Full Text Available Satariya Trakulsrichai,1,2 Korbtham Sathirakul,3,4 Saranya Auparakkitanon,5 Jatupon Krongvorakul,5 Jetjamnong Sueajai,5 Nantida Noumjad,5 Chonlaphat Sukasem,5 Winai Wananukul2,6 1Department of Emergency Medicine, Faculty of Medicine Ramathibodi Hospital, 2Ramathibodi Poison Center, Faculty of Medicine Ramathibodi Hospital, 3Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand; 4Center for Drug Research Discovery and Development, Thammasat Univerisity, Prathumthani, Thailand; 5Department of Pathology, Faculty of Medicine Ramathibodi Hospital, 6Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand 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

  6. The Pharmacokinetics and Pharmacodynamics of Iron Preparations

    Directory of Open Access Journals (Sweden)

    Susanna Burckhardt

    2011-01-01

    Full Text Available Standard approaches are not appropriate when assessing pharmacokinetics of iron supplements due to the ubiquity of endogenous iron, its compartmentalized sites of action, and the complexity of the iron metabolism. The primary site of action of iron is the erythrocyte, and, in contrast to conventional drugs, no drug-receptor interaction takes place. Notably, the process of erythropoiesis, i.e., formation of new erythrocytes, takes 3−4 weeks. Accordingly, serum iron concentration and area under the curve (AUC are clinically irrelevant for assessing iron utilization. Iron can be administered intravenously in the form of polynuclear iron(III-hydroxide complexes with carbohydrate ligands or orally as iron(II (ferrous salts or iron(III (ferric complexes. Several approaches have been employed to study the pharmacodynamics of iron after oral administration. Quantification of iron uptake from radiolabeled preparations by the whole body or the erythrocytes is optimal, but alternatively total iron transfer can be calculated based on known elimination rates and the intrinsic reactivity of individual preparations. Degradation kinetics, and thus the safety, of parenteral iron preparations are directly related to the molecular weight and the stability of the complex. High oral iron doses or rapid release of iron from intravenous iron preparations can saturate the iron transport system, resulting in oxidative stress with adverse clinical and subclinical consequences. Appropriate pharmacokinetics and pharmacodynamics analyses will greatly assist our understanding of the likely contribution of novel preparations to the management of anemia.

  7. 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

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

    Directory of Open Access Journals (Sweden)

    Minami Ohara

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

  9. 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...

  10. [Interspecies differences of noopept pharmacokinetics].

    Science.gov (United States)

    Boĭko, S S; Korotkov, S A; Zherdev, V P; Gudasheva, T A; Ostrovskaia, R U; Voronina, T A

    2004-01-01

    Significant interspecific differences in the pharmacokinetics of noopept are manifested by a decrease in the drug elimination rate on the passage from rats to rabbits and humans. Very intensive metabolism of noopept was observed upon intravenous administration in rats. In these animals, presystemic elimination mechanisms lead to the formation of a specific metabolite representing a product of drug biotransformation hydroxylated at the phenyl ring. In rabbits, unchanged noopept circulates in the blood for a longer time upon both intravenous and peroral introduction, biotransformation proceeds at a much slower rate, and no metabolites analogous to that found in rats are detected. The noopept pharmacokinetics in humans differs from that in animals by still slower elimination and considerable individual variability. No drug metabolites are found in the human blood plasma, probably because of a relatively small dose and low concentration. PMID:15079908

  11. Pharmacokinetic interactions and pharmacogenetics of aliskiren

    OpenAIRE

    Tapaninen, Tuija

    2012-01-01

    Aliskiren is an antihypertensive drug approved for clinical use in 2007. It acts by inhibiting renin, the first enzyme in the renin-angiotensin-aldosterone system. Marked interindividual variability exists in the pharmacokinetics of aliskiren. Interestingly, the pharmacokinetic properties of aliskiren suggest an important role for drug transporters in its pharmacokinetics. Aliskiren is poorly absorbed, and therefore, its oral bioavailability is only 2-3%. The elimination of aliskiren occurs m...

  12. Application of allometric principles for the prediction of pharmacokinetics in human and veterinary drug development.

    Science.gov (United States)

    Mahmood, Iftekhar

    2007-09-30

    The concept of correlating pharmacokinetic parameters with body weight (termed as pharmacokinetic interspecies scaling) from different animal species has become a useful tool in drug development. Interspecies scaling is based on the power function, where the body weight of the species is plotted against the pharmacokinetic parameter of interest. Clearance, volume of distribution, and elimination half-life are the three most frequently extrapolated pharmacokinetic parameters. The predicted pharmacokinetic parameter clearance can be used for estimating a first-in-human dose. Over the years, many approaches have been suggested to improve the prediction of aforementioned pharmacokinetic parameters in humans from animal data. A literature review indicates that there are different degrees of success with different methods for different drugs. Interspecies scaling is also a very useful tool in veterinary medicine. The knowledge of pharmacokinetics in veterinary medicine is important for dosage selection, particularly in the treatment of large animals such as horses, camels, elephants, or other large zoo animals. Despite the potential for extrapolation error, the reality is that interspecies scaling is needed across many veterinary practice situations, and therefore will be used. For this reason, it is important to consider mechanisms for reducing the risk of extrapolation errors that can seriously affect animal safety and therapeutic response. Overall, although interspecies scaling requires continuous refinement and better understanding, the rationale approach of interspecies scaling has a lot of potential during the drug development process. PMID:17826864

  13. Venlafaxine pharmacokinetics focused on drug metabolism and potential biomarkers.

    Science.gov (United States)

    Magalhães, Paulo; Alves, Gilberto; Llerena, Adrián; Falcão, Amílcar

    2014-01-01

    Venlafaxine (VEN) is one of the safest and most effective drugs used in the treatment of selective serotonin reuptake inhibitors-resistant depression, and thereby it is nowadays one of the most commonly prescribed antidepressants. Nevertheless, patients treated with antidepressant drugs including VEN have exhibited large inter-individual variability in drug outcomes, possibly due to the influence of genetic and nongenetic factors on the drug pharmacokinetics and/or pharmacodynamics. Among them, an increased interest has emerged over the last few years on the genetic and/or phenotypic profile for drug-metabolizing cytochrome P450 isoenzymes and drug transporters such as potential predictive pharmacokinetic-based biomarkers of the variability found in drug biodisposition and antidepressant response. The integration of some of these key therapeutic biomarkers with classic therapeutic drug monitoring constitutes a promising way to individualization of VEN's pharmacotherapy, offering to clinicians the ability to better predict and manage pharmacological treatments to maximize the drug effectiveness. Thus, this review provides an extensive discussion of the pharmacokinetics of VEN focusing in particular on metabolism issues, without forgetting the clinically relevant sources of pharmacokinetics variability (mainly the genetic sources) and aiming on the identification of phenotypic and/or genetic biomarkers for therapy optimization. PMID:24607919

  14. 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

  15. Multiple-dose acetaminophen pharmacokinetics.

    Science.gov (United States)

    Sahajwalla, C G; Ayres, J W

    1991-09-01

    Four different treatments of acetaminophen (Tylenol) were administered in multiple doses to eight healthy volunteers. Each treatment (325, 650, 825, and 1000 mg) was administered five times at 6-h intervals. Saliva acetaminophen concentration versus time profiles were determined. Noncompartmental pharmacokinetic parameters were calculated and compared to determine whether acetaminophen exhibited linear or dose-dependent pharmacokinetics. For doses less than or equal to 18 mg/kg, area under the curve (AUC), half-life (t1/2), mean residence time (MRT), and ratio of AUC to dose for the first dose were compared with the last dose. No statistically significant differences were observed in dose-corrected AUC for the first or last dose among subjects or treatments. Half-lives and MRT were not significantly different among treatments for the first or the last dose. Statistically significant differences in t1/2 and MRT were noted (p less than 0.05) among subjects for the last dose. A plot of AUC versus dose for the first and the last doses exhibited a linear relationship. Dose-corrected saliva concentration versus time curves for the treatments were superimposable. Thus, acetaminophen exhibits linear pharmacokinetics for doses of 18 mg/kg or less. Plots of AUC versus dose for one subject who received doses higher than 18 mg/kg were curved, suggesting nonlinear behavior of acetaminophen in this subject. PMID:1800709

  16. 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)

  17. Pharmacokinetics and pharmacodynamics of cannabinoids.

    Science.gov (United States)

    Grotenhermen, Franjo

    2003-01-01

    Delta(9)-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30-90 minutes, reach their maximum after 2-3 hours and last for about 4-12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial

  18. 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

  19. Comparative pharmacokinetics of intravenous fentanyl and buprenorphine in healthy Greyhound dogs

    OpenAIRE

    KuKanich, Butch; Allen, Philip

    2014-01-01

    The purpose of this study was to compare the pharmacokinetics of two highly protein bound, lipophilic opioid drugs. Fentanyl (10 μg/kg) and buprenorphine (20 μg/kg) were administered intravenously (IV) to six healthy Greyhound dogs (3 males and 3 females). The doses were based on clinically administered doses for dogs. Plasma drug concentrations were determined using liquid chromatography with mass spectrometry and noncompartmental pharmacokinetics were estimated with computer software. The v...

  20. Pharmacokinetics of Cannabis in Cancer Cachexia-Anorexia Syndrome.

    Science.gov (United States)

    Reuter, Stephanie E; Martin, Jennifer H

    2016-07-01

    Anorexia can affect up to 90 % of people with advanced cancer. It is a complex symptom associated with changes in taste, lack of hunger at mealtimes and lack of food enjoyment. Associated weight loss is part of the physical decline that occurs as cancer worsens. Weight loss can also occur from cachexia, the increased metabolism of energy due to raised inflammatory cytokines, liver metastases and other factors seen in several advanced cancers. Independent of anorexia, although frequently associated (where it is referred to as the cachexia-anorexia syndrome), it accounts for a significant amount of morbidity and deaths in people with cancer. In particular, quality of life for the patient and the family is significantly affected with this syndrome as it causes anxiety and distress. Therefore, it is important that research into therapies is undertaken, particularly focusing on an understanding of the pharmacokinetic properties of compounds in this cachexic population. Cannabinoids are one such group of therapies that have received a large amount of media focus recently. However, there appears to be a lack on rigorous pharmacokinetic data of these complex and varied compounds in the cachexic population. Similarly, there is a lack of pharmacokinetic data in any population group for the non- tetrahydrocannabinol (THC) and cannabidiol (CBD) cannabinoids (often due to the lack of analytical standards for quantification). This review will thus examine the pharmacokinetics of major cannabinoids i.e. THC and CBD in a cancer population. Overall, based on the current literature, evidence for the use of cannabinoids for the treatment of cancer-related cachexia-anorexia syndrome remains equivocal. A high-quality, rigorous, phase I/II study to elicit pharmacokinetic dose-concentration and concentration-response data, with a clinically acceptable mode of delivery to reduce intrapatient variability and enable more consistent bioavailability is needed in this population. PMID

  1. The role of patient-based treatment planning in peptide receptor radionuclide therapy

    Energy Technology Data Exchange (ETDEWEB)

    Hardiansyah, Deni; Attarwala, Ali Asgar [Heidelberg University, Medical Radiation Physics/Radiation Protection, Universitaetsmedizin Mannheim, Medical Faculty Mannheim, Mannheim (Germany); Universitaetsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Department of Radiation Oncology, Mannheim (Germany); Maass, Christian; Glatting, Gerhard [Heidelberg University, Medical Radiation Physics/Radiation Protection, Universitaetsmedizin Mannheim, Medical Faculty Mannheim, Mannheim (Germany); Mueller, Berthold [University Hospital, RWTH Aachen University, Klinik fuer Nuklearmedizin, Aachen (Germany); Kletting, Peter [Universitaet Ulm, Klinik fuer Nuklearmedizin, Ulm (Germany); Mottaghy, Felix M. [University Hospital, RWTH Aachen University, Klinik fuer Nuklearmedizin, Aachen (Germany); Maastricht University Medical Center (MUMC+), Department of Nuclear Medicine, Maastricht (Netherlands)

    2016-05-15

    Accurate treatment planning is recommended in peptide-receptor radionuclide therapy (PRRT) to minimize the toxicity to organs at risk while maximizing tumor cell sterilization. The aim of this study was to quantify the effect of different degrees of individualization on the prediction accuracy of individual therapeutic biodistributions in patients with neuroendocrine tumors (NETs). A recently developed physiologically based pharmacokinetic (PBPK) model was fitted to the biokinetic data of 15 patients with NETs after pre-therapeutic injection of {sup 111}In-DTPAOC. Mathematical phantom patients (MPP) were defined using the assumed true (true MPP), mean (MPP 1A) and median (MPP 1B) parameter values of the patient group. Alterations of the degree of individualization were introduced to both mean and median patients by including patient-specific information as a priori knowledge: physical parameters and hematocrit (MPP 2A/2B). Successively, measurable individual biokinetic parameters were added: tumor volume V{sub tu} (MPP 3A/3B), glomerular filtration rate GFR (MPP 4A/4B), and tumor perfusion f{sub tu} (MPP 5A/5B). Furthermore, parameters of MPP 5A/5B and a simulated {sup 68}Ga-DOTATATE PET measurement 60 min p.i. were used together with the population values used as Bayesian parameters (MPP 6A/6B). Therapeutic biodistributions were simulated assuming an infusion of {sup 90}Y-DOTATATE (3.3 GBq) over 30 min to all MPPs. Time-integrated activity coefficients were predicted for all MPPs and compared to the true MPPs for each patient in tumor, kidneys, spleen, liver, remainder, and whole body to obtain the relative differences RD. The large RD values of MPP 1A [RD{sub tumor} = (625 ± 1266)%, RD{sub kidneys} = (11 ± 38)% ], and MPP 1B [RD{sub tumor} = (197 ± 505)%, RD{sub kidneys} = (11 ± 39)% ] demonstrate that individual treatment planning is needed due to large physiological differences between patients. Although addition of individual patient parameters reduced the

  2. 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.

  3. 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.

  4. Drug Transport and Pharmacokinetics for Chemical Engineers

    Science.gov (United States)

    Simon, Laurent; Kanneganti, Kumud; Kim, Kwang Seok

    2010-01-01

    Experiments in continuous-stirred vessels were proposed to introduce methods in pharmacokinetics and drug transport to chemical engineering students. The activities can be incorporated into the curriculum to illustrate fundamentals learned in the classroom. An appreciation for the role of pharmacokinetics in drug discovery will also be gained…

  5. Population Pharmacokinetics of Abacavir in Pregnant Women

    OpenAIRE

    Fauchet, Floris; Treluyer, Jean-Marc; Préta, Laure-Helene; Valade, Elodie; Pannier, Emmanuelle; Urien, Saik; Hirt, Déborah

    2014-01-01

    For the first time, a population approach was used to describe abacavir (ABC) pharmacokinetics in HIV-infected pregnant and nonpregnant women. A total of 266 samples from 150 women were obtained. No covariate effect (from age, body weight, pregnancy, or gestational age) on ABC pharmacokinetics was found. Thus, it seems unnecessary to adapt the ABC dosing regimen during pregnancy.

  6. Pharmacokinetics of oral gabapentin in Greyhound dogs

    OpenAIRE

    KuKanich, Butch; Cohen, Rachael L

    2009-01-01

    The purpose of this study was to assess the pharmacokinetics of gabapentin in healthy Greyhound dogs after single oral doses targeted at 10 and 20 mg/kg PO. Six healthy Greyhounds were enrolled (3 males, 3 females). Blood was obtained at predetermined times for the measurement of gabapentin plasma concentrations by liquid chromatography/mass spectrometry. Pharmacokinetic parameters were determined with computer software.

  7. Pharmacokinetic Profile of Oral Magnesium Hydroxide

    DEFF Research Database (Denmark)

    Dolberg, Mette Konow Bøgebjerg; Nielsen, Lars Peter; Dahl, Ronald

    2016-01-01

    Despite the presumption of a beneficial effect of magnesium (Mg) supplementation on various diseases, little is known concerning the pharmacokinetics of Mg hydroxide. This study was designed to provide a pharmacokinetic profile of Mg hydroxide after a single oral dose. Ten healthy male adults...

  8. 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

  9. Reconstruction of Exposure to m-Xylene from Human Biomonitoring Data Using PBPK Modelling, Bayesian Inference, and Markov Chain Monte Carlo Simulation

    Directory of Open Access Journals (Sweden)

    Kevin McNally

    2012-01-01

    Full Text Available There are numerous biomonitoring programs, both recent and ongoing, to evaluate environmental exposure of humans to chemicals. Due to the lack of exposure and kinetic data, the correlation of biomarker levels with exposure concentrations leads to difficulty in utilizing biomonitoring data for biological guidance values. Exposure reconstruction or reverse dosimetry is the retrospective interpretation of external exposure consistent with biomonitoring data. We investigated the integration of physiologically based pharmacokinetic modelling, global sensitivity analysis, Bayesian inference, and Markov chain Monte Carlo simulation to obtain a population estimate of inhalation exposure to m-xylene. We used exhaled breath and venous blood m-xylene and urinary 3-methylhippuric acid measurements from a controlled human volunteer study in order to evaluate the ability of our computational framework to predict known inhalation exposures. We also investigated the importance of model structure and dimensionality with respect to its ability to reconstruct exposure.

  10. Alfentanil pharmacokinetics in preterm infants.

    OpenAIRE

    Marlow, N; Weindling, A M; Van Peer, A; Heykants, J.

    1990-01-01

    The pharmacokinetics of alfentanil were studied during the first four days after birth in 22 ventilated preterm infants who were all receiving muscle relaxants. Five minutes after a single dose of 20 micrograms/kg alfentanil median serum concentration was 66 ng/ml (range: 20-606). The median clearance was 0.87 ml/kg/min (range: 0.4-9.62) and median elimination half life 321 mins (64-1251). There were wide differences in the manner in which individual infants handled the drug and transient dep...

  11. 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.

  12. Pharmacokinetics of topically applied sparfloxacin in rabbits

    Directory of Open Access Journals (Sweden)

    Satia Milan

    2005-01-01

    Full Text Available PURPOSE: Fluoroquinolones are antimicrobial agents that have a broad spectrum of activity and are widely used against many of the ocular pathogens, responsible for conjunctivitis, blepharitis, corneal ulcers etc. The aim of our study was to evaluate the ocular pharmacokinetics of sparfloxacin (0.3% w/v in the aqueous humour of rabbits. MATERIALS AND METHODS: Pharmacokinetics of topically administered sparfloxacin were determined after a single application of 50 µl topically. The aqueous humour samples were collected at 0, 0.25, 0.5, 1, 2, 3, 4, 5 or 6 hours after instillation. High Performance Thin Layer Chromatographic method was used to analyse the drug concentration in the aqueous humour samples. RESULTS: Fifteen minutes after the instillation of 50 µl of sparfloxacin 0.3% solution, the mean concentration in aqueous humour was found to be 1.4 µg/ml, which reaches the peak level of 3.7 µg/ml after 1.3 hours. At 6 hours, the sparfloxacin aqueous levels were 0.562 µg/ml. The clinical efficacy was predicted based on the Maximum Concentration (Cmax: Minimum Inhibitory Concentration (MIC and Area Under the Concentration-time curve (AUC:MIC ratios. CONCLUSION: The sparfloxacin levels in aqueous humour of rabbits are sufficiently high up to the 6 hours after instillation in the conjunctival sac to provide bactericidal effect against most of the ocular pathogens. Both Cmax:MIC and AUC:MIC ratios are high enough to provide bactericidal effect against most of the ocular pathogens. Sparfloxacin (0.3% ophthalmic preparation has excellent penetration through cornea.

  13. Pharmacokinetics of procaterol in thoroughbred horses.

    Science.gov (United States)

    Kusano, K; Nomura, M; Toju, K; Ishikawa, Y; Minamijima, Y; Yamashita, S; Nagata, S

    2016-06-01

    Procaterol (PCR) is a beta-2-adrenergic bronchodilator widely used in Japanese racehorses for treating lower respiratory disease. The pharmacokinetics of PCR following single intravenous (0.5 μg/kg) and oral (2.0 μg/kg) administrations were investigated in six thoroughbred horses. Plasma and urine concentrations of PCR were measured using liquid chromatography-mass spectrometry. Plasma PCR concentration following intravenous administration showed a biphasic elimination pattern. The systemic clearance was 0.47 ± 0.16 L/h/kg, the steady-state volume of the distribution was 1.21 ± 0.23 L/kg, and the elimination half-life was 2.85 ± 1.35 h. Heart rate rapidly increased after intravenous administration and gradually decreased thereafter. A strong correlation between heart rate and plasma concentration of PCR was observed. Plasma concentrations of PCR after oral administration were not quantifiable in all horses. Urine concentrations of PCR following intravenous and oral administrations were quantified in all horses until 32 h after administration. Urine PCR concentrations were not significantly different on and after 24 h between intravenous and oral administrations. These results suggest that the bioavailability of orally administrated PCR in horses is very poor, and the drug was eliminated from the body slowly based on urinary concentrations. This report is the first study to demonstrate the pharmacokinetic character of PCR in thoroughbred horses. PMID:26538319

  14. Heritability of metoprolol and torsemide pharmacokinetics

    DEFF Research Database (Denmark)

    Matthaei, Johannes; Brockmöller, Jürgen; Tzvetkov, Mladen;

    2015-01-01

    Genetic variation in the pharmacokinetics of metoprolol and torsemide due to polymorphisms in CYP2D6, CYP2C9 and OATP1B1 has been extensively studied. However, it is still unknown how much of variation in pharmacokinetics of these two clinically important drugs in total is due to genetic factors...... genetic variants of CYP2D6, -2C9 and OATP1B1 explained only 39%, 2% and 39% of that variation. Comparable results for genetically explained variation in pharmacokinetics and pharmacodynamics have been found for other substrates of these enzymes earlier. These findings indicate that a substantial fraction...

  15. 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...

  16. Development of a PBPK model of thiocyanate in rats with an extrapolation to humans: A computational study to quantify the mechanism of action of thiocyanate kinetics in thyroid.

    Science.gov (United States)

    Willemin, Marie-Emilie; Lumen, Annie

    2016-09-15

    Thyroid homeostasis can be disturbed due to thiocyanate exposure from the diet or tobacco smoke. Thiocyanate inhibits both thyroidal uptake of iodide, via the sodium-iodide symporter (NIS), and thyroid hormone (TH) synthesis in the thyroid, via thyroid peroxidase (TPO), but the mode of action of thiocyanate is poorly quantified in the literature. The characterization of the link between intra-thyroidal thiocyanate concentrations and dose of exposure is crucial for assessing the risk of thyroid perturbations due to thiocyanate exposure. We developed a PBPK model for thiocyanate that describes its kinetics in the whole-body up to daily doses of 0.15mmol/kg, with a mechanistic description of the thyroidal kinetics including NIS, passive diffusion, and TPO. The model was calibrated in a Bayesian framework using published studies in rats. Goodness-of-fit was satisfactory, especially for intra-thyroidal thiocyanate concentrations. Thiocyanate kinetic processes were quantified in vivo, including the metabolic clearance by TPO. The passive diffusion rate was found to be greater than NIS-mediated uptake rate. The model captured the dose-dependent kinetics of thiocyanate after acute and chronic exposures. Model behavior was evaluated using a Morris screening test. The distribution of thiocyanate into the thyroid was found to be determined primarily by the partition coefficient, followed by NIS and passive diffusion; the impact of the latter two mechanisms appears to increase at very low doses. Extrapolation to humans resulted in good predictions of thiocyanate kinetics during chronic exposure. The developed PBPK model can be used in risk assessment to quantify dose-response effects of thiocyanate on TH. PMID:27445130

  17. PHARMACOKINETICS OF RU486 IN RABBITS

    Institute of Scientific and Technical Information of China (English)

    ZHANGMing-Hua; CHUYun-Hong; LIQui; CHANGLi-Min; FANGZhen; JINGZuao-Ying

    1989-01-01

    Intravaginal release of contraceptive steroid by avoiding the first-pass effect may provide a suitable route of administration, thus leading to higher bioavailabilities. RU486 is significantly metabolizlcd by the first-pass metabolism. We have studied its pharmacokinetics

  18. Pharmacokinetics, safety, and tolerability of voriconazole in immunocompromised children.

    Science.gov (United States)

    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

    2010-10-01

    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.-to-oral regimen of voriconazole in immunocompromised children aged 2 to formulation in children was approximately 65%. The safety profiles were similar in the two cohorts and age groups. The most common treatment-related adverse event was increased gamma glutamyl transpeptidase levels. There was no correlation between adverse events and voriconazole exposure. In summary, voriconazole was tolerated to a similar degree regardless of dosage and age; the mean plasma AUCτ for 8 mg/kg i.v. in children approached that for 4 mg/kg i.v. in adults, thus representing a rationally selected dosage for the pediatric population. PMID:20660687

  19. 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 ...

  20. Population Pharmacokinetics of Voriconazole in Adults

    OpenAIRE

    Hope, William W.

    2012-01-01

    Voriconazole is a first-line agent for the treatment of invasive fungal infections. The pharmacology of voriconazole is characterized by extensive interindividual variability and nonlinear pharmacokinetics. The population pharmacokinetics of voriconazole in 64 adults is described. The patient population consisted of 21 healthy volunteers, who received a range of intravenous (i.v.) and oral voriconazole regimens, and 43 patients with proven or probable invasive aspergillosis, who received the ...

  1. 4-Aminopyridyl-Based CYP51 Inhibitors as Anti-Trypanosoma cruzi Drug Leads with Improved Pharmacokinetic Profile and in Vivo Potency

    OpenAIRE

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

    2014-01-01

    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...

  2. Pharmacokinetics of oral amantadine in greyhound dogs.

    Science.gov (United States)

    Norkus, C; Rankin, D; Warner, M; KuKanich, B

    2015-06-01

    This study reports the pharmacokinetics of amantadine in greyhound dogs after oral administration. Five healthy greyhound dogs were used. A single oral dose of 100 mg amantadine hydrochloride (mean dose 2.8 mg/kg as amantadine hydrochloride) was administered to nonfasted subjects. Blood samples were collected at predetermined time points from 0 to 24 h after administration, and plasma concentrations of amantadine were measured by liquid chromatography with triple quadrupole mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Amantadine was well tolerated in all dogs with no adverse effects observed. The mean (range) amantadine CMAX was 275 ng/mL (225-351 ng/mL) at 2.6 h (1-4 h) with a terminal half-life of 4.96 h (4.11-6.59 h). The results of this study can be used to design dosages to assess multidose pharmacokinetics and dosages designed to achieve targeted concentrations in order to assess the clinical effects of amantadine in a variety of conditions including chronic pain. Further studies should also assess the pharmacokinetics of amantadine in other dog breeds or using population pharmacokinetics studies including multiple dog breeds to assess potential breed-specific differences in the pharmacokinetics of amantadine in dogs. PMID:25427541

  3. Magnetic resonance imaging and computational fluid dynamics (CFD) simulations of rabbit nasal airflows for the development of hybrid CFD/PBPK models

    Energy Technology Data Exchange (ETDEWEB)

    Corley, Richard A; Minard, Kevin R; Kabilan, Senthil; Einstein, Daniel R; Kuprat, Andrew P; harkema, J R; Kimbell, Julia; Gargas, M L; Kinzell, John H

    2009-06-01

    The percentages of total airflows over the nasal respiratory and olfactory epithelium of female rabbits were calculated from computational fluid dynamics (CFD) simulations of steady-state inhalation. These airflows calculations, along with nasal airway geometry determinations, are critical parameters for hybrid CFD/physiologically based pharmacokinetic models that describe the nasal dosimetry of water-soluble or reactive gases and vapors in rabbits. CFD simulations were based upon three-dimensional computational meshes derived from magnetic resonance images of three adult female New Zealand White (NZW) rabbits. In the anterior portion of the nose, the maxillary turbinates of rabbits are considerably more complex than comparable regions in rats, mice, monkeys, or humans. This leads to a greater surface area to volume ratio in this region and thus the potential for increased extraction of water soluble or reactive gases and vapors in the anterior portion of the nose compared to many other species. Although there was considerable interanimal variability in the fine structures of the nasal turbinates and airflows in the anterior portions of the nose, there was remarkable consistency between rabbits in the percentage of total inspired airflows that reached the ethmoid turbinate region (~50%) that is presumably lined with olfactory epithelium. These latter results (airflows reaching the ethmoid turbinate region) were higher than previous published estimates for the male F344 rat (19%) and human (7%). These differences in regional airflows can have significant implications in interspecies extrapolations of nasal dosimetry.

  4. Pharmacokinetic drug interactions of macrolides.

    Science.gov (United States)

    Periti, P; Mazzei, T; Mini, E; Novelli, A

    1992-08-01

    The macrolide antibiotics include natural members, prodrugs and semisynthetic derivatives. These drugs are indicated in a variety of infections and are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions. Macrolides can both inhibit drug metabolism in the liver by complex formation and inactivation of microsomal drug oxidising enzymes and also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 years, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard and not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes and the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin and midecamycin) form complexes to a lesser extent and rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin and azithromycin) do not inactivate cytochrome P450 and are unable to modify the pharmacokinetics of other compounds. It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 and the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group and the hydrophobic character of the drug. Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decrease of the metabolism of methylprednisolone, theophylline

  5. Clinical pharmacokinetics of the salicylates.

    Science.gov (United States)

    Needs, C J; Brooks, P M

    1985-01-01

    -order kinetics. The serum half-life of salicylic acid is dose-dependent; thus, the larger the dose employed, the longer it will take to reach steady-state. There is also evidence that enzyme induction of salicyluric acid formation occurs. No significant differences exist between the pharmacokinetics of the salicylates in the elderly or in children when compared with young adults. Apart from differences in free versus albumin-bound salicylate in various disease states and physiological conditions associated with low serum albumin, pharmacokinetic parameters in patients with rheumatoid arthritis, osteoarthritis, chronic renal failure or liver disease are essentially the same.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:3888490

  6. Physical characterization and in vivo pharmacokinetic study of self-assembling amphotericin B-loaded lecithin-based mixed polymeric micelles

    Directory of Open Access Journals (Sweden)

    Chen YC

    2015-12-01

    Full Text Available Ying-Chen Chen,* Chia-Yu Su,* Hua-Jun Jhan, Hsiu-O Ho, Ming-Thau Sheu School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan *These authors contributed equally to this work Abstract: To alleviate the inherent problems of amphotericin B (AmB, such as poor water solubility and nephrotoxicity, a novel self-assembling mixed polymeric micelle delivery system based on lecithin and combined with amphiphilic polymers, Pluronic®, Kolliphor®, d-alpha tocopheryl polyethylene glycol succinate, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(poly(ethylene glycol-2000 (DSPE-PEG2K was developed. An optimal formulation (Ambicelles composed of AmB:lecithin:DSPE-PEG2K in a 1:1:10 weight ratio was obtained. The particle size, polydispersion index, drug encapsulation efficiency, and drug loading were 187.20±10.55 nm, 0.51±0.017, 90.14%, and 7.51%, respectively, and the solubility was increased from 0.001 to 5 mg/mL. Compared with that of Fungizone®, the bioavailability of Ambicelles administered intravenously and orally increased 2.18- and 1.50-fold, respectively. Regarding the in vitro cytotoxicity, Ambicelles had a higher cell viability than free AmB solution or Fungizone® did. With pretreatment of 50 µg/mL ethanolic extract of Taiwanofungus camphoratus followed by AmB to HT29 colon cancer cells, the 50% inhibitory concentration of AmB solution was 12 µg/mL, whereas that of Ambicelles was 1 µg/mL, indicating that Ambicelles exerted a greater synergistic anticancer effect. Keywords: amphotericin B, micelle, amphiphilic polymer, lecithin, DSPE-PEG

  7. 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.

  8. Effects of Dose and Route of Administration on Pharmacokinetics of (±)-3,4-Methylenedioxymethamphetamine in the Rat

    OpenAIRE

    Baumann, Michael H.; Zolkowska, Dorota; Kim, Insook; Scheidweiler, Karl B.; Rothman, Richard B.; Huestis, Marilyn A.

    2009-01-01

    Based on animal data, there is speculation that (±)-3,4-methylenedioxymethamphetamine (MDMA) is neurotoxic to humans. Extrapolation of MDMA findings from animals to humans requires assessment of pharmacokinetics in various species, and low-dose administration data from rats are lacking. In this study, we examine MDMA pharmacokinetics in rats given low (2 mg/kg) and high (10 mg/kg) doses of racemic MDMA via intraperitoneal, subcutaneous, and oral routes. Repeated blood specimens were collected...

  9. Steady-state pharmacokinetics of lithium carbonate in healthy subjects.

    OpenAIRE

    Hunter, R.

    1988-01-01

    1. The pharmacokinetics of lithium in six healthy volunteers stabilised on lithium were investigated and appropriate pharmacokinetic parameters calculated. 2. The results illustrate important differences in single and multiple dose lithium pharmacokinetics; the implications for minimising lithium-induced renal damage are discussed.

  10. Drug disposition and modelling before and after gastric bypass: immediate and controlled-release metoprolol formulations

    OpenAIRE

    Gesquiere, Ina; Darwich, Adam S; Van der Schueren, Bart; de Hoon, Jan; Lannoo, Matthias; Matthys, Christophe; Rostami, Amin; Foulon, Veerle; Augustijns, Patrick

    2015-01-01

    The aim of the present study was to evaluate the disposition of metoprolol after oral administration of an immediate and controlled-release formulation before and after Roux-en-Y gastric bypass (RYGB) surgery in the same individuals and to validate a physiologically based pharmacokinetic (PBPK) model for predicting oral bioavailability following RYGB.

  11. Antimicrobial breakpoint estimation accounting for variability in pharmacokinetics

    OpenAIRE

    Nekka Fahima; Li Jun; Bi Goue

    2009-01-01

    Abstract Background Pharmacokinetic and pharmacodynamic (PK/PD) indices are increasingly being used in the microbiological field to assess the efficacy of a dosing regimen. In contrast to methods using MIC, PK/PD-based methods reflect in vivo conditions and are more predictive of efficacy. Unfortunately, they entail the use of one PK-derived value such as AUC or Cmax and may thus lead to biased efficiency information when the variability is large. The aim of the present work was to evaluate t...

  12. Clinical pharmacokinetics of 5-methyltetrahydrohomofolate

    International Nuclear Information System (INIS)

    DL-N5-Methyltetrahydrohomofolate (MTHHF; NSC-139490; N- [(4-[(2-(2-amino-3,4,5,6,7,8-hexahydro-4-oxo-5-methyl-6- pteridinyl)ethyl) amino) benzoyl)] -L-glutamate), a new folate antagonist of relatively low toxicity, is active against experimental tumor systems resistant to methotrexate and consequently now in clinical trial. We investigated its clinical pharmacokinetics in six patients; four of them received by rapid i.v. infusion tracer doses of [N5-methyl-14C]MTHHF ranging from 13 to 16 mg/sq m, and 2 received 150 mg/sq m; the total radioactivity dose was 100 to 200 mu Ci/patient. MTHHF was assayed by radiochemical and chromatographic techniques. The elimination of MTHHF from the plasma followed a triexponential pattern, with a harmonic mean initial half-life of 20.1 min, an intermediary half-life of 4.5 hr, and a terminal half-life of 74.6 hr. The apparent volume of distribution was 1.6 liters/kg, suggesting rapid and extensive tissue binding. This, together with the low total clearance of 0.2 ml/kg/min, contributed to the long half-life of this agent. Although 68% of the administered dose was excreted in the urine on the first day, only an additional 1% was excreted on the ensuing 3 days. In the two patients who received the higher dose, very little MTHHF was found in the cerebrospinal fluid. In concentrations ranging from 25 to 500 micrograms/ml, the drug was about 50% bound to plasma protein. MTHHF was not metabolized in humans as also reported in animals. These results suggest that MTHHF is excreted in the bile to certain extent. Moreover, since it tends to localize and persist in the body, to forestall cumulative toxicity, frequent administration of this agent should be undertaken only with caution

  13. Clinical pharmacokinetics of 5-methyltetrahydrohomofolate

    Energy Technology Data Exchange (ETDEWEB)

    Loo, T.L.; Jiushi, L.; Lu, K.; Savaraj, N.

    1983-02-01

    DL-N5-Methyltetrahydrohomofolate (MTHHF; NSC-139490; N- ((4-((2-(2-amino-3,4,5,6,7,8-hexahydro-4-oxo-5-methyl-6- pteridinyl)ethyl) amino) benzoyl)) -L-glutamate), a new folate antagonist of relatively low toxicity, is active against experimental tumor systems resistant to methotrexate and consequently now in clinical trial. We investigated its clinical pharmacokinetics in six patients; four of them received by rapid i.v. infusion tracer doses of (N5-methyl-/sup 14/C)MTHHF ranging from 13 to 16 mg/sq m, and 2 received 150 mg/sq m; the total radioactivity dose was 100 to 200 mu Ci/patient. MTHHF was assayed by radiochemical and chromatographic techniques. The elimination of MTHHF from the plasma followed a triexponential pattern, with a harmonic mean initial half-life of 20.1 min, an intermediary half-life of 4.5 hr, and a terminal half-life of 74.6 hr. The apparent volume of distribution was 1.6 liters/kg, suggesting rapid and extensive tissue binding. This, together with the low total clearance of 0.2 ml/kg/min, contributed to the long half-life of this agent. Although 68% of the administered dose was excreted in the urine on the first day, only an additional 1% was excreted on the ensuing 3 days. In the two patients who received the higher dose, very little MTHHF was found in the cerebrospinal fluid. In concentrations ranging from 25 to 500 micrograms/ml, the drug was about 50% bound to plasma protein. MTHHF was not metabolized in humans as also reported in animals. These results suggest that MTHHF is excreted in the bile to certain extent. Moreover, since it tends to localize and persist in the body, to forestall cumulative toxicity, frequent administration of this agent should be undertaken only with caution.

  14. 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

  15. Front cover: Quantitative MS analysis of therapeutic mAbs and their glycosylation for pharmacokinetics study.

    Science.gov (United States)

    Cong, Yuting; Zhang, Zhang; Zhang, Shen; Hu, Lianghai; Gu, Jingkai

    2016-04-01

    DOI: 10.1002/prca.201500098 The cover image describes the pharmacokinetics study of therapeutic monoclonal antibodies. The post translational modifications of proteins will affect the pharmacokinetic behavior and thus it's of critical importance to develop novel approaches for the quantification of therapeutic monoclonal antibodies and their modification forms. Mass spectrometry-based technologies provide an alternative way for the qualitative and quantitative analysis of therapeutic monoclonal antibodies. Further details can be found in the article by Yuting Cong et al. on page 303. PMID:27061325

  16. Pharmacokinetics of Oral Taurine in Healthy Volunteers

    OpenAIRE

    Mohammadreza Ghandforoush-Sattari; Siminozar Mashayekhi; Krishna, Channarayapatna V.; Thompson, John P.; Routledge, Philipp A.

    2010-01-01

    Taurine, a sulfur-containing amino acid, is a normal constituent of the human diet. Little is known of the pharmacokinetics of taurine in man after oral administration. We studied the pharmacokinetics of 4 g taurine in eight healthy male volunteers (median age 27.5, range 22–45) following orally administration in the fasting state in the morning. Blood samples were taken at regular intervals and plasma taurine concentration was measured by a modified HPLC method. Data were subjected to noncom...

  17. 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)

  18. A phase I study evaluating the pharmacokinetics, safety and tolerability of an antibody-based tissue factor antagonist in subjects with acute lung injury or acute respiratory distress syndrome

    Directory of Open Access Journals (Sweden)

    Morris Peter E

    2012-02-01

    Full Text Available Abstract Background The tissue factor (TF-dependent extrinsic pathway has been suggested to be a central mechanism by which the coagulation cascade is locally activated in the lungs of patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS and thus represents an attractive target for therapeutic intervention. This study was designed to determine the pharmacokinetic and safety profiles of ALT-836, an anti-TF antibody, in patients with ALI/ARDS. Methods This was a prospective, randomized, placebo-controlled, dose-escalation Phase I clinical trial in adult patients who had suspected or proven infection, were receiving mechanical ventilation and had ALI/ARDS (PaO2/FiO2 ≤ 300 mm. Eighteen patients (6 per cohort were randomized in a 5:1 ratio to receive ALT-836 or placebo, and were treated within 48 hours after meeting screening criteria. Cohorts of patients were administered a single intravenously dose of 0.06, 0.08 or 0.1 mg/kg ALT-836 or placebo. Blood samples were taken for pharmacokinetic and immunogenicity measurements. Safety was assessed by adverse events, vital signs, ECGs, laboratory, coagulation and pulmonary function parameters. Results Pharmacokinetic analysis showed a dose dependent exposure to ALT-836 across the infusion range of 0.06 to 0.1 mg/kg. No anti-ALT-836 antibody response was observed in the study population during the trial. No major bleeding episodes were reported in the ALT-836 treated patients. The most frequent adverse events were anemia, observed in both placebo and ALT-836 treated patients, and ALT-836 dose dependent, self-resolved hematuria, which suggested 0.08 mg/kg as an acceptable dose level of ALT-836 in this patient population. Conclusions Overall, this study showed that ALT-836 could be safely administered to patients with sepsis-induced ALI/ARDS. Trial registration ClinicalTrials.gov: NCT01438853

  19. 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.

  20. Interaction Between Domperidone and Ketoconazole: Toward Prediction of Consequent QTc Prolongation Using Purely In Vitro Information

    OpenAIRE

    Mishra, H.; S. Polak; Jamei, M.; Rostami-Hodjegan, A

    2014-01-01

    We aimed to investigate the application of combined mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation in predicting the domperidone (DOM) triggered pseudo-electrocardiogram modification in the presence of a CYP3A inhibitor, ketoconazole (KETO), using in vitro–in vivo extrapolation. In vitro metabolic and inhibitory data were incorporated into physiologically based pharmacokinetic (PBPK) models within Simcyp to simulate time course of plasma DOM and KETO concent...

  1. Pharmacokinetic of antimony in mice with cutaneous Leishmaniasis

    International Nuclear Information System (INIS)

    Cutaneous Leishmaniasis (CL) remains a major world health problem, with about 1.5 million new cases each year. Caused by protozoa Leishmania, in South America, this infection can vary from a chronic skin ulcer, to an erosive mucosal disease and severe facial disfigurement. Pentavalent antimony (Sb+5) as sodium stibogluconate (Pentostam) or meglumine antimoniate (Glucantime) are main drugs for treating most forms of human leishmaniasis. For six decades, despite the recent developments, the effective therapy to cutaneous leishmaniasis has been based on long parenteral courses of such drugs, even though these are fairly costly, toxic and inconvenient to use, without adequate knowledge on their pharmacokinetics or mechanism of action. Pharmacokinetics studies could be based on bioactive traceable drugs, usually with radioactive isotopes, but antimony radioisotopes are unavailable commercially. Neutron irradiation is a powerful tool in the analysis of mineral content of samples, for antimony, there are at least two main isotopes that could be formed after neutron irradiation in nuclear reactor. The aim of the present study was to construct antimony salts with those radioisotopes to obtain tracers to compare the pharmacokinetic and the tissue distribution of neutron irradiated meglumine antimoniate in healthy and cutaneous leishmaniasis experimentally infected mice. Meglumine antimoniate, (Glucantime, Aventis, S.P, Brazil), was neutron irradiated inside the IEA-R1 nuclear reactor (IPEN/CNEN-SP), producing two radioisotopes 122Sb and 124Sb. Its biodistribution was verified in BALB/c mice experimentally infected with Leishmania (Leishmania) Amazonensis, which received a single intraperitoneal dose of the drug. At different times after injection, the tissues and blood were excised and activity measured in a NaI (Tl) scintillation counter. Compared with the healthy mice, experimentally infected mice had significantly lower maximum concentration of antimony and high uptake in

  2. Pharmacokinetic of antimony in mice with cutaneous Leishmaniasis

    Energy Technology Data Exchange (ETDEWEB)

    Borborema, Samanta E.T.; Nascimento, Nanci do [Instituto de Pesquisas Energeticas e Nucleares IPEN/CNEN-SP, Sao Paulo, SP (Brazil). Lab. de Biologia Molecular]. E-mails: samanta@usp.br; nnascime@ipen.br; Andrade Junior, Heitor F. de [Instituto de Pesquisas Energeticas e Nucleares IPEN/CNEN-SP, Sao Paulo, SP (Brazil). Lab. de Biologia Molecular; Instituto de Medicina Tropical de Sao Paulo, Sao Paulo, SP (Brazil); E-mail: hfandrad@usp.br; Osso Junior, Joao A. [Instituto de Pesquisas Energeticas e Nucleares IPEN/CNEN-SP, Sao Paulo, SP (Brazil). Centro de Radiofarmacia]. E-mail: jaosso@ipen.br

    2007-07-01

    Cutaneous Leishmaniasis (CL) remains a major world health problem, with about 1.5 million new cases each year. Caused by protozoa Leishmania, in South America, this infection can vary from a chronic skin ulcer, to an erosive mucosal disease and severe facial disfigurement. Pentavalent antimony (Sb{sup +5}) as sodium stibogluconate (Pentostam) or meglumine antimoniate (Glucantime) are main drugs for treating most forms of human leishmaniasis. For six decades, despite the recent developments, the effective therapy to cutaneous leishmaniasis has been based on long parenteral courses of such drugs, even though these are fairly costly, toxic and inconvenient to use, without adequate knowledge on their pharmacokinetics or mechanism of action. Pharmacokinetics studies could be based on bioactive traceable drugs, usually with radioactive isotopes, but antimony radioisotopes are unavailable commercially. Neutron irradiation is a powerful tool in the analysis of mineral content of samples, for antimony, there are at least two main isotopes that could be formed after neutron irradiation in nuclear reactor. The aim of the present study was to construct antimony salts with those radioisotopes to obtain tracers to compare the pharmacokinetic and the tissue distribution of neutron irradiated meglumine antimoniate in healthy and cutaneous leishmaniasis experimentally infected mice. Meglumine antimoniate, (Glucantime, Aventis, S.P, Brazil), was neutron irradiated inside the IEA-R1 nuclear reactor (IPEN/CNEN-SP), producing two radioisotopes {sup 122}Sb and {sup 124}Sb. Its biodistribution was verified in BALB/c mice experimentally infected with Leishmania (Leishmania) Amazonensis, which received a single intraperitoneal dose of the drug. At different times after injection, the tissues and blood were excised and activity measured in a NaI (Tl) scintillation counter. Compared with the healthy mice, experimentally infected mice had significantly lower maximum concentration of antimony

  3. Assessment of juvenile pigs to serve as human pediatric surrogates for preclinical formulation pharmacokinetic testing

    Science.gov (United States)

    Pediatric drug development is hampered by the various biological, clinical, and formulation challenges associated with age-based populations. A primary cause for this lack of development is the inability to accurately predict ontogenic changes that affect pharmacokinetics (PK) in children using trad...

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

    NARCIS (Netherlands)

    Viby-Mogensen, J; Ostergaard, D; Donati, F; Fisher, D; Hunter, J; Kampmann, JP; Kopman, A; Proost, JH; Rasmussen, SN; Skovgaard, LT; Varin, F; Wright, PMC

    2000-01-01

    In September 1997, an international consensus conference on standardization of studies of neuromuscular blocking agents was held in Copenhagen, Denmark. Based on the conference, a set of guidelines fur good clinical research practice (GCRT) in pharmacokinetic studies of neuromuscular blocking agents

  5. Are Pharmacokinetic Approaches Feasible for Treatment of Cocaine Addiction and Overdose?

    Science.gov (United States)

    Zheng, Fang

    2015-01-01

    “… we discuss the main challenges for developing therapeutic treatment of cocaine addiction and explain why pharmacokinetic approaches, particularly those based on our recently developed efficient cocaine-metabolizing enzymes, are feasible for treatment of cocaine addiction and overdose.” PMID:22300091

  6. Are Pharmacokinetic Approaches Feasible for Treatment of Cocaine Addiction and Overdose?

    OpenAIRE

    Zheng, Fang; Zhan, Chang-Guo

    2012-01-01

    “… we discuss the main challenges for developing therapeutic treatment of cocaine addiction and explain why pharmacokinetic approaches, particularly those based on our recently developed efficient cocaine-metabolizing enzymes, are feasible for treatment of cocaine addiction and overdose.”

  7. 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

  8. Pharmacokinetics and metabolism of neurotensin in man

    DEFF Research Database (Denmark)

    Pedersen, J H; Andersen, H O; Olsen, P S;

    1989-01-01

    We studied the pharmacokinetics, arteriovenous extraction, and degradation sites of neurotensin (NT) in man during iv infusions of synthetic intact NT [NT-(1-13)] and the NH2-terminal metabolite NT-(1-8) during lipid ingestion and by catheterization of various vascular beds in normal subjects and...

  9. Human pharmacokinetics of proguanil and its metabolites

    DEFF Research Database (Denmark)

    Bygbjerg, Ib Christian; Ravn, P; Rønn, A;

    1987-01-01

    The pharmacokinetics of proguanil and its metabolites cycloguanil and p-chlorophenylbiguanide were studied in five healthy volunteers taking 200 mg orally for 14 days. A highly sensitive and specific high-performance liquid chromatographic assay was applied, clearly identifying all three compounds...

  10. 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.

  11. Pharmacokinetics Applications of Traditional Chinese Medicines

    Institute of Scientific and Technical Information of China (English)

    Qiu-Ju Li; Ai-Hua Zhang; Hui Sun; Xi-Jun Wang

    2016-01-01

    Traditional Chinese medicine (TCM) has been widely used in many oriental countries for thousands of years and played an indispensable role in the prevention and treatment of diseases, especially the complicated and chronic ones. It is a very complex mixture containing hundreds or thousands of different components. Pharmacokinetic study on active constituents in TCM preparations is a good way for us to explain and predict a variety of events related to the efficacy and toxicity of TCM. In the drug discovery phases, pharmacokinetics is a key to guide medicinal chemists in the optimization process of a chemical series and to assist pharmacologists to design in vivo studies. To explore the potentially bioactive components in TCM, it is necessary to further study the in vivo pharmacokinetic characteristics of multiple absorbed components and find out the optical time-course behavior to providing more substantial research for new leads in drug discovery. Pharmacokinetics screening method could provide a reliable means of prospecting natural products in the search for new leads in drug discovery. This review summarizes the research progress of PK on TCM in the search for suitable lead compounds in recent years.

  12. Evaluation of phenytoin pharmacokinetics in neurotrauma patients

    Directory of Open Access Journals (Sweden)

    Shohrati M.

    2007-04-01

    Full Text Available Previous studies have suggested that drug metabolism may be altered in patients with severe neurotrauma. The purpose of this prospective study was to observe the alteration of phenytoin pharmacokinetic and the resulting drug plasma level among these patients. Twenty patients with severe head injury (Glasgow Coma Scale≤8 requiring intravenous phenytoin were included in the study. Phenytoin sodium was diluted to a concentration of 25mg/ml and infused for 20 minutes at the rate of not faster than 25mg/min. Maintenance dose of phenytoin sodium was administered in the first day of head trauma and vital signs were monitored at hourly intervals while the patients remained in the neurosurgical intensive care unit. Blood samples were obtained for peak and trough concentrations. Free and total phenytoin levels were determined by both liquid chromatography and fluorescence polarization immunoassay (Éclair of plasma samples after ultrafiltration and deproteinization respectively. Based on the reported Km (Km = 5.4 mg/l, predicted population Vmax was calculated to be (7.3  0.4 mg/kg/d which was significantly lower than calculated individual Vmax (9.3  3.2 mg/kg/d (P=0.026. Moreover, significant differences was found between mean daily dose of phenytoin administered to patients (257  4 mg/d and calculated mean daily dose based on individual Vmax (479  3 mg/d (p=0.0015. Mean plasma concentrations determined by fluorescence polarization immunoassay (FPIA (6.11  2.9 mg/l and HPLC method (5.78 ± 2.8 mg/l were not statistically different Metabolic rate increased non-proportionally with increase in phenytoin concentration, and as a result decrease in clearance. Significant alteration in the metabolism of phenytoin occurred after severe neurotrauma. Based on our results, to keep phenytoin concentrations in the range of 10-20 mg/l, an increase in the phenytoin maintenance dose and more frequent monitoring of concentration is commonly required.

  13. Quantitative Structure Pharmacokinetic Relationship Using Artificial Neural Network: A Review

    Directory of Open Access Journals (Sweden)

    S. K. Singh

    2009-10-01

    Full Text Available Quantitative structure activity relationship (QSAR has become a tool for designing in various areas like drugs, food additive, Pesticides, biochemical reactant, environmental pollutant and toxic products. In QSAR biological activity can be related with physicochemical properties and in QSPkR (Quantitative Structure Pharmacokinetic Relationship, pharmacokinetic properties can be related with physicochemical properties, relation found in terms of quantity. A number of literature and review article have been published on Quantitative structure pharmacokinetic relationship. But prediction of human pharmacokinetic properties of known and unknown is much difficult job in pharmaceutical industry. Pharmacokinetic data of animal cannot be put straightforward. Artificial neural network (ANN is used to predict the pharmacokinetic properties. Artificial neural network has basic structure like biological brain and compose of neurons which are interconnected to each other. The present review not only compiles the literature of QSPkR using ANN, but gives detail about the physicochemical properties and artificial neural network.

  14. Clinical Pharmacology and Pharmacokinetics of Levetiracetam

    Directory of Open Access Journals (Sweden)

    Chanin Clark Wright

    2013-12-01

    Full Text Available Status epilepticus and acute repetitive seizures still pose a management challenge despite the recent advances in the field of epilepsy. Parenteral formulations of old anticonvulsants are still a cornerstone in acute seizure management and are approved by the FDA. Intravenous levetiracetam, a second generation anticonvulsant, is approved by the FDA as an adjunctive treatment in patients 16 years or older when oral administration is not available. Data have shown that it has a unique mechanism of action, linear pharmacokinetics and no known drug interactions with other anticonvulsants. In this paper, we will review the current literature about the pharmacology and pharmacokinetics of intravenous levetiracetam and the safety profile of this new anticonvulsant in acute seizure management of both adults and children.

  15. Sorafenib in advanced melanoma: a critical role for pharmacokinetics?

    OpenAIRE

    Pécuchet, N; Lebbe, C; Mir, O; Billemont, B; Blanchet, B; Franck, N; Viguier, M; Coriat, R.; Tod, M; Avril, M-F; Goldwasser, F

    2012-01-01

    Background: Inter-patient pharmacokinetic variability can lead to suboptimal drug exposure, and therefore might impact the efficacy of sorafenib. This study reports long-term pharmacokinetic monitoring of patients treated with sorafenib and a retrospective pharmacodynamic/pharmacokinetic analysis in melanoma patients. Patients and methods: Heavily pretreated patients with stage IV melanoma were started on sorafenib 400 mg twice daily (bid). In the absence of limiting toxicity, dose escalation...

  16. 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 ...

  17. Pharmacokinetic evaluation of cefoperazone in infants.

    OpenAIRE

    Varghese, M; Khan, A. J.; K Kumar; Rosenfeld, W.; Schaeffer, H A; Evans, H E

    1985-01-01

    The pharmacokinetics of cefoperazone were evaluated in 25 infants (mean age, 26 days) after intramuscular and intravenous routes of administration. The levels in blood that were achieved were severalfold higher than those required to inhibit common pathogens. The mean half-life of 240 min was one-half of that observed in 1- to 2-day-old infants but about twice that seen in adults. Further evaluation is needed to study the efficacy of the drug in infants and children.

  18. Change in Erythropoietin Pharmacokinetics Following Hematopoietic Transplantation

    OpenAIRE

    Widness, JA; Schmidt, RL; Hohl, RJ; Goldman, FD; Al-Huniti, NH; Freise, KJ; Veng-Pedersen, P.

    2007-01-01

    Pre-clinical studies have demonstrated that bone marrow ablation has a profound effect in decreasing erythropoietin (EPO) elimination. The study’s objective was to determine in humans if EPO pharmacokinetics (PKs) are perturbed following bone marrow ablation. EPO PK studies were performed in eight subjects, aged 4 to 61 years, undergoing fully myeloablative hematopoietic stem cell transplantation. Serial PK studies using intravenous injection of recombinant human EPO (92±2.0 U/kg) (mean±SEM) ...

  19. Pharmacokinetics of mercury from dental amalgam

    OpenAIRE

    Sandborgh Englund, Gunilla

    1998-01-01

    PHARMACOKINETICS OF MERCURY FROM DENTAL AMALGAM Gunilla Sandborgh Englund Dept. of Basal Oral Sciences, Karolinska Institutet, S-141 04Huddinge The overall aim of the present work has been to obtain quantitative and qualitativedata on mercury from dental amalgam in humans. The influence of amalgam removal on mercury levels in blood, plasma and urine hasbeen studied in twelve volunteers. All amalgam fillings were removed during one dentalsession. A transient increase of...

  20. 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...

  1. 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...

  2. Cocaine: analysis, pharmacokinetics, and metabolic disposition.

    OpenAIRE

    Jatlow, P.

    1988-01-01

    The ability to measure concentrations of cocaine in body fluids can contribute substantially to any investigation of cocaine's pharmacological effects. Design of research which involves the administration of cocaine must take into account current knowledge regarding the drug's pharmacokinetics. Cocaine's very rapid elimination from the body should be considered in attempting to understand patterns of cocaine abuse, and such phenomena as bingeing and acute tolerance. Accurate analysis of cocai...

  3. Understanding the pharmacokinetics of Coartem®

    OpenAIRE

    Djimdé, Abdoulaye; Lefèvre, Gilbert

    2009-01-01

    Artemether and lumefantrine (AL), the active constituents of Coartem® exhibit complementary pharmacokinetic profiles. Artemether is absorbed quickly; peak concentrations of artemether and its main active metabolite, dihydroartemisinin (DHA) occur at approximately two hours post-dose, leading to a rapid reduction in asexual parasite mass and a prompt resolution of symptoms. Lumefantrine is absorbed and cleared more slowly (terminal elimination half-life 3-4 days in malaria patients), and accum...

  4. Pharmacokinetics and Bioequivalence Evaluation of Cyclobenzaprine Tablets

    OpenAIRE

    Tatiane Maria de Lima Souza Brioschi; Simone Grigoleto Schramm; Eunice Kazue Kano; Eunice Emiko Mori Koono; Ting Hui Ching; Cristina Helena dos Reis Serra; Valentina Porta

    2013-01-01

    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. Pharmaco...

  5. Pharmacokinetic Interaction between Telaprevir and Methadone

    OpenAIRE

    Van Heeswijk, Rolf; Verboven, Peter; Vandevoorde, Ann; Vinck, Petra; Snoeys, Jan; Boogaerts, Griet; De Paepe, Els; Van Solingen-Ristea, Rodica; Witek, James; Garg, Varun

    2013-01-01

    Hepatitis C virus (HCV) antibody is present in most patients enrolled in methadone maintenance programs. Therefore, interactions between the HCV protease inhibitor telaprevir and methadone were investigated. The pharmacokinetics of R- and S-methadone were measured after administration of methadone alone and after 7 days of telaprevir (750 mg every 8 h [q8h]) coadministration in HCV-negative subjects on stable, individualized methadone therapy. Unbound R-methadone was measured in predose plasm...

  6. Safety, pharmacokinetics and efficacy of artemisinins in pregnancy

    Directory of Open Access Journals (Sweden)

    Veronica Ades

    2011-05-01

    Full Text Available Malaria in pregnancy can lead to serious maternal and fetal morbidity and mortality. Access to the most effective antimalarials in pregnancy is essential. Resistance to current therapies is high for all antimalarial therapies except artemisinins. Artemisinin-based combination therapy is current the first line of malaria treatment recommended by the WHO for children, adults and pregnant women in second or third trimester. Due to potential embryotoxicity of artemisinins identified in animal studies, artemisinins are not considered safe for use in first trimester of pregnancy. Artemisinins are more rapidly metabolized in pregnant women, but this does not seem to reduce efficacy. Most studies show very high cure rates for pregnant women. Areas for further research include the safety profile in first trimester of pregnancy, the effect of HIV infection on artemisinin use in pregnancy, the relationship between the pharmacokinetic profile and efficacy, and the use of artemisinin-based combination therapy for intermittent preventive treatment in pregnancy.  

  7. Design, recruitment, and retention of African-American smokers in a pharmacokinetic study

    Directory of Open Access Journals (Sweden)

    Mayo Matthew S

    2010-01-01

    Full Text Available Abstract Background African-Americans remain underrepresented in clinical research despite experiencing a higher burden of disease compared to all other ethnic groups in the United States. The purpose of this article is to describe the study design and discuss strategies used to recruit and retain African-American smokers in a pharmacokinetic study. Methods The parent study was designed to evaluate the differences in the steady-state concentrations of bupropion and its three principal metabolites between African-American menthol and non-menthol cigarette smokers. Study participation consisted of four visits at a General Clinical Research Center (GCRC over six weeks. After meeting telephone eligibility requirements, phone-eligible participants underwent additional screening during the first two GCRC visits. The last two visits (pharmacokinetic study phase required repeated blood draws using an intravenous catheter over the course of 12 hours. Results Five hundred and fifteen African-American smokers completed telephone screening; 187 were phone-eligible and 92 were scheduled for the first GCRC visit. Of the 81 who attended the first visit, 48 individuals were enrolled in the pharmacokinetic study, and a total of 40 individuals completed the study (83% retention rate. Conclusions Although recruitment of African-American smokers into a non-treatment, pharmacokinetic study poses challenges, retention is feasible. The results provide valuable information for investigators embarking on non-treatment laboratory-based studies among minority populations.

  8. 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

  9. 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

  10. Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition.

    Science.gov (United States)

    Yu, Guo; Li, Guo-Fu; Markowitz, John S

    2016-05-01

    Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children (≥6 years of age), adolescents, and adults. Its metabolism and disposition are fairly complex, and primarily governed by cytochrome P450 (CYP) 2D6 (CYP2D6), whose protein expression varies substantially from person to person, and by race and ethnicity because of genetic polymorphism. These differences can be substantial, resulting in 8-10-fold differences in atomoxetine exposure between CYP2D6 poor metabolizers and extensive metabolizers. In this review, we have attempted to revisit and analyze all published clinical pharmacokinetic data on atomoxetine inclusive of public access documents from the new drug application submitted to the United States Food and Drug Administration (FDA). The present review focuses on atomoxetine metabolism, disposition, and genetic polymorphisms of CYP2D6 as they specifically relate to atomoxetine, and provides an in-depth discussion of the fundamental pharmacokinetics of the drug including its absorption, distribution, metabolism, and excretion in pediatric and adult populations. Further, a summary of relationships between genetic variants of CYP2D6 and to some degree, CYP2C19, are provided with respect to atomoxetine plasma concentrations, central nervous system (CNS) pharmacokinetics, and associated clinical implications for pharmacotherapy. Lastly, dosage adjustments based on pharmacokinetic principles are discussed. PMID:26859445

  11. Comparative pharmacokinetics of intravenous fentanyl and buprenorphine in healthy greyhound dogs.

    Science.gov (United States)

    KuKanich, B; Allen, P

    2014-12-01

    The purpose of this study was to compare the pharmacokinetics of two highly protein-bound, lipophilic opioid drugs. Fentanyl (10 μg/kg) and buprenorphine (20 μg/kg) were administered intravenously (IV) to six healthy greyhound dogs (three males and three females). The doses were based on clinically administered doses for dogs. Plasma drug concentrations were determined using liquid chromatography with mass spectrometry, and noncompartmental pharmacokinetics were estimated with computer software. The volume of distribution (area) was larger for fentanyl (7.42 L/kg) compared to buprenorphine (3.54 L/kg). The plasma clearance of fentanyl (38.6 mL·min/kg) was faster than buprenorphine (10.3 mL·min/kg). The terminal half-life of fentanyl (2.22 h) was shorter than buprenorphine (3.96 h). Despite similar physicochemical properties including octanol-water partition coefficient and pKa, the pharmacokinetics of fentanyl and buprenorphine were not similar. Both fentanyl (84%) and buprenorphine (95-98%) are considered highly protein bound, but the differences in protein binding may contribute to the lack of similarity of pharmacokinetics in healthy dogs. PMID:24684621

  12. 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.

  13. Pharmacokinetics of Hoasca alkaloids in healthy humans.

    Science.gov (United States)

    Callaway, J C; McKenna, D J; Grob, C S; Brito, G S; Raymon, L P; Poland, R E; Andrade, E N; Andrade, E O; Mash, D C

    1999-06-01

    N,N-Dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine (THH) are the characteristic alkaloids found in Amazonian sacraments known as hoasca, ayahuasca, and yajè. Such beverages are characterized by the presence of these three harmala alkaloids, where harmine and harmaline reversibly inhibit monoamine oxidase A (MAO-A) while tetrahydroharmine weakly inhibits the uptake of serotonin. Together, both actions increase central and peripheral serotonergic activity while facilitating the psychoactivity of DMT. Though the use of such 'teas' has be known to western science for over 100 years, little is known of their pharmacokinetics. In this study, hoasca was prepared and administered in a ceremonial context. All four alkaloids were measured in the tea and in the plasma of 15 volunteers, subsequent to the ingestion of 2 ml hoasca/kg body weight, using gas (GC) and high pressure liquid chromatographic (HPLC) methods. Pharmacokinetic parameters were calculated and peak times of psychoactivity coincided with high alkaloid concentrations, particularly DMT which had an average Tmax of 107.5 +/- 32.5 min. While DMT parameters correlated with those of harmine, THH showed a pharmacokinetic profile relatively independent of harmine's. PMID:10404423

  14. [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

  15. Pharmacokinetics of ketoprofen syrup in small children.

    Science.gov (United States)

    Kokki, H; Le Liboux, A; Jekunen, A; Montay, G; Heikkinen, M

    2000-04-01

    Ketoprofen is a nonsteroidal anti-inflammatory drug with analgesic, anti-inflammatory, and antipyretic properties. Its pharmacokinetics has not been determined in small children. The objective here was to determine the pharmacokinetics of ketoprofen syrup, 0.5 mg/kg, in two groups of 10 children. Group 1 was from ages 6 months up to 2 years (7/10 younger than 1 year), and Group 2 was from ages 2 to 7 years. Venous blood samples were collected before drug administration and 0.5, 1, 2, 4, 6, 8, and 12 hours after. A validated HPLC method was used to determine plasma levels of ketoprofen. The lower limit of quantification was 0.02 microgram/ml of plasma. Ketoprofen syrup was absorbed rapidly, the plasma level reaching its maximum at 0.5 hours, with C0.5 hours = 3 micrograms/ml. The pharmacokinetics was similar between the two groups of children. The elimination half-life, 2.0 hours in Group 1 or 1.9 hours in Group 2, was similar to that reported in adults. PMID:10761162

  16. Drug metabolism and pharmacokinetic diversity of ranunculaceae medicinal compounds.

    Science.gov (United States)

    Hao, Da-Cheng; Ge, Guang-Bo; Xiao, Pei-Gen; Wang, Ping; Yang, Ling

    2015-01-01

    The wide-reaching distributed angiosperm family Ranunculaceae has approximately 2200 species in around 60 genera. Chemical components of this family include several representative groups: benzylisoquinoline alkaloid (BIA), ranunculin, triterpenoid saponin and diterpene alkaloid, etc. Their extensive clinical utility has been validated by traditional uses of thousands of years and current evidence-based medicine studies. Drug metabolism and pharmacokinetic (DMPK) studies of plant-based natural products are an indispensable part of comprehensive medicinal plant exploration, which could facilitate conservation and sustainable utilization of Ranunculaceae pharmaceutical resources, as well as new chemical entity development with improved DMPK parameters. However, DMPK characteristics of Ranunculaceaederived medicinal compounds have not been summarized. Black cohosh (Cimicifuga) and goldenseal (Hydrastis) raise concerns of herbdrug interaction. DMPK studies of other Ranunculaceae genera, e.g., Nigella, Delphinium, Aconitum, Trollius, and Coptis, are also rapidly increasing and becoming more and more clinically relevant. In this contribution, we highlight the up-to-date awareness, as well as the challenges around the DMPK-related issues in optimization of drug development and clinical practice of Ranunculaceae compounds. Herb-herb interaction of Ranunculaceae herb-containing traditional Chinese medicine (TCM) formula could significantly influence the in vivo pharmacokinetic behavior of compounds thereof, which may partially explain the complicated therapeutic mechanism of TCM formula. Although progress has been made on revealing the absorption, distribution, metabolism, excretion and toxicity (ADME/T) of Ranunculaceae compounds, there is a lack of DMPK studies of traditional medicinal genera Aquilegia, Thalictrum and Clematis. Fluorescent probe compounds could be promising substrate, inhibitor and/or inducer in future DMPK studies of Ranunculaceae compounds. A better

  17. Pharmacokinetics of bisphenol A in neonatal and adult rhesus monkeys

    International Nuclear Information System (INIS)

    Bisphenol A (BPA) is a high-production volume industrial chemical used in the manufacture of polycarbonate plastic products and epoxy resin-based food can liners. The presence of BPA in urine of > 90% of Americans aged 6-60 is controversial because of the potential for endocrine disruption, particularly during perinatal development, as suggested by in vitro, experimental animal, and epidemiological studies. The current study used LC/MS/MS to measure serum pharmacokinetics of aglycone (active) and conjugated (inactive) BPA in adult and neonatal rhesus monkeys by oral (PND 5, 35, 70) and intravenous injection (PND 77) routes using d6-BPA to avoid sample contamination. The concentration-time profiles observed in adult monkeys following oral administration of 100 μg/kg bw were remarkably similar to those previously reported in human volunteers given a similar dose; moreover, minimal pharmacokinetic differences were observed between neonatal and adult monkeys for the receptor-active aglycone form of BPA. Circulating concentrations of BPA aglycone were quite low following oral administration (< 1% of total), which reflects the redundancy of active UDP-glucuronosyl transferase isoforms in both gut and liver. No age-related changes were seen in internal exposure metrics for aglycone BPA in monkeys, a result clearly different from developing rats where significant inverse age-related changes, based on immaturity of Phase II metabolism and renal excretion, were recently reported. These observations imply that any toxicological effect observed in rats from early postnatal exposures to BPA could over-predict those possible in primates of the same age, based on significantly higher internal exposures and overall immaturity at birth.

  18. 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

  19. 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

  20. 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

  1. 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

  2. Cross-validation of a mass spectrometric-based method for the therapeutic drug monitoring of irinotecan: implementation of matrix-assisted laser desorption/ionization mass spectrometry in pharmacokinetic measurements.

    Science.gov (United States)

    Calandra, Eleonora; Posocco, Bianca; Crotti, Sara; Marangon, Elena; Giodini, Luciana; Nitti, Donato; Toffoli, Giuseppe; Traldi, Pietro; Agostini, Marco

    2016-07-01

    Irinotecan is a widely used antineoplastic drug, mostly employed for the treatment of colorectal cancer. This drug is a feasible candidate for therapeutic drug monitoring due to the presence of a wide inter-individual variability in the pharmacokinetic and pharmacodynamic parameters. In order to determine the drug concentration during the administration protocol, we developed a quantitative MALDI-MS method using CHCA as MALDI matrix. Here, we demonstrate that MALDI-TOF can be applied in a routine setting for therapeutic drug monitoring in humans offering quick and accurate results. To reach this aim, we cross validated, according to FDA and EMA guidelines, the MALDI-TOF method in comparison with a standard LC-MS/MS method, applying it for the quantification of 108 patients' plasma samples from a clinical trial. Standard curves for irinotecan were linear (R (2) ≥ 0.9842) over the concentration ranges between 300 and 10,000 ng/mL and showed good back-calculated accuracy and precision. Intra- and inter-day precision and accuracy, determined on three quality control levels were always <12.8 % and between 90.1 and 106.9 %, respectively. The cross-validation procedure showed a good reproducibility between the two methods, the percentage differences within 20 % in more than 70 % of the total amount of clinical samples analysed. PMID:27235158

  3. Pharmacokinetics of Moxifloxacin in an Infant with Mycoplasma hominis Meningitis

    OpenAIRE

    Watt, Kevin M; Massaro, Matthew M; Smith, Brian; Cohen-Wolkowiez, Michael; Benjamin, Daniel K; Laughon, Matthew M

    2012-01-01

    Treatment of Mycoplasma hominis meningitis in infants is limited by a lack of consensus regarding therapy and limited pharmacokinetic data for agents to which M. hominis is susceptible. We report the successful treatment of a premature infant with M. hominis meningitis with doxycycline and moxifloxacin and provide a pharmacokinetic profile of moxifloxacin.

  4. Acetaminophen developmental pharmacokinetics in premature neonates and infants

    DEFF Research Database (Denmark)

    Anderson, Brian J; van Lingen, Richard A; Hansen, Tom G;

    2002-01-01

    The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens.......The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens....

  5. Multiple-Dose Pharmacokinetics of Fluvoxamine in Children and Adolescents.

    Science.gov (United States)

    Labellarte, Michael; Biederman, Joseph; Emslie, Graham; Ferguson, James; Khan, Arifulla; Ruckle, Jon; Sallee, Randy; Riddle, Mark

    2004-01-01

    Objective: To determine the pharmacokinetics of fluvoxamine in children and adolescents and to compare pharmacokinetic data from adolescents to adults from a previous study. Method: Fluvoxamine was titrated to a target dose of 100 mg b.i.d. in children (6-11 years) and 150 mg b.i.d. in adolescents (12-17 years) with obsessive-compulsive disorder…

  6. PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES ON VAGINALLY ADMINISTERED LEVONORGESTREL

    Institute of Scientific and Technical Information of China (English)

    HEChang-Hai; XUJian-Qiu; ZHUYue-Hua; SHIYong-En

    1989-01-01

    Comparative studies on pharmacokinetics of vaginally and orally administered levonorgestrel (LNG) tablet (Postinor) in one single dose containing 0,75mg LNG were performed. The pharmacokinetics of LNG and its effects on ovarian functions werealso studied after repeated vaginal administration.

  7. Pharmacokinetics of oral terbinafine in horses and Greyhound dogs

    OpenAIRE

    Williams, Megan M.; Davis, Elizabeth G.; KuKanich, Butch

    2011-01-01

    The objective of the study was to assess the pharmacokinetics of terbinafine administered orally to horses and Greyhound dogs. A secondary objective was to assess terbinafine metabolites. Six healthy horses and six healthy Greyhound dogs were included in the pharmacokinetic data.

  8. 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....

  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. Pharmacokinetics of morphine infusion in premature neonates.

    OpenAIRE

    Hartley, R.; Green, M; Quinn, M; Levene, M I

    1993-01-01

    Morphine pharmacokinetics were studied in 17 premature neonates (26-34 weeks' gestation) after intravenous infusion during the first 24 hours of life. Infants received either standard dose morphine that comprised of a 100 micrograms/kg/hour loading infusion for 2 hours followed by a maintenance infusion of 12.5 micrograms/kg/hour, or a high dose of 200 micrograms/kg/hour for 2 hours followed by 50 micrograms/kg/hour. Mean plasma concentrations of morphine (SD) after 2 and 24 hours were 99 (12...

  11. Pharmacokinetic Drug Interaction Studies with Enzalutamide

    OpenAIRE

    Gibbons, Jacqueline A; de Vries, Michiel; Krauwinkel, Walter; Ohtsu, Yoshiaki; Noukens, Jan; van der Walt, Jan-Stefan; Mol, Roelof; Mordenti, Joyce; Ouatas, Taoufik

    2015-01-01

    Background and Objectives Two phase I drug interaction studies were performed with oral enzalutamide, which is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Methods A parallel-treatment design (n = 41) was used to evaluate the effects of a strong cytochrome P450 (CYP) 2C8 inhibitor (oral gemfibrozil 600 mg twice daily) or strong CYP3A4 inhibitor (oral itraconazole 200 mg once daily) on the pharmacokinetics of enzalutamide and its active metabolite N-de...

  12. Pharmacokinetic interactions between contraceptives and antiepileptic drugs

    DEFF Research Database (Denmark)

    Sabers, A.

    2008-01-01

    The occurrence of bi-directional drug interactions between antiepileptic drugs (AEDs) and combined oral contraceptives (M) pose potential risks of unintended pregnancy and as well as seizure deterioration. It is well established that several of the older AEDs (carbamazepine, phenytoin and...... phenobarbital), are strong inducers of the hepatic cytochrome P450 (CYP) 3A4 enzyme system, and are associated with increased the risk of contraceptive failure. In addition, it is demonstrated that also some of the newer AEDs, oxcarbazepine and topiramate influence on the pharmacokinetics of OCs, which is...

  13. Pharmacokinetic comparison of seven 8-methoxypsoralen brands

    DEFF Research Database (Denmark)

    Menne, T; Andersen, Klaus Ejner; Larsen, E;

    1981-01-01

    The pharmacokinetics of seven 8-MOP brands were evaluated in 7 volunteers using an incomplete bloc design. After a single oral dose the 8-MOP plasma level was followed for 3 hours. The plasma concentration was measured with a gas chromatographic - mass spectrometric method, using an isotopic...... dilution technique. The different brands could be divided into three groups. Two gave a high maximum concentration, four a medium, and one a low concentration. The large interbrand variation observed in this study can explain the variations in the results of the treatment and the differing numbers...

  14. 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

  15. 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...

  16. Physicochemical and Pharmacokinetic Parameters in Drug Selection and Loading for Transdermal Drug Delivery

    OpenAIRE

    Chandrashekar N; Shobha Rani R

    2008-01-01

    Skin of an average adult body covers a surface of approximately 2 m2 and receives about one-third of the blood circulating through the body. The transdermal route of administration cannot be employed for a large number of drugs. The rationality of drug selection based on pharmacokinetic parameters and physicochemical properties of the drug are the important factors to be considered for deciding its suitability of drug for delivery by transdermal route.

  17. 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...

  18. Effects of Chungsinoryungsan, a polyherbal complex, on the pharmacokinetic profiles of perindopril in rats

    OpenAIRE

    KANG, SEOK-BONG; Shon, Ho-Sang; Park, Soo-Jin; Song, Chang-Hyun; Ku, Sae-Kwang

    2014-01-01

    For sufficient antihypertension with less adverse effects, numerous clinical trials have recommended combination therapy using two or more hypertensive drugs. Chungsinoryungsan (CSORS) is a polyherbal complex based on oriental medicine, which has shown therapeutic potentials for antihypertension and additional renal improvement. Therefore, the affect of CSORS on the pharmacokinetic profiles of perindopril, an antihypertensive drug, was analyzed as a novel combination of hypertensive drugs. Ra...

  19. Pharmacokinetics, efficacy, and safety of LMWHs in venous thrombosis and stroke in neonates, infants and children

    OpenAIRE

    Nowak-Göttl, U; Bidlingmaier, C; Krümpel, A; Göttl, L; KENET, G.

    2007-01-01

    Since the early nineties it has been shown that low molecular weight heparin (LMWH) has significant advantages over unfractionated heparin and oral anticoagulants for both the treatment and the prevention of thrombosis, not only in adults, but also in children. The present review was based on an ‘EMBASE', ‘Medline' and ‘PubMed' search including literature published in any language since 1980 on LMWH in neonates, infants and children. It included paediatric pharmacokinetic studies, the use of ...

  20. Etravirine Pharmacokinetics in HIV-Infected Pregnant Women

    Science.gov (United States)

    Mulligan, Nikki; Schalkwijk, Stein; Best, Brookie M.; Colbers, Angela; Wang, Jiajia; Capparelli, Edmund V.; Moltó, José; Stek, Alice M.; Taylor, Graham; Smith, Elizabeth; Hidalgo Tenorio, Carmen; Chakhtoura, Nahida; van Kasteren, Marjo; Fletcher, Courtney V.; Mirochnick, Mark; Burger, David

    2016-01-01

    Background: The study goal was to describe etravirine pharmacokinetics during pregnancy and postpartum in HIV-infected women. Methods: IMPAACT P1026s and PANNA are on-going, non-randomized, open-label, parallel-group, multi-center phase-IV prospective studies in HIV-infected pregnant women. Intensive steady-state 12-h pharmacokinetic profiles were performed from 2nd trimester through postpartum. Etravirine was measured at two labs using validated ultra performance liquid chromatography (detection limits: 0.020 and 0.026 mcg/mL). Results: Fifteen women took etravirine 200 mg twice-daily. Etravirine AUC0–12 was higher in the 3rd trimester compared to paired postpartum data by 34% (median 8.3 vs. 5.3 mcg*h/mL, p = 0.068). Etravirine apparent oral clearance was significantly lower in the 3rd trimester of pregnancy compared to paired postpartum data by 52% (median 24 vs. 38 L/h, p = 0.025). The median ratio of cord blood to maternal plasma concentration at delivery was 0.52 (range: 0.19–4.25) and no perinatal transmission occurred. Conclusion: Etravirine apparent oral clearance is reduced and exposure increased during the third trimester of pregnancy. Based on prior dose-ranging and safety data, no dose adjustment is necessary for maternal health but the effects of etravirine in utero are unknown. Maternal health and infant outcomes should be closely monitored until further infant safety data are available. Clinical Trial registration: The IMPAACT protocol P1026s and PANNA study are registered at ClinicalTrials.gov under NCT00042289 and NCT00825929.

  1. Liraglutide in Type 2 Diabetes Mellitus: Clinical Pharmacokinetics and Pharmacodynamics.

    Science.gov (United States)

    Jacobsen, Lisbeth V; Flint, Anne; Olsen, Anette K; Ingwersen, Steen H

    2016-06-01

    Liraglutide is an acylated glucagon-like peptide-1 analogue with 97 % amino acid homology with native glucagon-like peptide-1 and greatly protracted action. It is widely used for the treatment of type 2 diabetes mellitus, and administered by subcutaneous injection once daily. The pharmacokinetic properties of liraglutide enable 24-h exposure coverage, a requirement for 24-h glycaemic control with once-daily dosing. The mechanism of protraction relates to slowed release from the injection site, and a reduced elimination rate owing to metabolic stabilisation and reduced renal filtration. Drug exposure is largely independent of injection site, as well as age, race and ethnicity. Increasing body weight and male sex are associated with reduced concentrations, but there is substantial overlap between subgroups; therefore, dose escalation should be based on individual treatment outcome. Exposure is reduced with mild, moderate or severe renal or hepatic impairment. There are no clinically relevant changes in overall concentrations of various drugs (e.g. paracetamol, atorvastatin, griseofulvin, digoxin, lisinopril and oral combination contraceptives) when co-administered with liraglutide. Pharmacodynamic studies show multiple beneficial actions with liraglutide, including improved fasting and postprandial glycaemic control (mediated by increased insulin and reduced glucagon levels and minor delays in gastric emptying), reduced appetite and energy intake, and effects on postprandial lipid profiles. The counter-regulatory hormone response to hypoglycaemia is largely unaltered. The effects of liraglutide on insulin and glucagon secretion are glucose dependent, and hence the risk of hypoglycaemia is low. The pharmacokinetic and pharmacodynamic properties of liraglutide make it an important treatment option for many patients with type 2 diabetes. PMID:26597252

  2. Mefloquine pharmacokinetics and mefloquine-artesunate effectiveness in Peruvian patients with uncomplicated Plasmodium falciparum malaria

    Directory of Open Access Journals (Sweden)

    Quezada Wilmer

    2009-04-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT is recommended as a means of prolonging the effectiveness of first-line malaria treatment regimens. Different brands of mefloquine (MQ have been reported to be non-bioequivalent; this could result in sub-therapeutic levels of mefloquine with decreased efficacy. In 2002, mefloquine-artesunate (MQ-AS combination therapy was adopted as the first-line treatment for uncomplicated Plasmodium falciparum malaria in the Amazon region of Peru. Although MQ resistance has yet to be reported from the Peruvian Amazon, it has been reported from other countries in the Amazon Region. Therefore, continuous monitoring is warranted to ensure that the first-line therapy remains efficacious. This study examines the in vivo efficacy and pharmacokinetic parameters through Day 56 of three commercial formulations of MQ (Lariam®, Mephaquin®, and Mefloquina-AC® Farma given in combination with artesunate. Methods Thirty-nine non-pregnant adults with P. falciparum mono-infection were randomly assigned to receive artesunate in combination with either (1 Lariam, (2 Mephaquin, or (3 Mefloquina AC. Patients were assessed on Day 0 (with blood samples for pharmacokinetics at 0, 2, 4, and 8 hours, 1, 2, 3, 7, and then weekly until day 56. Clinical and parasitological outcomes were based on the standardized WHO protocol. Whole blood mefloquine concentrations were determined by high-performance liquid chromatography and pharmacokinetic parameters were determined using non-compartmental analysis of concentration versus time data. Results By day 3, all patients had cleared parasitaemia except for one patient in the AC Farma arm; this patient cleared by day 4. No recurrences of parasitaemia were seen in any of the 34 patients. All three MQ formulations had a terminal half-life of 14–15 days and time to maximum plasma concentration of 45–52 hours. The maximal concentration (Cmax and interquartile range was 2,820 ng

  3. Drug pharmacokinetics and pharmacodynamics: Technological considerations

    International Nuclear Information System (INIS)

    Additionally, the use of PET to examine drug pharmacokinetics and pharmacadynamics and the relationship of these properties to the behavioral, therapeutic and toxic properties of drugs and substances of abuse is emerging as a powerful new scientific tool. The pharmacokinetic properties of a drug, which comprises all of the biological processes which determine the fraction of the drug available, can be measured using the labeled drug itself. For example, the labeled drug can be used to measure the absolute uptake, regional distribution and kinetics of a drug at its site of action in the body. Additionally the labeled drug and whole body its labeled metabolites and thus provide information an potential toxic effects as well as tissue half lives. On the other hand, different labeled tracers can be used to assess drug pharmacodynamics which include the biological Processes involved in the drug's effects. For example, with appropriate radiotracers, the effects of a drug on metabolism, neurotransmitter activity, blood flew, enzyme activity or other processes can be probed

  4. Darunavir pharmacokinetics throughout pregnancy and postpartum

    Directory of Open Access Journals (Sweden)

    John Lambert

    2014-11-01

    Full Text Available Introduction: Antiretroviral therapy is recommended during pregnancy for prevention of mother-to-child transmission (MTCT of HIV. Physiological changes during pregnancy are known to affect the pharmacokinetics (PK of protease inhibitors (PIs, leading to lower exposures in pregnant women. Here we examine the PK of DRV/r 800/100 mg once daily (OD over the course of pregnancy and postpartum (PP. Material and Methods: In this prospective open-labelled study, HIV-positive pregnant women receiving darunavir/ritonavir as part of their routine maternity care were enrolled. DRV plasma trough concentrations [DRV] were determined in the first (T1 and/or second (T2 and/or third (T3 trimester and PP using a validated HPLC-MS/MS methodology (Lab21, Cambridge UK. Where possible paired maternal and cord blood samples were taken at delivery. Results: To date 20 women (12 black African, 8 Caucasian have been enrolled. Median (range baseline CD4 count was 338 cells/µL (108–715, and median baseline plasma viral load was 555 copies/mL (550 ng/ml during pregnancy. However, reduced DRV plasma concentrations in the second/third trimesters highlights the need for TDM in this population and warrants further study of pregnancy-associated changes in DRV pharmacokinetics. The low C/M ratios reported here are consistent with previous reports [1] and suggest low transplacental transfer of DRV.

  5. Pharmacokinetics of metoprolol during pregnancy and lactation.

    Science.gov (United States)

    Ryu, Rachel J; Eyal, Sara; Easterling, Thomas R; Caritis, Steve N; Venkataraman, Raman; Hankins, Gary; Rytting, Erik; Thummel, Kenneth; Kelly, Edward J; Risler, Linda; Phillips, Brian; Honaker, Matthew T; Shen, Danny D; Hebert, Mary F

    2016-05-01

    The objective of this study was to evaluate the steady-state pharmacokinetics of metoprolol during pregnancy and lactation. Serial plasma, urine, and breast milk concentrations of metoprolol and its metabolite, α-hydroxymetoprolol, were measured over 1 dosing interval in women treated with metoprolol (25-750 mg/day) during early pregnancy (n = 4), mid-pregnancy (n = 14), and late pregnancy (n = 15), as well as postpartum (n = 9) with (n = 4) and without (n = 5) lactation. Subjects were genotyped for CYP2D6 loss-of-function allelic variants. Using paired analysis, mean metoprolol apparent oral clearance was significantly higher in mid-pregnancy (361 ± 223 L/h, n = 5, P metoprolol apparent oral clearance was significantly higher during both mid- and late pregnancy (P metoprolol through breast milk was metoprolol pharmacokinetics, if inadequate clinical responses are encountered, clinicians who prescribe metoprolol during pregnancy should be prepared to make aggressive changes in dosage (dose and frequency) or consider using an alternate beta-blocker. PMID:26461463

  6. Pharmacokinetics of subcutaneous fentanyl in Greyhounds.

    Science.gov (United States)

    KuKanich, Butch

    2011-11-01

    The purpose of the study was to describe the pharmacokinetics of subcutaneous fentanyl (15μg/kg) in six healthy Greyhound dogs. Fentanyl plasma concentrations were determined by a liquid chromatography with mass spectrometry method. Non-compartmental pharmacokinetic analysis was used. Fentanyl was rapidly absorbed with a mean peak concentration (C(MAX)) of 3.56ng/mL at 0.24h. The mean terminal half-life, volume of distribution per bioavailability, and clearance per bioavailability were 2.97h, 7.09L/kg, 27.60mL/min/kg, respectively. Pain occurred on injection in all six dogs, but addition of 8.4% sodium bicarbonate (1mL per 20mL fentanyl) resulted in no pain on injection in 3/3 dogs but similar C(MAX) values. The subcutaneous route may be an alternative route of fentanyl administration if intravenous administration is not practical. PMID:21388844

  7. Physiologic and Pharmacokinetic Changes in Pregnancy

    Directory of Open Access Journals (Sweden)

    Maged eCostantine

    2014-04-01

    Full Text Available Physiologic changes in pregnancy induce profound alterations to the pharmacokinetic properties of many medications. These changes affect distribution, absorption, metabolism, and excretion of drugs, and thus may impact their pharmacodynamic properties during pregnancy. Pregnant women undergo several adaptations in many organ systems. Some adaptations are secondary to hormonal changes in pregnancy, while others occur to support the gravid woman and her developing fetus. Some of the changes in maternal physiology during pregnancy include, for example, increased maternal fat and total body water, decreased plasma protein concentrations, especially albumin, increased maternal blood volume, cardiac output and blood flow to the kidneys and uteroplacental unit, and decreased blood pressure. The maternal blood volume expansion occurs at a larger proportion than the increase in red blood cell mass, which results in physiologic anemia and hemodilution. Other physiologic changes include increased tidal volume, partially compensated respiratory alkalosis, delayed gastric emptying and gastrointestinal motility, and altered activity of hepatic drug metabolizing enzymes. Understating these changes and their profound impact on the pharmacokinetic properties of drugs in pregnancy is essential to optimize maternal and fetal health.

  8. Physiologic and pharmacokinetic changes in pregnancy.

    Science.gov (United States)

    Costantine, Maged M

    2014-01-01

    Physiologic changes in pregnancy induce profound alterations to the pharmacokinetic properties of many medications. These changes affect distribution, absorption, metabolism, and excretion of drugs, and thus may impact their pharmacodynamic properties during pregnancy. Pregnant women undergo several adaptations in many organ systems. Some adaptations are secondary to hormonal changes in pregnancy, while others occur to support the gravid woman and her developing fetus. Some of the changes in maternal physiology during pregnancy include, for example, increased maternal fat and total body water, decreased plasma protein concentrations, especially albumin, increased maternal blood volume, cardiac output, and blood flow to the kidneys and uteroplacental unit, and decreased blood pressure. The maternal blood volume expansion occurs at a larger proportion than the increase in red blood cell mass, which results in physiologic anemia and hemodilution. Other physiologic changes include increased tidal volume, partially compensated respiratory alkalosis, delayed gastric emptying and gastrointestinal motility, and altered activity of hepatic drug metabolizing enzymes. Understating these changes and their profound impact on the pharmacokinetic properties of drugs in pregnancy is essential to optimize maternal and fetal health. PMID:24772083

  9. Pharmacokinetics of rilmenidine in healthy subjects

    International Nuclear Information System (INIS)

    Rilmenidine is a novel alpha 2-adrenoceptor agonist, used in the treatment of mild or moderate hypertension at the oral dose of 1 mg once or twice daily. The pharmacokinetic parameters were investigated after single or repeated administration in healthy subjects, using labeled and unlabeled compounds. Rilmenidine was rapidly and extensively absorbed, with an absolute bioavailability factor close to 1 and a maximal plasma concentration achieved within 2 hours. Rilmenidine was not subject to presystemic metabolism. Distribution was independent of the free fraction because rilmenidine was weakly bound to plasma proteins (less than 10%). The volume of distribution was approximately 5 l.kg-1 (315 liters). Elimination was rapid with a total body plasma clearance of approximately 450 ml.min-1 and an elimination half-life of approximately 8 hours. Renal excretion was the major elimination process (two-thirds of the total clearance). Metabolism was very poor, with a renal elimination of rilmenidine as the parent drug (urinary fraction of rilmenidine was about 65% and no metabolite plasma levels were detected). Linear pharmacokinetics were demonstrated for rilmenidine from 0.5 to 2 mg but, at 3 mg, a slight deviation from linearity was observed. In repeated administration, the linear disposition of rilmenidine with dose was confirmed

  10. Population 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.

  11. 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.

  12. 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

  13. 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

  14. Dextran-PLGA-loaded docetaxel micelles with enhanced cytotoxicity and better pharmacokinetic profile.

    Science.gov (United States)

    Raza, Kaisar; Kumar, Nitesh; Misra, Charu; Kaushik, Lokesh; Guru, Santosh Kumar; Kumar, Pramod; Malik, Ruchi; Bhushan, Shashi; Katare, O P

    2016-07-01

    Docetaxel is one of the promising drugs and employed for the management of variety of cancers. However, challenges like poor-bioavailability, low tissue-permeability, compromised aqueous solubility and dose-dependent side-effects limit its clinical applications. Whereas, PLGA-based polymeric micelles possess the ability to enhance the tissue permeability of drugs and increase their biocompatibility. Henceforth, it was aimed to fabricate the dextran-PLGA-based polymeric-micelles loaded with docetaxel to explore the potential benefits in drug delivery. Dextran was chemically linked to PLGA and the linkage was confirmed by FT-IR, UV and NMR-spectroscopy. Critical-micelle-concentration of amphiphilic polymer was determined and drug was encapsulated by diffusion technique and erythrocyte compatibility. The system was evaluated for drug release profile and in vitro cytotoxicity studies. The pharmacokinetic profile was studied in rats. The micelles obtained were of 96.5±2.5nm and offered drug encapsulation of order of 54.85±1.21%.The cytotoxicity of drug against MCF-7 and MDA-MB-231 cell lines was enhanced by approx. 100%. The pharmacokinetic profile was substantially modified and about 16-folds enhancement in bioavailability was observed vis-à-vis plain drug. The approach was not only able to control the drug release, but also offered promise to enhance the pharmacokinetic and pharmacodynamic potential of docetaxel and similar anticancer agents. PMID:27037052

  15. Pharmacokinetics of high-dose intravenous melatonin in humans

    DEFF Research Database (Denmark)

    Andersen, Lars P H; Werner, Mads U; Rosenkilde, Mette Marie;

    2016-01-01

    This crossover study investigated the pharmacokinetics and adverse effects of high-dose intravenous melatonin. Volunteers participated in 3 identical study sessions, receiving an intravenous bolus of 10 mg melatonin, 100 mg melatonin, and placebo. Blood samples were collected at baseline and 0, 60......, 120, 180, 240, 300, 360, and 420 minutes after the bolus. Quantitative determination of plasma melatonin concentrations was performed using a radioimmunoassay technique. Pharmacokinetic parameters were estimated by a compartmental pharmacokinetic analysis. Adverse effects included assessments of...

  16. 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.

  17. Pharmacokinetic drug interactions with oral contraceptives.

    Science.gov (United States)

    Back, D J; Orme, M L

    1990-06-01

    Oral contraceptive steroids are used by an estimated 60 to 70 million women world-wide. Over the past 20 years there have been both case reports and clinical studies on the topic of drug interactions with these agents. Some of the interactions are of definite therapeutic relevance, whereas others can be discounted as being of no clinical significance. Pharmacological interactions between oral contraceptive steroids and other compounds may be of 2 kinds: (a) drugs may impair the efficacy of oral contraceptive steroids, leading to breakthrough bleeding and pregnancy (in a few cases, the activity of the contraceptive is enhanced); (b) oral contraceptive steroids may interfere with the metabolism of other drugs. A number of anticonvulsants (phenobarbital, phenytoin, carbamazepine) are enzyme-inducing agents and thereby increase the clearance of the oral contraceptive steroids. Valproic acid has no enzyme-inducing properties, and thus women on this anticonvulsant can rely on their low dose oral contraceptive steroids for contraceptive protection. Researchers are now beginning to unravel the molecular basis of this interaction, with evidence of specific forms of cytochrome P450 (P450IIC and IIIA gene families) being induced by phenobarbital. Rifampicin, the antituberculous drug, also induces a cytochrome P450 which is a product of the P450IIIA gene subfamily. This isozyme is one of the major forms involved in 2-hydroxylation of ethinylestradiol. Broad spectrum antibiotics have been implicated in causing pill failure; case reports document the interaction, and general practitioners are convinced that it is real. The problem remains that there is still no firm clinical pharmacokinetic evidence which indicates that blood concentrations of oral contraceptive steroids are altered by antibiotics. However, perhaps this should not be a surprise, given that the incidence of the interaction may be very low. It is suggested that an individual at risk will have a low bioavailability

  18. Cyclosporine pharmacokinetics in pancreas transplant recipients.

    Science.gov (United States)

    Munda, R; Schroeder, T J; Pedersen, S A; Clardy, C W; Wadhwa, N K; Myre, S A; Stephens, G W; Pesce, A J; Alexander, J W; First, M R

    1988-04-01

    Ten CsA pharmacokinetic studies were performed on five pancreas transplant recipients to determine proper doses and dosing intervals. These cadaver pancreas transplants were performed with exocrine ductal drainage into the urinary tract through a bladder anastomosis in four cases and into the bowel in one case. Four CsA pharmacokinetic studies were performed on diabetic renal transplant recipients and an additional six studies were performed while with pancreas transplant patients taking metoclopramide in an effort to enhance absorption of CsA. Mean CsA dose was 3.7 mg/kg/dose (range 2.1 to 7.5 mg/kg/dose). All patients but one were on twice daily dosing intervals yielding an average daily dose of 7.4 mg/kg/d. Noncompartmental pharmacokinetic analyses were used. The adequacy of a 1-, 2-, or 3-exponential model was determined by breakpoint analysis of the log concentration v time curve using the F statistic. The terminal rate constant was calculated by nonlinear regression analysis. The AUC and AUMC were calculated by the trapezoidal method with exponential extrapolation and these were used to calculate the MRT and Vdss. The unknown fractional absorption, F, was used to correct the oral data. The average CsA concentration maximum (Cmax) was 528 ng/mL with an average time to maximum concentration (Tmax) of 4.7 hours, a mean residence time of 7.75 hours, with a Vdss/%F of 9.61 L/kg in the pancreas transplant recipients. Additional studies of six patients receiving metoclopramide with CsA revealed an average Cmax of 723 ng/mL, an average Tmax of 2.3 hours, an average MRT of 6.08 hours, and an average Vdss/%F of 5.7% L/kg. These results indicate that coexistent gastroparesis in diabetic recipients of either pancreatic or renal transplants may result in reduced bioavailability of CsA. PMID:3284095

  19. Pharmacokinetics and interactions of headache medications, part I: introduction, pharmacokinetics, metabolism and acute treatments.

    Science.gov (United States)

    Sternieri, Emilio; Coccia, Ciro Pio Rosario; Pinetti, Diego; Ferrari, Anna

    2006-12-01

    Recent progress in the treatment of primary headaches has made available specific, effective and safe medications for these disorders, which are widely spread among the general population. One of the negative consequences of this undoubtedly positive progress is the risk of drug-drug interactions. This review is the first in a two-part series on pharmacokinetic drug-drug interactions of headache medications. Part I addresses acute treatments. Part II focuses on prophylactic treatments. The overall aim of this series is to increase the awareness of physicians, either primary care providers or specialists, regarding this topic. Pharmacokinetic drug-drug interactions of major severity involving acute medications are a minority among those reported in literature. The main drug combinations to avoid are: i) NSAIDs plus drugs with a narrow therapeutic range (i.e., digoxin, methotrexate, etc.); ii) sumatriptan, rizatriptan or zolmitriptan plus monoamine oxidase inhibitors; iii) substrates and inhibitors of CYP2D6 (i.e., chlorpromazine, metoclopramide, etc.) and -3A4 (i.e., ergot derivatives, eletriptan, etc.), as well as other substrates or inhibitors of the same CYP isoenzymes. The risk of having clinically significant pharmacokinetic drug-drug interactions seems to be limited in patients with low frequency headaches, but could be higher in chronic headache sufferers with medication overuse. PMID:17125411

  20. Circadian variation in the pharmacokinetics of verapamil

    DEFF Research Database (Denmark)

    Jespersen, C M; Frederiksen, M; Hansen, J F;

    1989-01-01

    Circadian variation in the metabolism of verapamil was investigated in 10 patients with stable angina pectoris during treatment with sustained-release verapamil 360 mg at 08.00 h or 22.0 h. No major difference in exercise parameters was found. During the evening dosage schedule a significantly...... greater bioavailability (AUC) and a prolonged time to peak concentration was found. During the night (24.00 h-06.00 h) the half-life of verapamil was significantly longer than during the day (16.00 h-22.00 h). These differences in pharmacokinetics may be due to reduced hepatic blood flow at night...... or to circadian variation in hepatic microsomal metabolism....

  1. Pharmacokinetics of hypoxic cell radiosensitizers: a review

    International Nuclear Information System (INIS)

    The comparative pharmacokinetics of various nitroimidazole radiosensitizers in different species are reviewed. Radiosensitization is dependent upon the tumor concentration at the time of radiotherapy, whereas host toxicity, including peripheral neuropathy, appears to be related to the tissue exposure or area under the curve (AUC). Nitroimidazoles penetrate lipoid membranes by passive diffusion, the rate increasing with lipophilicity. Derivatives more hydrophilic than misonidazole penetrate nervous tissues comparatively slowly. They are eliminated mainly by renal clearance. Most plasma data for intravenous radiosensitizers can be described by a two-compartment open model. But in the mouse, the kinetics of misonidazole are dose dependent with increasing apparent t1/2 and AUC at higher doses due to saturable Michaelis-Menten kinetics for metabolism

  2. Minocycline pharmacokinetics and pharmacodynamics in dogs

    DEFF Research Database (Denmark)

    Maaland, Marit Gaastra; Guardabassi, Luca; Papich, Mark G.

    2014-01-01

    BACKGROUND: Although minocycline is not licensed for use in dogs, this tetracycline has therapeutic potential against meticillin-resistant Staphylococcus pseudintermedius. HYPOTHESIS/OBJECTIVES: The aim of this study was to establish rational dosage recommendations for minocycline use in dogs....... Specific objectives were to generate and analyse minocycline pharmacokinetic (PK) data on plasma and interstitial fluid (ISF) concentrations, plasma protein binding and pharmacodynamic (PD) data on antimicrobial activity against S. pseudintermedius. ANIMALS: Six healthy dogs from a research colony were...... used in this study. METHODS: Dogs were administered 5 mg/kg intravenously and 10 mg/kg orally (p.o.) of minocycline hydrochloride in separate crossover experiments. In vivo drug concentrations in plasma and in ISF collected by ultrafiltration were measured by high-performance liquid chromatography...

  3. 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.

  4. 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

  5. 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

  6. Modulation of pharmacokinetics of theophylline by antofloxacin, a novel 8-amino-fluoroquinolone, in humans

    Institute of Scientific and Technical Information of China (English)

    Li LIU; Xian PAN; Hai-yan LIU; Xiao-dong LIU; Hui-wen YANG; Lin XIE; Jun-lin CHENG; Hong-wei FAN; Da-wei XIAO

    2011-01-01

    Aim:To evaluate the pharmacokinetic interactions between theophylline and antofloxacin in vivo and in vitro.Methods:A randomized,5-day treatment and 3-way crossover design was documented in 12 healthy subjects.The subjects were orally administered with antofloxacin (400 mg on d 1 and 200 mg on d 2 to 5),theophylline (100 mg twice a day and morning dose 200 mg on d 1 and 5),or theophylline plus antofloxacin.The plasma and urinary pharmacokinetics of antofloxacin and theophylline were characterized after the first and last dose.The effect of antofioxacin on theophylline metabolism was also investigated in pooled human liver microsomes.Results:The 5-day treatment with antofioxacin significantly increased the area of the plasma concentration-time curve and peak plasma concentration of theophylline,accompanied by a decrease in the excretion of theophylline metabolites.On the contrary,theophylline did not affect the pharmacokinetics of antofloxacin.In vitro studies using pooled human hepatic microsomes demonstrated that antofloxacin was a weak reversible and mechanism-based inhibitor of CYP1A2.The clinical interaction between theophylline and antofloxacin was further validated by the in vitro results.Conclusion:The results showed that antofloxacin increases the plasma theophylline concentration,partly by acting as a mechanismbased inhibitor of CYP1A2.

  7. 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

  8. 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

  9. Pharmacokinetics of azithromycin in the blue and gold macaw (Ara ararauna) after intravenous and oral administration.

    Science.gov (United States)

    Carpenter, James W; Olsen, John H; Randle-Port, Mary; Koch, David E; Isaza, Ramiro; Hunter, Robert P

    2005-12-01

    Azithromycin is classified as an azalide, a subclass of macrolide antimicrobials with a broad spectrum of activity in vitro against many potential bacterial pathogens including spirochetes, anaerobes, and Chlamydia trachomatis. Because of limited data on the use of azithromycin in avian medicine, this study was designed to determine the pharmacokinetics of azithromycin in blue and gold macaws (Ara ararauna), a species commonly seen in clinical practice. Azithromycin (10 mg/kg) was administered via crop lavage to five birds and intravenously to five birds, and blood samples were obtained at 0, 0.5, 1, 3, 6, 12, 24, 48, 72, and 96 hr post-azithromycin administration. Following a 4-wk washout period, the study was repeated with a complete crossover study performed. Concentration of azithromycin in plasma samples was quantified using a validated liquid chromatography/mass spectrometry assay. Pharmacokinetic parameters were determined using noncompartmental analysis. Based on the pharmacokinetic data generated from this study, a starting dose of azithromycin at 10 mg/kg p.o. every 48 hr for susceptible bacterial infections in blue and gold macaws is recommended. PMID:17312716

  10. Pharmacokinetics and tissue distribution of a novel PDE5 inhibitor,SK-3530, in rats

    Institute of Scientific and Technical Information of China (English)

    Hye-hyun YOO; Nam-sun KIM; Guang-jin Im; Dong-hyun KIM

    2007-01-01

    Aim: To investigate the pharmacokinetic profile and tissue distribution of a novel phosphodiesterase type 5 inhibitor, 5-ethyl-2-{5-[4-(2-hydroxy-ethyl)-piperazine-1-sulfonyl]-2-propoxy-phenyl }-7-propyl-3,5-dihydro-pyrrolo(3,2-d)pyrimidin-4-one (SK-3530), in rats after administration of the 14C-labeled compound. Methods:The pharmacokinetic parameters of SK-3530 were measured based on the total radioactivity and parent SK-3530 concentration in rat plasma after intravenous and oral administration. The tissue distribution of total radioactivity after a single oral administration of [14C]SK-3530 at a dose of 40 mg/kg was assayed. The plasma protein binding rates of SK-3530 were assessed by in vitro and ex vivo assay. Results: The total radioactivity profiles showed linear pharmacokinetics.The maximum plasma concentration and area under the curve of the parent SK3530 were 10%-20% compared to those of the total radioactivity. After the oral admin-istration of [14C]SK-3530, the radioactivity was widely distributed in all tissues,and the tissue/plasma ratio of the radioactivity 1 h after administration was calcu-lated as 0.5-2.6 with the exception of excretory organs. A relatively high penetra-tion was shown in the adrenal glands, liver, and lung. In vitro and ex vivo plasma protein binding assay by ultrafiltration showed a considerably high binding rate of more than 97%. Conclusion: SK-3530 was relatively well absorbed in the gas-trointestinal tract and showed linear pharmacokinetics over the investigated dose range. SK-3530 had low oral bioavailability due to a high, first-pass metabolism.

  11. Clinical Pharmacokinetics of Penicillins, Cephalosporins and Aminoglycosides in the Neonate: A Review

    Directory of Open Access Journals (Sweden)

    Gian Maria Pacifici

    2010-08-01

    Full Text Available Bacterial infections are common in the neonates and are a major cause of morbidity and mortality. Sixty percent of preterm infants admitted to neonatal intensive care units received at least one antibiotic during the first week of life. Penicillins, aminoglycosides and cephalosporins comprised 53, 43 and 16%, respectively. Kinetic parameters such as the half-life (t1/2, clearance (Cl, and volume of distribution (Vd change with development, so the kinetics of penicillins, cephalosporins and aminoglycosides need to be studied in order to optimise therapy with these drugs. The aim of this study is to review the pharmacokinetics of penicillins, cephalosporins and aminoglycosides in the neonate in a single article in order to provide a critical analysis of the literature and thus provide a useful tool in the hands of physicians. The bibliographic search was performed electronically using PubMed, as the search engine, until February 2nd, 2010. Medline search terms were as follows: pharmacokinetics AND (penicillins OR cephalosporins OR aminoglycosides AND infant, newborn, limiting to humans. Penicillins, cephalosporins and aminoglycosides are fairly water soluble and are mainly eliminated by the kidneys. The maturation of the kidneys governs the pharmacokinetics of penicillins, cephalosporins and aminoglycosides in the neonate. The renal excretory function is reduced in preterms compared to term infants and Cl of these drugs is reduced in premature infants. Gestational and postnatal ages are important factors in the maturation of the neonate and, as these ages proceed, Cl of penicillins, cephalosporins and aminoglycosides increases. Cl and t1/2 are influenced by development and this must be taken into consideration when planning a dosage regimen with these drugs. More pharmacokinetic studies are required to ensure that the dose recommended for the treatment of sepsis in the neonate is evidence based.

  12. 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...

  13. 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...

  14. 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...

  15. The intravenous pharmacokinetics of diminazene in healthy dogs

    OpenAIRE

    Naidoo, V.; M.S.G. Mulders; Swan, G E

    2009-01-01

    Diminazene remains one of South Africa's most commonly used antiprotozoal agents for the management of babesiosis in dogs . Although the drug has been on the market for over 40 years, its intravenous pharmacokinetics are poorly known. To better understand the pharmacokinetics of the drug Berenil®, it was reconstituted in sterile water and administered intravenously to 6 adult German shepherd dogs. All 6 dogs demonstrated the previously described secondary peak in the plasma concentration vers...

  16. Colistin Pharmacokinetics in Burn Patients during Continuous Venovenous Hemofiltration

    OpenAIRE

    Akers, Kevin S.; Rowan, Matthew P.; Niece, Krista L.; Stewart, Ian J.; Mende, Katrin; Cota, Jason M.; Murray, Clinton K.; Chung, Kevin K.

    2014-01-01

    While colistin is considered a last resort for the treatment of multidrug-resistant Gram-negative bacterial infections, there has been an increase in its use due to the increasing prevalence of drug-resistant infections worldwide. The pharmacology of colistin is complex, and pharmacokinetic data are limited, especially in patients requiring renal replacement therapy. As a result, dosing for patients who require renal replacement remains a challenge. Here, we present pharmacokinetic data for c...

  17. Pharmacokinetics and pharmacodynamics of nifedipine infusion in normal volunteers.

    OpenAIRE

    Walley, T J; Heagerty, A M; Woods, K. L.; Bing, R F; Pohl, J E; Barnett, D B

    1987-01-01

    Two studies of the pharmacokinetics and pharmacodynamics of intravenous nifedipine infusion were performed: the first, a randomised double-blind crossover study of nifedipine and its vehicle in eight subjects, the second a dose ranging study in nine subjects. Nifedipine pharmacokinetics did not vary with dose or duration of infusion up to 8 h, and are similar to those reported for other nifedipine preparations. Nifedipine increased heart rate and forearm blood flow and decreased blood pressur...

  18. 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.

  19. Bioavailability and Population Pharmacokinetics of Voriconazole in Lung Transplant Recipients▿

    OpenAIRE

    Han, K.; Capitano, B.; Bies, R.; Potoski, B. A.; Husain, S.; Gilbert, S; Paterson, D. L.; McCurry, K.; Venkataramanan, R.

    2010-01-01

    This study was undertaken to characterize the pharmacokinetics and bioavailability of voriconazole in adult lung transplant patients during the early postoperative period, identify factors significantly associated with various pharmacokinetic parameters, and make recommendations for adequate dosing regimens. Thirteen lung transplant patients received two intravenous infusions (6 mg/kg, twice daily [b.i.d.]) immediately posttransplant followed by oral doses (200 mg, b.i.d.) for prophylaxis. Bl...

  20. Absorption and pharmacokinetics of grapefruit flavanones in beagles

    OpenAIRE

    Mata Bilbao, María de Lourdes; Andrés Lacueva, Ma. Cristina; Roura, Elena; Jáuregui Pallarés, Olga; Escribano Ferrer, Elvira; Torre, Celina; Lamuela Raventós, Rosa Ma.

    2007-01-01

    The present study evaluated the pharmacokinetics of three different grapefruit flavanone forms in dog plasma and demonstrated their absorption after an oral intake of a grapefruit extract; pharmacokinetic parameters of these forms were also determined. Ten healthy beagles were administered 70 mg citrus flavonoids as a grapefruit extract contained in capsules, while two additional dogs were used as controls and given an excipient. The grapefruit flavanone naringin, along with its metabolites n...

  1. In vivo pharmacokinetic studies of prodrugs of ibuprofen

    Directory of Open Access Journals (Sweden)

    Doshi Abha

    2007-01-01

    Full Text Available In vivo pharmacokinetic studies of N-Mannich base derivatives of ibuprofenamide as prodrugs were performed on rabbits. Ibuprofen and both the prodrugs (IBMB-M and IBMB-P were administered orally and at different time intervals blood samples were collected and assayed for ibuprofen and ibuprofenamide by HPLC method. From the plasma concentration-time profile; (C p max , t max , AUC and the time required to achieve minimum effective concentration were calculated. N-Mannich base prodrugs first get hydrolyzed to ibuprofenamide which in turn gets hydrolyzed to ibuprofen by the enzyme amidase. The (C p max and AUC values of IBMB-M were found to be more compared to IBMB-P. In both the cases ibuprofen started appearing after 2 h and it required minimum 4 h to get the ibuprofen in therapeutic range. Both the prodrugs released ibuprofen slowly which gave sustained effect. IBMB-M provided ibuprofen in therapeutic range for 48 h and IBMB-P for 24 h.

  2. 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

  3. Pharmacokinetically guided dose adjustment of 5-fluorouracil: a rational approach to improving therapeutic outcomes.

    Science.gov (United States)

    Saif, M Wasif; Choma, Adrienne; Salamone, Salvatore J; Chu, Edward

    2009-11-18

    Chemotherapy dosing of the fluoropyrimidine 5-fluorouracil (5-FU) is currently based on body surface area. However, body surface area-based dosing has been associated with clinically significant pharmacokinetic variability, and as such, dosing based on body surface area may be of limited use. The clinical activity of 5-FU is modest at standard doses, and in general, dosing is limited by the safety profile, with myelosuppression and gastrointestinal toxicity being the most commonly observed side effects. Various strategies have been developed to enhance the clinical activity of 5-FU, such as biochemical modulation, alterations in scheduling of administration, and the use of oral chemotherapy. Studies that have shown an association between plasma concentration with toxicity and clinical efficacy have shown that pharmacokinetically guided dose adjustments can substantially improve the therapeutic index of 5-FU treatment. These studies have shown that only 20%-30% of patients treated with a 5-FU-based regimen have 5-FU levels that are in the appropriate therapeutic range--approximately 40%-60% of patients are underdosed and 10%-20% of patients are overdosed. To date, 5-FU drug testing has not been widely used because of the lack of a simple, fast, and inexpensive method. Recent advances in testing based on liquid chromatography-mass spectroscopy and a nanoparticle antibody-based immunoassay for 5-FU may now allow for routine monitoring of 5-FU in clinical practice. We review the data on pharmacokinetically guided dose adjustment of 5-FU and discuss the potential of this approach to advance therapeutic outcomes. PMID:19841331

  4. Determination of ifenprodil by LC–MS/MS and its application to a pharmacokinetic study in healthy Chinese volunteers

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    Jing Yang

    2013-05-01

    Full Text Available This paper reports the development and validation of an assay for ifenprodil based on liquid chromatography–tandem mass spectrometry (LC–MS/MS and its application to a pharmacokinetic study involving single and multiple intravenous infusions to healthy Chinese volunteers. After sample preparation of plasma by liquid–liquid extraction with ethyl acetate, the analyte and internal standard, urapidil, were separated by reversed phase chromatography in a run time of 4 min and detected by positive ion electrospray ionization followed by multiple reaction monitoring of the precursor-to-product ion transitions at m/z 326.2→308.1 for ifenprodil and m/z 388.4→205.3 for IS. The assay was linear in the concentration range 0.2–50.0 ng/mL with recovery >76.4%. In the pharmacokinetic study of single intravenous infusions of 5, 10 and 15 mg ifenprodil, peak plasma concentrations and areas under the plasma concentration–time curve were both linearly related to dose. In the pharmacokinetic study of multiple once daily intravenous infusions of 10 mg ifenprodil for 7 days, pharmacokinetic parameters were similar to those after the single dose showing that ifenprodil does not accumulate on repeated administration.

  5. Pharmacokinetic herb-drug interactions with traditional Chinese medicine: progress, causes of conflicting results and suggestions for future research.

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    Ma, Bing-Liang; Ma, Yue-Ming

    2016-02-01

    Traditional Chinese medicine (TCM) has a long history of medical use in China and is still used worldwide. Unexpected herb-drug interactions (HDIs) may lead to adverse drug reactions or loss of therapeutic efficacy of the victim drug. Here, based on searches of Medline, EBSCO, Science Direct and Web of Science using various keywords, we summarize the TCM-derived pharmacokinetic HDIs that were reported from 1990 to 2015 and discuss the underlying mechanisms. In general, many pre-clinical and clinical pharmacokinetic HDIs have been reported. Our searches show that TCMs cause pharmacokinetic interactions with therapeutic drugs mainly by inhibiting or inducing drug-metabolizing enzymes and transporters. However, most of the interactions result from a small number of prescription medications and the actual potential for harm is low. Moreover, such HDIs can be avoided by discontinuing the TCMs. Despite the extensive number of reports on TCM-derived HDIs, the findings are frequently conflicting and can be confusing. The causes of the conflicts vary, but we classified them into three basic categories as follows: (1) complicated nature and poor quality control of TCMs, (2) different responses of various test systems to TCM exposure and (3) diverse study designs. Accordingly, we propose rational study designs for future HDI research. We also propose that a specific authoritative guide be established that provides recommendations for HDI studies. This review provides insights into the progress and challenges in TCM-derived pharmacokinetic HDI research. PMID:26915920

  6. Population pharmacokinetic analysis of voriconazole from a pharmacokinetic study with immunocompromised Japanese pediatric subjects.

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    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 modifications. Bayesian priors were applied to this analysis by using the NONMEM routine NWPRI, which allowed priors for the fixed-effect parameter vector and variance matrix of the random-effect parameters to be a normal distribution and an inverse Wishart distribution, respectively. Large intersubject variabilities in oral bioavailability and voriconazole exposure were observed in these pediatric subjects. The mean oral bioavailability estimated in Japanese pediatric subjects was 73% (range, 17% to 99%), which is consistent with the reported estimates of 64% in the previous model and less than what was originally estimated for healthy adults-96%. Voriconazole exposures in Japanese pediatric subjects were generally comparable to those in non-Japanese pediatric subjects receiving the same dosing regimens, given the large intersubject variability. Consistent with the previous findings, the CYP2C19 genotyping status did not have a clinically relevant effect on voriconazole exposure in Japanese pediatric subjects, although it was identified as a covariate in the model to help explain the intersubject variability in voriconazole exposure. The CYP2C19 genotyping status alone does not warrant dose adjustment of voriconazole. No other factors besides age and weight were identified to explain the PK variability of voriconazole. PMID:25801557

  7. Simultaneous magnetic resonance imaging and pharmacokinetic analysis of intramuscular depots.

    Science.gov (United States)

    Probst, Mareike; Kühn, Jens-Peter; Scheuch, Eberhard; Seidlitz, Anne; Hadlich, Stefan; Evert, Katja; Oswald, Stefan; Siegmund, Werner; Weitschies, Werner

    2016-04-10

    The present pilot study introduces a method that might give novel insights in drug absorption processes from intramuscularly administered depots. An oily suspension or an aqueous solution of paracetamol (6 mg/kg body mass), prednisolone or its hemisuccinate sodium salt for the aqueous solutions (10mg/kg body mass) or diclofenac (10mg/kg body mass) was injected into the muscle tissue of the hind leg of female Lewis-rats (n=47). For the oily suspensions the micronized particles were suspended in medium-chain triglycerides. The aqueous solutions were buffered to a pH of 7.4 ± 0.5. Polyethylene glycol was added as a cosolvent in the formulations containing paracetamol (acetaminophen) and diclofenac and sodium chloride was added to the aqueous solutions of prednisolone hemisuccinate sodium to achieve nearly isotonic formulations. The formed depot was visualized by magnetic resonance imaging (MRI) and characterized with regard to volume and surface area. A 7 T-small animal scanner was used and T1-weighted and T2-weighted sequences including a fat saturation were performed. Simultaneously blood samples were taken and the drugs were quantitatively analyzed. The water based solvent and the oily dispersion agent were visible in the MRI images without the use of contrast agents. Since a free hand injection mostly led to an application directly into the fascia, resulting in a fast removal of the depot, MRI-guided injection was conducted. Comparing pharmacokinetic data with MRI data it was observed that maximal blood levels occurred before the solvent and the dispersion agent were removed from the muscle tissue. Thus, the drug is not absorbed together with the depot. Furthermore, no correlation was found between the shape of the depot and the rate of absorption. Consequently, a higher surface area or volume of the depot did not result in a faster release or absorption of the drugs from the tested formulations. In contrast to the paracetamol and prednisolone formulations the

  8. Pharmacokinetics of Ethanol - Issues of Forensic Importance.

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    Jones, A W

    2011-07-01

    A reliable method for the quantitative analysis of ethanol in microvolumes (50-100 μL) of blood became available in 1922, making it possible to investigate the absorption, distribution, metabolism, and excretion (ADME) of ethanol in healthy volunteers. The basic principles of ethanol pharmacokinetics were established in the 1930s, including the notion of zero-order elimination kinetics from blood and distribution of the absorbed dose into the total body water. The hepatic enzyme alcohol dehydrogenase (ADH) is primarily responsible for the oxidative metabolism of ethanol. This enzyme was purified and characterized in the early 1950s and shown to have a low Michaelis constant (km), being about ~0.1 g/L. Liver ADH is therefore saturated with substrate after the first couple of drinks and for all practical purposes the concentration-time (C-T) profiles of ethanol are a good approximation to zero-order kinetics. However, because of dose-dependent saturation kinetics, the entire postabsorptive declining part of the blood-alcohol concentration (BAC) curve looks more like a hockey stick rather than a straight line. A faster rate of ethanol elimination from blood in habituated individuals (alcoholics) is explained by participation of a high km microsomal enzyme (CYP2E1), which is inducible after a period of chronic heavy drinking. Owing to the combined influences of genetic and environmental factors, one expects a roughly threefold difference in elimination rates of ethanol from blood (0.1-0.3 g/L/h) between individuals. The volume of distribution (Vd) of ethanol, which depends on a person's age, gender, and proportion of fat to lean body mass, shows a twofold variation between individuals (0.4-0.8 L/kg). This forensic science review traces the development of forensic pharmacokinetics of ethanol from a historical perspective, followed by a discussion of important issues related to the disposition and fate of ethanol in the body, including (a) quantitative evaluation of

  9. Population pharmacokinetics of olprinone in healthy male volunteers

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    Kunisawa T

    2014-03-01

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

  10. 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

  11. Pharmacokinetics, Pharmacodynamics and Pharmacogenomics of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I.

    Science.gov (United States)

    McCune, Jeannine S; Bemer, Meagan J

    2016-05-01

    Although immunosuppressive treatments and target concentration intervention (TCI) have significantly contributed to the success of allogeneic haematopoietic cell transplantation (alloHCT), there is currently no consensus on the best immunosuppressive strategies. Compared with solid organ transplantation, alloHCT is unique because of the potential for bidirectional reactions (i.e. host-versus-graft and graft-versus-host). Postgraft immunosuppression typically includes a calcineurin inhibitor (cyclosporine or tacrolimus) and a short course of methotrexate after high-dose myeloablative conditioning, or a calcineurin inhibitor and mycophenolate mofetil after reduced-intensity conditioning. There are evolving roles for the antithymyocyte globulins (ATGs) and sirolimus as postgraft immunosuppression. A review of the pharmacokinetics and TCI of the main postgraft immunosuppressants is presented in this two-part review. All immunosuppressants are characterized by large intra- and interindividual pharmacokinetic variability and by narrow therapeutic indices. It is essential to understand immunosuppressants' pharmacokinetic properties and how to use them for individualized treatment incorporating TCI to improve outcomes. TCI, which is mandatory for the calcineurin inhibitors and sirolimus, has become an integral part of postgraft immunosuppression. TCI is usually based on trough concentration monitoring, but other approaches include measurement of the area under the concentration-time curve (AUC) over the dosing interval or limited sampling schedules with maximum a posteriori Bayesian personalization approaches. Interpretation of pharmacodynamic results is hindered by the prevalence of studies enrolling only a small number of patients, variability in the allogeneic graft source and variability in postgraft immunosuppression. Given the curative potential of alloHCT, the pharmacodynamics of these immunosuppressants deserves to be explored in depth. Development of

  12. Antimicrobial breakpoint estimation accounting for variability in pharmacokinetics

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    Nekka Fahima

    2009-06-01

    Full Text Available Abstract Background Pharmacokinetic and pharmacodynamic (PK/PD indices are increasingly being used in the microbiological field to assess the efficacy of a dosing regimen. In contrast to methods using MIC, PK/PD-based methods reflect in vivo conditions and are more predictive of efficacy. Unfortunately, they entail the use of one PK-derived value such as AUC or Cmax and may thus lead to biased efficiency information when the variability is large. The aim of the present work was to evaluate the efficacy of a treatment by adjusting classical breakpoint estimation methods to the situation of variable PK profiles. Methods and results We propose a logical generalisation of the usual AUC methods by introducing the concept of "efficiency" for a PK profile, which involves the efficacy function as a weight. We formulated these methods for both classes of concentration- and time-dependent antibiotics. Using drug models and in silico approaches, we provide a theoretical basis for characterizing the efficiency of a PK profile under in vivo conditions. We also used the particular case of variable drug intake to assess the effect of the variable PK profiles generated and to analyse the implications for breakpoint estimation. Conclusion Compared to traditional methods, our weighted AUC approach gives a more powerful PK/PD link and reveals, through examples, interesting issues about the uniqueness of therapeutic outcome indices and antibiotic resistance problems.

  13. 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.

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

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    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.

  15. Validity of a two-point acetaminophen pharmacokinetic study.

    Science.gov (United States)

    Scavone, J M; Greenblatt, D J; Blyden, G T; Luna, B G; Harmatz, J S

    1990-01-01

    The pharmacokinetics of a single 650-mg intravenous dose of acetaminophen were determined in 82 volunteers using multiple (13 or more) plasma acetaminophen concentrations measured by high pressure liquid chromatography during 24 h after dosage. Kinetic values from the complete study were compared with kinetic estimates based on only two data points: (a) the 2- and 6-h points only; and (b) the 3 and 6-h points only. For elimination half-life, values from the complete study (mean 2.42 h) were highly correlated (r = 0.87 and 0.84) with methods a and b (means 2.41 and 2.43 h), with regression slopes of 1.00 and 0.99, respectively. For clearance, the complete study values (mean 312 ml/min) were highly correlated (r = 0.97 and 0.97) with method a and b values, but both two-point methods significantly overestimated clearance (means 350 and 355 ml/min) by an average of 13 and 14%, respectively. Results for volume of distribution were similar to those for clearance. Although acetaminophen elimination half-life can be estimated with reasonable precision using a two-point blood-sampling procedure, clearance and volume of distribution values using the two-point method overestimate the actual values. PMID:2305419

  16. Population pharmacokinetics of levofloxacin in Korean patients.

    Science.gov (United States)

    Kiem, Sungmin; Ryu, Sung-Mun; Lee, Yun-Mi; Schentag, Jerome J; Kim, Yang-Wook; Kim, Hyeon-Kuk; Jang, Hang-Jae; Joo, Yong-Don; Jin, Kyubok; Shin, Jae-Gook; Ghim, Jong-Lyul

    2016-08-01

    Levofloxacin (LVFX) has different effects depending on the area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC) ratio. While AUC can be expressed as dose/clearance (CL), we measured serial concentrations of LVFX in Koreans and tried to set a Korean-specific equation, estimating the CL of the antibiotic. In total, 38 patients, aged 18-87 years, received once daily intravenous LVFX doses of 500 mg or 250 mg, depending on their renal function. Four plasma samples were obtained according to a D optimal sampling design. The population pharmacokinetic (PK) parameters of LVFX were estimated using non-linear mixed-effect modeling (NONMEM, ver. 7.2). The CL of LVFX was dependent on creatinine clearance (CLCR) as a covariate. The mean population PK parameters of LVFX in Koreans were as follows: CL (l/hour) = 6.19 ×  (CLCR/75)(1.32). The CL of LVFX in Koreans is expected to be lower than that in Western people. PMID:25976699

  17. Pharmacokinetic interaction of intravenous fentanyl with ketoconazole.

    Science.gov (United States)

    Ziesenitz, Victoria C; König, Sonja K; Mahlke, Nina S; Skopp, Gisela; Haefeli, Walter E; Mikus, Gerd

    2015-06-01

    Fentanyl is primarily metabolized by CYP3A, but has also been suggested to act as a weak inhibitor of CYP3A. We investigated the influence of CYP3A inhibition by ketoconazole on the pharmacokinetics of intravenously administered fentanyl and the effect of fentanyl on CYP3A activity. A prospective, open-label, randomized, monocentre, crossover study was conducted in 16 healthy volunteers. They received fentanyl alone (5 microgram per kilogram) or fentanyl plus ketoconazole (200 milligram orally B.I.D. over 2 days). Naloxone (2 × 0.2 milligram i.v.) was given simultaneously with fentanyl to mitigate any opioid effect. Midazolam was administered as a CYP3A probe drug. Fentanyl and its metabolites were quantified by LC/MS/MS in blood and urine samples obtained over 24 hour. Exposure of fentanyl (AUC0- ∞ ) was significantly increased to 133% and systemic clearance was reduced to 78% by ketoconazole, norfentanyl formation was significantly delayed and partial metabolic clearance decreased to 18%. Fentanyl had no influence on midazolam exposure and CYP3A activity whereas ketoconazole decreased CYP3A activity to 13%. Although fentanyl N-dealkylation is substantially inhibited by ketoconazole, exposure of fentanyl itself increased by one third only. Clinically fentanyl dosage adjustments may become necessary when ketoconazole or other strong CYP3A inhibitors are given simultaneously. Fentanyl itself does not influence CYP3A activity. PMID:25651378

  18. Pharmacokinetics and drug interactions of eslicarbazepine acetate.

    Science.gov (United States)

    Bialer, Meir; Soares-da-Silva, Patricio

    2012-06-01

    Eslicarbazepine acetate (ESL) is a novel once-daily antiepileptic drug (AED) approved in Europe since 2009 that was found to be efficacious and well tolerated in a phase III clinical program in adult patients with partial onset seizures previously not controlled with treatment with one to three AEDs, including carbamazepine (CBZ). ESL shares with CBZ and oxcarbazepine (OXC) the dibenzazepine nucleus bearing the 5-carboxamide substitute, but is structurally different at the 10,11 position. This molecular variation results in differences in metabolism, preventing the formation of toxic epoxide metabolites such as carbamazepine-10,11-epoxide. Unlike OXC, which is metabolized to both eslicarbazepine and (R)-licarbazepine, ESL is extensively converted to eslicarbazepine. The systemic exposure to eslicarbazepine after ESL oral administration is approximately 94% of the parent dose, with minimal exposure to (R)-licarbazepine and OXC. After ESL oral administration, the effective half-life (t(1/2,eff) ) of eslicarbazepine was 20-24 h, which is approximately two times longer than its terminal half-life (t(1/2)). At clinically relevant doses (400-1,600 mg/day) ESL has linear pharmacokinetics (PK) with no effects of gender or moderate liver impairment. However, because eslicarbazepine is eliminated primarily (66%) by renal excretion, dose adjustment is recommended for patients with renal impairment. Eslicarbazepine clearance is induced by phenobarbital, phenytoin, and CBZ and it dose-dependently decreases plasma exposure of oral contraceptive and simvastatin. PMID:22612290

  19. Pharmacokinetics and biodegradation of chitosan in rats

    Science.gov (United States)

    Li, Hui; Jiang, Zhiwen; Han, Baoqin; Niu, Shuyi; Dong, Wen; Liu, Wanshun

    2015-10-01

    Chitosan, an excellent biomedical material, has received a widespread in vivo application. In contrast, its metabolism and distribution once being implanted were less documented. In this study, the pharmacokinetics and biodegradation of fluorescein isothiocyanate (FITC) labeled and muscle implantation administrated chitosan in rats were investigated with fluorescence spectrophotometry, histological assay and gel chromatography. After implantation, chitosan was degraded gradually during its distribution to diverse organs. Among the tested organs, liver and kidney were found to be the first two highest in chitosan content, which was followed by heart, brain and spleen. Urinary excretion was believed to be the major pathway of chitosan elimination, yet 80% of chitosan administered to rats was not trackable in their urine. This indicated that the majority of chitosan was degraded in tissues. In average, the molecular weight of the degradation products of chitosan in diverse organs and urine was found to be <65 kDa. This further confirmed the in vivo degradation of chitosan. Our findings provided new evidences for the intensive and safe application of chitosan as a biomedical material.

  20. Pharmacokinetics and biotransformation of tea polyphenols.

    Science.gov (United States)

    Qiao, Jinping; Kong, Xiangyi; Kong, Aiying; Han, Mei

    2014-01-01

    Tea is an infusion of the leaves of the Camellia sinensis plant and is the most widely consumed beverage in the world after water. The main chemical components in teas are phenolic compounds (tea polyphenols, mainly tea catechins). A large number of in vitro and in vivo scientific studies have supported that the tea polyphenols can provide a number of health benefits such as, reducing the incidence of coronary heart disease, diabetes and cancer. Recently, tea polyphenols have proven highly attractive as lead compounds for drug discovery programs. A clear understanding of chemistry, stability, pharmacokinetics and metabolic fate of tea will be significant to elucidate many medicinal effects by biochemical theory and pharmaceutical development. This article reviews the current literature on the pharmacoknetics and biotransformation of tea catechins. The half-lives of tea polyphenols are 2-4h and their absorption and elimination are rapid in humans. The peak times (tmax) are 1 and 3 h after oral administration and the peak plasma concentrations are low μM range. It has been reported that catechins are easily metabolized by enzyme and microbe, and the main metabolic pathways are methylation, glucuronidation, sulfation, ring-fission metabolism, and so on. The information is important to discuss some of the challenges and benefits of pursuing this family of compounds for drug discovery. PMID:24527703

  1. Pharmacokinetics of bacmecillinam and pivmecillinam in volunteers.

    Science.gov (United States)

    Josefsson, K; Bergan, T; Magni, L; Pring, B G; Westerlund, D

    1982-01-01

    The pharmacokinetics of bacmecillinam and pivmecillinam were studied in healthy fasting volunteers given tablets in a cross-over, randomized order. The mean (+/- SD) peak levels of plasma mecillinam were 1.43 +/- 0.34, 2.73 +/- 0.43, and 4.62 +/- 1.41 mg/l after bacmecillinam 100, 200, and 400 mg and 2.38 +/- 0.65 mg/l after pivmecillinam 400 mg. The corresponding areas under plasma Vs time curves (AUC) were 2.21 +/- 0.19, 3.99 +/- 0.63, and 7.74 +/- 1.38 mg . h. l-1 for bacmecillinam and 5.35 +/- 0.93 mg . h. l-1 for pivmecillinam. The elimination half-lives were 0.8-1.1 h for bacmecillinam and 0.7 h for pivmecillinam. The 12 h urinary recovery of unchanged mecillinam after the 400 mg doses was 41% for bacmecillinam and 30% for pivmecillinam. The 400 mg dose of bacmecillinam gave a significantly higher plasma peak (p less than 0.001), AUC (p less than 0.001) and urinary recovery (p less than 0.001) than did pivmecillinam 400 mg. The plasma peaks appeared earlier and the rate of absorption was higher after bacmecillinam than after pivmecillinam (p less than 0.05). In conclusion, bacmecillinam had a better bioavailability than pivmecillinam in the tablet formulations studied. The AUC increased linearly with increasing doses of bacmecillinam. PMID:6293834

  2. Pharmacokinetics of azithromycin in rats and dogs.

    Science.gov (United States)

    Shepard, R M; Falkner, F C

    1990-01-01

    After intravenous or oral administration to rats and dogs, azithromycin was rapidly distributed into the tissues, where concentrations frequently exceeded those in serum by 100-fold or more within 24 h of a single dose. Tissue concentrations were proportional to the dose following single administrations of 10 to 40 mg/kg in rats and dogs. Tissue concentrations were higher after multiple dosing and became greater as the dose was increased from 10 to 40 mg/kg. Elimination half-lives were similar in most tissues and were about 40 h in rats after seven doses of 20 mg/kg and about 90 h in dogs after five doses of 30 mg/kg. Serum concentrations declined in a multi-exponential manner, reflecting initial rapid distribution into tissues and then slow return to serum from tissues. Azithromycin had good oral bioavailability in rats and dogs (46% and 97%, respectively). Rapid uptake of azithromycin by tissues from serum and slow redistribution from tissues to serum are apparently factors governing the pharmacokinetics of azithromycin in rats and dogs. Serum concentrations do not reflect the availability of azithromycin in tissues. PMID:2154438

  3. Computational Systems Chemical Biology

    OpenAIRE

    Oprea, Tudor I.; May, Elebeoba E.; Leitão, Andrei; Tropsha, Alexander

    2011-01-01

    There is a critical need for improving the level of chemistry awareness in systems biology. The data and information related to modulation of genes and proteins by small molecules continue to accumulate at the same time as simulation tools in systems biology and whole body physiologically-based pharmacokinetics (PBPK) continue to evolve. We called this emerging area at the interface between chemical biology and systems biology systems chemical biology, SCB (Oprea et al., 2007).

  4. A framework incorporating the impact of exposure scenarios and application conditions on risk assessment of chemicals applied to skin

    OpenAIRE

    Dancik, Yuri; Troutman, John A; Jaworska, Joanna

    2013-01-01

    Purpose 1. To develop a framework for exposure calculation via the dermal route to meet the needs of 21st century toxicity testing and refine current approaches; 2. To demonstrate the impact of exposure scenario and application conditions on the plasma concentration following dermal exposure. Method A workflow connecting a dynamic skin penetration model with a generic whole-body physiologically-based pharmacokinetic (PBPK) model was developed. The impact of modifying exposure scenarios and ap...

  5. Study to Evaluate the Effect of Rifampicin, Ketoconazole, and Omeprazole on the Pharmacokinetics of Sativex

    Science.gov (United States)

    2013-06-13

    Evaluation of Pharmacokinetics of Sativex in the Absence and Presence of a Known Inducer of CYP3A4; Evaluation of Pharmacokinetics of Sativex in the Absence and Presence of a Potent Inhibitor of CYP3A4; Evaluation of Pharmacokinetics of Sativex in the Absence and Presence of a CYP2C19 Inhibitor.

  6. 78 FR 73199 - Draft Guidance for Industry on Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs...

    Science.gov (United States)

    2013-12-05

    ... Pharmacokinetic Endpoints for Drugs Submitted Under an Abbreviated New Drug Application; Availability AGENCY: Food... Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA.'' This guidance provides recommendations to... Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA.'' The guidance is applicable...

  7. Cardiovascular Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics for the Clinical Practitioner.

    Science.gov (United States)

    Sleder, Anna T; Kalus, James; Lanfear, David E

    2016-01-01

    Current clinical cardiovascular practice requires a clinician to have a strong foundation in multiple aspects of pharmacology. Modern cardiovascular regimens are complex, and optimal management, application of evolving guidelines, and adoption of new therapies build off a more basic understanding of pharmacokinetics and pharmacodynamics. In addition, it is likely time to add a third pillar into this discussion, the expanding field of pharmacogenomics referring to the genetic influences on drug response. This field has increasing applications in medicine and clearly holds significant promise for cardiovascular disease management. Awareness of pharmacogenomic advances and the fundamentals of pharmacokinetics and pharmacodynamics can help the clinician more easily deliver great care. Here we attempt to briefly summarize and simplify key concepts of pharmacokinetics, pharmacodynamics, and pharmacogenomics relevant to the cardiovascular disease practitioner. PMID:26054891

  8. Pharmacokinetics of ractopamine and its organ distribution in rats.

    Science.gov (United States)

    Ho, Jing-Kai; Huo, Teh-Ia; Lin, Lie-Chwen; Tsai, Tung-Hu

    2014-09-24

    Ractopamine, a β-agonist, is used to increase the proportion of lean meat in livestock. However, due to potential cardiovascular risks, ractopamine has been banned for use in food-producing animals in many countries. Nevertheless, pharmacokinetic studies of ractopamine have not been completed. The aim of this study was to develop a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the determination of ractopamine. This validated method was used to investigate the pharmacokinetics and organ distribution of ractopamine in rats. The validation results complied with the U.S. Food and Drug Administration's standards. The oral bioavailability of ractopamine was 2.99%. After intravenous administration, ractopamine concentrations varied as follows: kidney > lung > spleen > heart > liver > muscle > plasma > brain. Nonlinear pharmacokinetics and strong partitioning into tissues were observed after intravenous administration of ractopamine. These effects may be due to nonlinear elimination via the kidney. PMID:25207456

  9. 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...

  10. The Brain and Propranolol Pharmacokinetics in the Elderly

    Science.gov (United States)

    Eugene, Andy R.; Nicholson, Wayne T.

    2015-01-01

    Propranolol, a non-selective β-blocker, has been found to have a tremendous array of indications. Recent evidence has suggested that propranolol may be effective in patients suffering from post-traumatic stress disorder by suppressing activity in the amygdala and thereby inhibiting emotional memory formation. Dosage requirements have been well established in the pediatric and adult population, however, there has been no definitive geriatric dose recommended in the package inserts made available to the public. The aim of this paper is to use pharmacokinetic simulations in order to establish a pharmacokinetic profile dosage equivalent for the elderly as has been found in young patients. After completing the Monte-Carlo simulations for the elderly and young patients, a single 10mg dose in the elderly has shown comparable pharmacokinetic profiles as found in young patients administered a 40mg single dose. PMID:26609425

  11. Pharmacokinetics of oral and intravenous melatonin in healthy volunteers

    DEFF Research Database (Denmark)

    Andersen, Lars P H; Werner, Mads U; Rosenkilde, Mette M;

    2016-01-01

    BACKGROUND: The aim was to investigate the pharmacokinetics of oral and iv melatonin in healthy volunteers. METHODS: The study was performed as a cohort crossover study. The volunteers received either 10 mg oral melatonin or 10 mg intravenous melatonin on two separate study days. Blood samples were...... collected at different time points following oral administration and short iv infusion, respectively. Plasma melatonin concentrations were determined by RIA technique. Pharmacokinetic analyses were performed by "the method of residuals" and compartmental analysis. The pharmacokinetic variables: k a, t 1....../2 absorption, t max, C max, t 1/2 elimination, AUC 0-∞, and bioavailability were determined for oral melatonin. C max, t 1/2 elimination, V d, CL and AUC 0-∞ were determined for intravenous melatonin. RESULTS: Twelve male volunteers completed the study. Baseline melatonin plasma levels did not differ...

  12. 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...

  13. Pharmacokinetic Analysis of (64)Cu-ATSM Dynamic PET in Human Xenograft Tumors in Mice

    DEFF Research Database (Denmark)

    Li, Fan; Jørgensen, Jesper Tranekjær; Madsen, Jacob; Kjaer, Andreas

    2015-01-01

    PET scans with (64)Cu-ATSM and CT scans with contrast. Irreversible and reversible two-tissue compartment models were fitted to time activity curves (TACs) obtained from whole tumor volumes and compared using the Akaike information criterion (AIC). Based on voxel-wise pharmacokinetic analysis...... early tracer uptake (mean spearman R = 0.88) 5 min post injection (pi). Moreover, positive relationships were found between late tracer uptake (90 min pi) and both k₃ and the net influx rate constant, Ki (mean spearman R = 0.56 and R = 0.86; respectively). CONCLUSION: This study shows the feasibility to...

  14. Pharmacokinetics of heparin and related polysaccharides

    Energy Technology Data Exchange (ETDEWEB)

    Boneu, B.; Dol, F.; Caranobe, C.; Sie, P.; Houin, G.

    1989-01-01

    The pharmacodynamic profile of standard heparin (SH), a low molecular weight derivative (CY 216) and of dermatan sulfate (DS), a new potential antithrombotic drug, was investigated in the rabbit over a large range of doses. After bolus i.v. injection of low doses, the biological activity of SH disappeared exponentially; however, its half-life was prolonged when the dose injected increased, and over 158 micrograms/kg (100 anti-factor Xa U/kg) the biological activity disappeared as a concave-convex curve. CY 216 disappeared more slowly than SH at low doses but faster than SH at higher doses. More than 90% of the DS biological activity present 1 minute after the i.v. injection disappeared exponentially without dose-dependent effects. Increasing doses of the three drugs were then delivered for 5 h under continuous infusions. Below 500 micrograms/kg/h the DS and CY 216 plateau concentrations were higher than that of SH while above this dose the SH concentration was higher than that of DS and CY 216. These observations may be explained by the results of pharmacokinetics experiments where /sup 125/I-labeled compounds were delivered by bolus i.v. injection in association with increasing doses of their unlabeled counterparts. For SH there was a 10-fold difference between the half-life of the lower dose (32 micrograms/kg or 5 anti-factor Xa U/kg) and that of the higher dose (3200 micrograms/kg); it was demonstrated that the half-life of SH continuously shortened as its plasma concentration decreased. In contrast the CY 216 and DS half-lives were very close, independent of the dose delivered, and therefore longer than that of SH at low doses and shorter than that of SH at higher doses.

  15. Pharmacokinetics of heparin and related polysaccharides

    International Nuclear Information System (INIS)

    The pharmacodynamic profile of standard heparin (SH), a low molecular weight derivative (CY 216) and of dermatan sulfate (DS), a new potential antithrombotic drug, was investigated in the rabbit over a large range of doses. After bolus i.v. injection of low doses, the biological activity of SH disappeared exponentially; however, its half-life was prolonged when the dose injected increased, and over 158 micrograms/kg (100 anti-factor Xa U/kg) the biological activity disappeared as a concave-convex curve. CY 216 disappeared more slowly than SH at low doses but faster than SH at higher doses. More than 90% of the DS biological activity present 1 minute after the i.v. injection disappeared exponentially without dose-dependent effects. Increasing doses of the three drugs were then delivered for 5 h under continuous infusions. Below 500 micrograms/kg/h the DS and CY 216 plateau concentrations were higher than that of SH while above this dose the SH concentration was higher than that of DS and CY 216. These observations may be explained by the results of pharmacokinetics experiments where 125I-labeled compounds were delivered by bolus i.v. injection in association with increasing doses of their unlabeled counterparts. For SH there was a 10-fold difference between the half-life of the lower dose (32 micrograms/kg or 5 anti-factor Xa U/kg) and that of the higher dose (3200 micrograms/kg); it was demonstrated that the half-life of SH continuously shortened as its plasma concentration decreased. In contrast the CY 216 and DS half-lives were very close, independent of the dose delivered, and therefore longer than that of SH at low doses and shorter than that of SH at higher doses

  16. Pharmacokinetics of aerosol amphotericin B in rats.

    Science.gov (United States)

    Niki, Y; Bernard, E M; Schmitt, H J; Tong, W P; Edwards, F F; Armstrong, D

    1990-01-01

    The distributions of amphotericin B (AmB) in tissue were compared after intraperitoneal or aerosol administration. Rats were sacrificed 24 h after receiving single or repeated daily doses; AmB concentrations in tissues were determined by high-performance liquid chromatography. After intraperitoneal doses of 4 mg/kg of body weight per day for 7 days, mean concentrations of AmB were 122.7, 55.2, and 4.31 micrograms/g in the spleen, liver, and lung, respectively. After aerosol doses (aero-AmB) of 1.6 mg/kg per day, the mean concentrations of AmB in the lung were 2.79 micrograms/g after a single dose and 9.88 micrograms/g after four doses, while the drug was undetectable (less than 0.1 micrograms/g) in serum, spleen, liver, kidney, and brain. The half-life of elimination of AmB from the lungs was 4.8 days according to serial sacrifices done after a single dose of 3.2 mg of aero-AmB per kg. Treatment with 60 mg of aero-AmB per kg was well tolerated and produced no histopathologic changes in the lungs. The aerosol route was much more efficient than the systemic route in delivering AmB to the lungs, and it limited the accumulation of AmB in other organs. Because AmB is eliminated slowly, infrequent dosing schedules can be used. These pharmacokinetic characteristics and its proven effectiveness in an animal model make aero-AmB a highly promising new method for the prevention of pulmonary aspergillosis. Aero-AmB should also be considered for use as an adjunct to intravenous AmB for treatment of fungal pneumonias. PMID:2327759

  17. Pharmacokinetics of moxalactam and cefazolin compared in normal volunteers.

    OpenAIRE

    Srinivasan, S.; Fu, K P; Neu, H C

    1981-01-01

    The pharmacokinetics of moxalactam, a new beta-lactam antibiotic with an unusually broad spectrum of activity, were studied in normal volunteers and compared with the pharmacokinetics of cefazolin. After a 1,000-mg intramuscular injection of moxalactam, a mean peak serum level of 49 +/- 10 micrograms/ml was achieved at 30 to 60 min which was equivalent to the level achieved with 0.5 g of cefazolin. Serum levels of 4.57 +/- 0.63 micrograms/ml, above the inhibitory levels for most organisms, we...

  18. Factors Controlling Nanoparticle Pharmacokinetics: An Integrated Analysis and Perspective

    DEFF Research Database (Denmark)

    Moghimi, Seyed Moien; Hunter, A.C.; Andresen, T.L.

    2012-01-01

    Intravenously injected nanoparticulate drug carriers provide a wide range of unique opportunities for site-specific targeting of therapeutic agents to many areas within the vasculature and beyond. Pharmacokinetics and biodistribution of these carriers are controlled by a complex array of interrel......Intravenously injected nanoparticulate drug carriers provide a wide range of unique opportunities for site-specific targeting of therapeutic agents to many areas within the vasculature and beyond. Pharmacokinetics and biodistribution of these carriers are controlled by a complex array of...

  19. Effect of In Vivo Nicotine Exposure on Chlorpyrifos Pharmacokinetics and Pharmacodynamics in Rats

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Sookwang; Poet, Torka S.; Smith, Jordan N.; Busby-Hjerpe, Andrea L.; Timchalk, Charles

    2010-03-30

    Routine use of tobacco products may modify physiological and metabolic functions, including drug metabolizing enzymes, which may impact the pharmacokinetics of environmental contaminants. Chlorpyrifos is an organophosphorus (OP) insecticide that is bioactivated to chlorpyrifos-oxon, and manifests its neurotoxicity by inhibiting acetylcholinesterase (AChE). The objective of this study was to evaluate the impact of repeated nicotine exposure on the pharmacokinetics of chlorpyrifos (CPF) and its major metabolite, 3,5,6-trichloro-2-pyridinol (TCPy) in blood and urine and also to determine the impact on cholinesterase (ChE) activity in plasma and brain. Animals were exposed to 7-daily doses of either 1 mg nicotine/kg or saline (sc), and to either a single oral dose of 35 mg CPF/kg or a repeated dose of 5 mg CPF/kg/day for 7 days. Groups of rats were then sacrificed at multiple time-points after receiving the last dose of CPF. Repeated nicotine and CPF exposures resulted in enhanced metabolism of CPF to TCPy, as evidenced by increases in the measured TCPy concentration and AUC in blood. However, there was no significant difference in the amount of TCPy (free or total) excreted in the urine. The extent of brain acetylcholinesterase (AChE) inhibition was reduced due to nicotine co-exposure consistent with an increase in CYP450-mediated dearylation (detoxification) versus desulfuration. It was of interest to note that the impact of nicotine co-exposure was experimentally observed only after repeated CPF doses. Physiologically based pharmacokinetic model simulations of CPF-oxon concentrations in blood and brain were predicted to be lower in nicotine treated groups, which were simulated by increasing the dearylation Vmax based upon previously conducted in vitro metabolism studies. These results were consistent with the experimental data. The current study demonstrated that repeated nicotine exposure could alter CPF metabolism in vivo, further modulating brain AChE inhibition.

  20. 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...

  1. 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...

  2. The pharmacokinetic effect of coadministration of apremilast and methotrexate in individuals with rheumatoid arthritis and psoriatic arthritis

    OpenAIRE

    Liu, Yong; Zhou, Simon; Nissel, James; Wu, Anfan; Lau, Henry; Palmisano, Maria

    2014-01-01

    Apremilast is a novel agent for the treatment of inflammatory based autoimmune disorders. The objective of this study was to assess the pharmacokinetic effects of co administration of apremilast and methotrexate on both agents. This was an open-label, multi-center, 3-treatment period, sequential study conducted in otherwise healthy subjects with psoriatic arthritis or rheumatoid arthritis who were receiving a stable oral dose of methotrexate between 7.5 to 20 mg once weekly. Subjects received...

  3. Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether/lumefantrine in HIV-infected Ugandan adults

    OpenAIRE

    Byakika-Kibwika, Pauline; Lamorde, Mohammed; Okaba-Kayom, Violet; Mayanja-Kizza, Harriet; Katabira, Elly; Hanpithakpong, Warunee; Pakker, Nadine; Dorlo, Thomas P. C.; Tarning, Joel; Lindegardh, Niklas; de Vries, Peter J; Back, David; Khoo, Saye; Merry, Concepta

    2012-01-01

    Background Treatment of HIV/malaria-coinfected patients with antiretroviral therapy (ART) and artemisinin-based combination therapy has potential for drug interactions. We investigated the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine after administration of a single dose of 80/480 mg of artemether/lumefantrine to HIV-infected adults, taken with and without lopinavir/ritonavir. Methods A two-arm parallel study of 13 HIV-infected ART-naive adults and 16 HIV-infected adult...

  4. PKQuest: capillary permeability limitation and plasma protein binding – application to human inulin, dicloxacillin and ceftriaxone pharmacokinetics

    OpenAIRE

    Levitt, David G.

    2002-01-01

    Background It is generally assumed that the tissue exchange of antibiotics is flow limited (complete equilibration between the capillary and the tissue water). This assumption may not be valid if there is a large amount of plasma protein binding because the effective capillary permeability depends on the product of the intrinsic capillary permeability (PS) and the fraction of solute that is free in the blood (fwB). PKQuest, a new generic physiologically based pharmacokinetic software routine ...

  5. Combined analysis of pharmacokinetic and efficacy data of preclinical studies with statins markedly improves translation of drug efficacy to human trialss

    NARCIS (Netherlands)

    Steeg, E. van de; Kleemann, R.; Jansen, H.T.; Duyvenvoorde, W. van; Offerman, E.H.; Wortelboer, H.M.; DeGroot, J.

    2013-01-01

    Correct prediction of human pharmacokinetics (PK) and the safety and efficacy of novel compounds based on preclinical data, is essential but often fails. In the current study, we aimed to improve the predictive value of ApoE*3Leiden (E3L) trans-genic mice regarding the cholesterol-lowering efficacy

  6. Clinical pharmacokinetics of vasodilators. Part II.

    Science.gov (United States)

    Kirsten, R; Nelson, K; Kirsten, D; Heintz, B

    1998-07-01

    Stimulating cardiac beta 1-adrenoceptors with oxyfedrine causes dilatation of coronary vessels and positive inotropic effects on the myocardium. beta 1-adrenergic agonists increase coronary blood flow in nonstenotic and stenotic vessels. The main indication for the use of the phosphodiesterase inhibitors pamrinone, mirinone, enoximone and piroximone is acute treatment of severe congestive heart failure. Theophylline is indicated for the treatment of asthma, chronic obstructive pulmonary disease, apnea in preterm infants ans sleep apnea syndrome. Severe arterial occlusive disease associated with atherosclerosis can be beneficially affected by elcosanoids. These drugs must be administered parenterally and have a half-life of only a few minutes. Sublingual or buccal preparations of nitrates are the only prompt method (within 1 or 2 min) of terminating anginal pain, except for biting nifedipine capsules. The short half-life (about 2.5 min) of nitroglycerin (glyceryl trinitrate) makes long term therapy impossible. Tolerance is a problem encountered with longer-acting nitric oxide donors. Knowledge of the pharmacokinetic properties of vasodilating drugs can prevent a too sudden and severe blood pressure decrease in patients with chronic hypertension. In considering the administration of a second dose, or another drug, the time necessary for the initially administered drug to reach maximal efficacy should be taken into account. In hypertensive emergencies urapidil, sodium nitroprusside, nitroglycerin, hydralazine and phentolamine are the drugs of choice, with the addition of beta-blockers during catecholamine crisis or dissecting aortic aneurysm. Childhood hypertension is most often treated with angiotensin-converting enzyme (ACE) inhibitors or calcium antagonists, primarily nifedipine. Because of the teratogenic risk involved with ACE inhibitors, extreme caution must be exercised when prescribing for adolescent females. The propagation of health benefits to breast

  7. Specific pharmacokinetic aspects of the urinary tract.

    Science.gov (United States)

    Korstanje, Cees; Krauwinkel, Walter

    2011-01-01

    This chapter reviews the evidence for "specific" pharmacokinetics playing a role in currently marketed drugs intended to treat lower urinary tract (LUT) symptoms. Principles of drug targeting include intrinsic properties of drugs or organs as well as drug formulations to modify drug release or to create confinement of drug presence. Prodrugs and specific formulations to deliver high drug concentrations at the site(s) of action as well as other ways to manipulate drug distribution to achieve enrichment in target tissues are considered. In overactive bladder (OAB), specific formulations for oxybutynin have been introduced to reduce the level of side effects of the active drug. Extended release tablet formulations and a topical gel formulation have been introduced, with efficacy similar to immediate release (IR) tablets, but with a reduction in anticholinergic adverse effects. However, these modifications have not led to outstanding performance parameters compared to other anticholinergic drugs marketed as IR formulations. Urinary excretion is discussed as potential mechanism for targeting LUT symptoms, but no strong indications appear to exist that this mechanism would contribute for currently available drugs. Intravesical administration of drugs is not a preferred option and only considered for drugs like botulinum toxin, where the inconvenient application compensates for a reasonable degree of long-term efficacy in severe refractory OAB. Alpha acid glycoprotein binding is discussed as a potential factor to influence drug tissue distribution, and it is concluded that there is reasonable evidence that for tamsulosin this mechanism is responsible for the difference in free fraction of the drug observed in plasma and prostate, which could contribute to its relative absence of blood pressure effects in patients with LUT symptoms related to benign prostate hyperplasia (LUTS-BPH). The principle of irreversible inhibition of type II 5α-reductase as a tool to develop drugs

  8. Preparation of finasteride capsules-loaded drug nanoparticles: formulation, optimization, in vitro, and pharmacokinetic evaluation

    Directory of Open Access Journals (Sweden)

    Ahmed TA

    2016-02-01

    Full Text Available Tarek A Ahmed1,2 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt Abstract: In this study, optimized freeze-dried finasteride nanoparticles (NPs were prepared from drug nanosuspension formulation that was developed using the bottom–up technique. The effects of four formulation and processing variables that affect the particle size and solubility enhancement of the NPs were explored using the response surface optimization design. The optimized formulation was morphologically characterized using transmission electron microscopy (TEM. Physicochemical interaction among the studied components was investigated. Crystalline change was investigated using X-ray powder diffraction (XRPD. Crystal growth of the freeze-dried NPs was compared to the corresponding aqueous drug nanosuspension. Freeze-dried NPs formulation was subsequently loaded into hard gelatin capsules that were examined for in vitro dissolution and pharmacokinetic behavior. Results revealed that in most of the studied variables, some of the quadratic and interaction effects had a significant effect on the studied responses. TEM image illustrated homogeneity and shape of the prepared NPs. No interaction among components was noticed. XRPD confirmed crystalline state change in the optimized NPs. An enhancement in the dissolution rate of more than 2.5 times from capsules filled with optimum drug NPs, when compared to capsules filled with pure drug, was obtained. Crystal growth, due to Ostwald ripening phenomenon and positive Gibbs free energy, was reduced following lyophilization of the nanosuspension formulation. Pharmacokinetic parameters from drug NPs were superior to that of pure drug and drug microparticles. In conclusion, freeze-dried NPs based on drug nanosuspension formulation is a successful

  9. 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

  10. Pharmacokinetics of medroxyprogesterone acetate after single and multiple injection of Cyclofem in Chinese women.

    Science.gov (United States)

    Zhou, X F; Shao, Q X; Han, X J; Weng, L J; Sang, G W

    1998-06-01

    To provide pharmacokinetic data for safety evaluation on prolonged treatment with Cyclofem, which contains 25 mg medroxyprogesterone acetate (MPA) and 5 mg estradiol cypionate in 0.5 mL microcrystalline aqueous suspension, the pharmacokinetic profiles of MPA after single and multiple administration of this monthly injectable contraceptive were investigated in Chinese women. Nine healthy fertile women received Cyclofem based on a once-a-month regiment for up to 1 year. Blood samples were collected immediately prior to drug administration and on days 1, 3, 5, 7, 14, 21, and 28 after injection. After the 1st, 6th, and 12th injection, the maximum serum concentrations (Cmax) of MPA were observed on days 3.4 +/- 0.9, 4.3 +/- 2.2, and 3.7 +/- 2.6, respectively. Cmax of serum MPA during the 1st, 6th, and 12th treatment cycles were 3.75 +/- 1.27, 5.54 +/- 1.79, and 5.55 +/- 1.80 nmol/L, whereas the areas under the curve (AUC0-28 days) were 55.84 +/- 28.15, 95.45 +/- 26.56, and 98.81 +/- 21.84 nmol/L.day, respectively. There was significant interindividual variation in the pharmacokinetics of MPA after intramuscular injection of Cyclofem. No significant change was demonstrated in mean residence time (MRT) of MPA after single and multiple injection. There was a tendency of increase in Cmax and AUC0-28 days of MPA during the first 6 months of treatment, whereas no further enhancement was found between the 6th and 12th injection (p > 0.05). Peak levels of estradiol (E2) observed in Cyclofem users were within the normal range of the preovulatory phase. Results of this long-term study suggest that no drug accumulation occurred after repeated administration of Cyclofem in the Chinese women. PMID:9693401

  11. Single and multiple dose pharmacokinetics of etizolam in healthy subjects.

    Science.gov (United States)

    Fracasso, C; Confalonieri, S; Garattini, S; Caccia, S

    1991-01-01

    The pharmacokinetics of etizolam, a new thienodiazepine derivative, has been examined after single and multiple (0.5 mg tablet) (0.5 mg b.d for 1 week) oral therapeutic doses in healthy volunteers. The single-dose kinetic profile of etizolam suggested that absorption after oral dosage was reasonably rapid, the maximum plasma concentration (Cmax) being attained within 0.5-2 h in all subjects. The mean elimination half-life (t1/2) averaged 3.4 h. Consistent with this, steady-state concentration were rapidly achieved and accumulation was extremely limited. Predicted average plasma concentrations (Cp) did not differ significantly from those actually measured at steady-state, suggesting that the kinetics of etizolam was linear, at least at therapeutic doses. The mean wash-out t1/2 was comparable to the elimination t1/2 of the single dose, which means that the drug probably has no effect on hepatic microsomal enzymes and other kinetic variables after repeated dosing. At steady state plasma concentrations of the main metabolite, alpha-hydroxyetizolam, were higher and disappeared more slowly (mean t1/2 8.2 h) than those of the parent compound. Taken with the fact that in animals the metabolite shows almost the same potency of pharmacological action as etizolam, this suggests that it may contribute significantly to the clinical effects of the parent compound. Based on the kinetic characteristics of the parent drug and its metabolite, etizolam can be regarded as a short-acting benzodiazepine, with elimination kinetics between those of short-intermediate derivatives and ultra-rapidly eliminated benzodiazepines. PMID:2065698

  12. Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus

    NARCIS (Netherlands)

    Van Overmeire, B; Touw, D; Schepens, P J; Kearns, G L; van den Anker, J N

    2001-01-01

    OBJECTIVE: Our objective was to study the pharmacokinetics of ibuprofen in premature infants with patent ductus arteriosus on day 3 and day 5 after birth. METHODS: Ibuprofen was administered on days 3, 4, and 5 by a 15-minute intravenous infusion of 10, 5, and 5 mg/kg, respectively, with the aim of

  13. 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…

  14. Systemic Pharmacokinetics of Rifaximin in Volunteers with Shigellosis▿

    OpenAIRE

    Taylor, David N.; McKenzie, Robin; Durbin, Anna; Carpenter, Colleen; Haake, Robert; Bourgeois, A. Louis

    2007-01-01

    Rifaximin is an oral antibiotic indicated for treatment of traveler's diarrhea. Rifaximin pharmacokinetics were evaluated in individuals challenged with Shigella flexneri. Peak plasma rifaximin concentrations were low after nine consecutive doses, and no accumulation was observed. Rifaximin serum levels were minimal and similar to those previously reported in studies of healthy volunteers.

  15. Pharmacokinetic behaviors and oral bioavailability of oridonin in rat plasma

    Institute of Scientific and Technical Information of China (English)

    Wen XU; Jin SUN; Ting-ting ZHANG; Bo MA; Sheng-miao GUI; Da-wei CHEN; Zhong-gui HE

    2006-01-01

    Aim: To study the intravenous and oral pharmacokinetic behavior of oridonin and its extent of absolute oral bioavailability in rats. Methods: Oridonin was administered to rats via iv (5,10 and 15 mg/kg), po (20,40 and 80 mg/kg) or ip administration (10 mg/kg). The concentrations of oridonin in rat plasma were determined by a high performance liquid chromatography with electrospray ionization mass spec-trometric detection (HPLC/ESI-MS) method and the pharmacokinetic parameters were determined by non-compartmental analysis. Results: The plasma concentration of oridonin after intravenous administration decreased poly exponentially, and the pharmacokinetic parameters of oridonin were dose-independent within the examined range. Oridonin was absorbed rapidly after oral gavage with a pharmacokinetics were observed for oridonin within the range of iv doses, while the extent of absolute oral bioavailability was rather low and dose-dependent. The low and dose-dependent extent of oral bioavailability may be due to the saturation of first-pass effects.

  16. Stereoselective pharmacokinetics of methadone in chronic pain patients

    DEFF Research Database (Denmark)

    Kristensen, K; Blemmer, T; Angelo, H R;

    1996-01-01

    Ten patients with chronic pain were randomized to an open, balanced, crossover study. Each patients received two different preparations of racemic methadone, i.e., tablets and intravenous infusion. The pharmacokinetic parameters of the R- and S-enantiomers of the racemate are reported. The...

  17. Pharmacokinetics of ruminally-dosed sodium chlorate in beef cattle

    Science.gov (United States)

    The recently recognized potential of sodium chlorate as a possible pre-harvest food safety tool in meat animals has spurred interest in the pharmacokinetics of intraruminally-dosed chlorate. Six Loala cattle were assigned (one heifer and one steer per treatment) to one of three intraruminal doses of...

  18. Systemic and Brain Pharmacokinetics of Perforin Inhibitor Prodrugs

    DEFF Research Database (Denmark)

    Gynther, Mikko; Pickering, Darryl S; Spicer, Julie;

    2016-01-01

    We have recently reported that by converting a perforin inhibitor into an l-type amino acid transporter 1 (LAT1)-utilizing prodrug its cellular uptake can be greatly increased. The aim of the present study was to determine the in vivo and brain pharmacokinetics of two perforin inhibitors and their...

  19. Studies on pharmacokinetic drug interaction potential of vinpocetine

    Science.gov (United States)

    Background: Vinpocetine, a semi-synthetic derivative of vincamine, is a popular dietary supplement used for the treatment of several central nervous system related disorders. Despite its wide use, no pharmacokinetic drug interaction studies are reported in literature. Due to increasing use of dietar...

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

    DEFF Research Database (Denmark)

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

    2009-01-01

    The third generation cephalosporin cefovecin has been shown to have an exceptionally long elimination half-life in dogs and cats, making it suitable for antibacterial treatment with a 14-day dosing interval in these species. Pharmacokinetic parameters for cefovecin were investigated in juvenile...