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Sample records for physiologically-based pharmacokinetic pbpk

  1. Physiologically Based Pharmacokinetic (PBPK) Modeling of ...

    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 cases, are based on human toxicokinetic data.Objectives: To evaluate the utility of genetically diverse mouse strains for estimating toxicokinetic population variability for risk assessment, using trichloroethylene (TCE) metabolism as a case study. Methods: We used data on oxidative and glutathione conjugation metabolism of TCE in 16 inbred and one hybrid mouse strains to calibrate and extend existing physiologically-based pharmacokinetic (PBPK) models. We added one-compartment models for glutathione metabolites and a two-compartment model for dichloroacetic acid (DCA). A Bayesian population analysis of inter-strain variability was used to quantify variability in TCE metabolism. Results: Concentration-time profiles for TCE metabolism to oxidative and glutathione conjugation metabolites varied across strains. Median predictions for the metabolic flux through oxidation was less variable (5-fold range) than that through glutathione conjugation (10-fold range). For oxidative metabolites, median predictions of trichloroacetic acid production was less variable (2-fold range) than DCA production (5-fold range), although uncertainty bounds for DCA exceeded the predicted variability. Conclusions:

  2. A physiologically based pharmacokinetic (PB-PK) model for ethylene dibromide; relevance of extrahepatic metabolism

    NARCIS (Netherlands)

    Hissink, A.M.; Wormhoudt, L.W.; Sherratt, P.J.; Hayes, J.D.; Commandeur, J.N.M.; Vermeulen, N.P.E.; Bladeren, van P.J.

    2000-01-01

    A physiologically-based pharmacokinetic (PB-PK) model was developed for ethylene dibromide (1,2-dibromoethane, EDB) for rats and humans, partly based on previously published in vitro data (Ploemen et al., 1997). In the present study, this PB-PK model has been validated for the rat. In addition, new

  3. Evaluation of a Physiologically Based Pharmacokinetic (PBPK) Model Used to Develop Health Protective Levels for Trichloroethylene

    Science.gov (United States)

    2017-02-28

    AFRL-RH-WP-TR-2017-0014 EVALUATION OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODEL USED TO DEVELOP HEALTH PROTECTIVE LEVELS FOR...Pharmacokinetic (PBPK) Model Used to Develop Health Protective Levels for Trichloroethylene 5a. CONTRACT NUMBER FA8650-15-2-6608 5b. GRANT...Anita Meyer, Army Corps of Engineers (CEHNC-EMS) and Shannon S. Garcia, AFCEC/CZTE for their efforts to obtain the required funding. The authors also

  4. 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.

  5. Report from the EMA workshop on qualification and reporting of physiologically based pharmacokinetic (PBPK) modeling and simulation

    Science.gov (United States)

    2017-01-01

    On Nov 21, 2016, the European Medicines Agency (EMA) hosted a workshop to discuss its draft guideline on qualification and reporting of physiologically based pharmacokinetic (PBPK) analysis.1 Published on July 21, 2016, the draft PBPK guideline is currently under the period of public comments. PMID:28035755

  6. Physiologically Based Pharmacokinetic (PBPK model for biodistribution of radiolabeled peptides in patients with neuroendocrine tumours

    Directory of Open Access Journals (Sweden)

    Viktor Popov

    2016-07-01

    Full Text Available Objective(s: The objectives of this work was to assess the benefits of the application of Physiologically Based Pharmacokinetic (PBPK models in patients with different neuroendocrine tumours (NET who were treatedwith Lu-177 DOTATATE. The model utilises clinical data on biodistribution of radiolabeled peptides (RLPs obtained by whole body scintigraphy (WBS of the patients.Methods: The blood flow restricted (perfusion rate limited type of the PBPK model for biodistribution of radiolabeled peptides (RLPs in individual human organs is based on the multi-compartment approach, which takes into account the main physiological processes in the organism: absorption, distribution, metabolism and excretion (ADME. The approachcalibrates the PBPK model for each patient in order to increase the accuracy of the dose estimation. Datasets obtained using WBS in four patients have been used to obtain the unknown model parameters. The scintigraphic data were acquired using a double head gamma camera in patients with different neuroendocrine tumours who were treated with Lu-177 DOTATATE. The activity administered to each patient was 7400MBq.Results: Satisfactory agreement of the model predictions with the data obtained from the WBS for each patient has been achieved. Conclusion: The study indicates that the PBPK model can be used for more accurate calculation of biodistribution and absorbed doses in patients. This approach is the first attempt of utilizing scintigraphic data in PBPK models, which was obtained during Lu-177 peptide therapy of patients with NET.

  7. A physiologically based pharmacokinetic (PB/PK) model for multiple exposure routes for soman in multiple species

    NARCIS (Netherlands)

    Sweeney, R.E.; Langenberg, J.P.; Maxwell, D.M.

    2006-01-01

    A physiologically based pharmacokinetic (PB/PK) model has been developed in advanced computer simulation language (ACSL) to describe blood and tissue concentration-time profiles of the C(±)P(-) stereoisomers of soman after inhalation, subcutaneous and intravenous exposures at low (0.8-1.0 × LD50), m

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

    NARCIS (Netherlands)

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

    2002-01-01

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

  9. Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification.

    Science.gov (United States)

    Sager, Jennifer E; Yu, Jingjing; Ragueneau-Majlessi, Isabelle; Isoherranen, Nina

    2015-11-01

    Modeling and simulation of drug disposition has emerged as an important tool in drug development, clinical study design and regulatory review, and the number of physiologically based pharmacokinetic (PBPK) modeling related publications and regulatory submissions have risen dramatically in recent years. However, the extent of use of PBPK modeling by researchers, and the public availability of models has not been systematically evaluated. This review evaluates PBPK-related publications to 1) identify the common applications of PBPK modeling; 2) determine ways in which models are developed; 3) establish how model quality is assessed; and 4) provide a list of publically available PBPK models for sensitive P450 and transporter substrates as well as selective inhibitors and inducers. PubMed searches were conducted using the terms "PBPK" and "physiologically based pharmacokinetic model" to collect published models. Only papers on PBPK modeling of pharmaceutical agents in humans published in English between 2008 and May 2015 were reviewed. A total of 366 PBPK-related articles met the search criteria, with the number of articles published per year rising steadily. Published models were most commonly used for drug-drug interaction predictions (28%), followed by interindividual variability and general clinical pharmacokinetic predictions (23%), formulation or absorption modeling (12%), and predicting age-related changes in pharmacokinetics and disposition (10%). In total, 106 models of sensitive substrates, inhibitors, and inducers were identified. An in-depth analysis of the model development and verification revealed a lack of consistency in model development and quality assessment practices, demonstrating a need for development of best-practice guidelines.

  10. Development of Physiologically Based Pharmacokinetic Model (PBPK) of BMP2 in Mice.

    Science.gov (United States)

    Utturkar, Aditya; Paul, Bikram; Akkiraju, Hemanth; Bonor, Jeremy; Dhurjati, Prasad; Nohe, Anja

    2013-01-01

    Bone Morphogenetic protein 2 holds great promise for potential applications in the clinic. It is a potent growth factor for the use in the cervical spine surgery (FDA approved 2002) and has been marketed as "Infuse" for treating open tibial shaft fractures (FDA approved 2004). However, its use is limited by several significant side effects that maybe due to its potency and effect on different stem cell populations in the spine. BMP2 is expressed throughout the human body in several tissues and at a very high concentration in the blood. BMP receptors, especially BMP receptor type Ia, is ubiquitously expressed in most tissues. Currently, it is difficult to determine how BMP2 is physiologically distributed in mice or humans and no quantitative models are available. A Physiologically-Based Pharmaco-Kinetic (PBPK) model has been developed to determine steady-state distribution of BMP2 in mice. The multi-compartmental PBPK model represents relevant organ/tissues with physiological accuracy. The organs/tissue compartments chosen were brain, lung, heart, liver, pancreas, kidney, uterus, bone and fat. A blood compartment maintained connectivity among the various organs. Four processes characterized the change in the concentration of the protein in every compartment: blood flow in, blood flow out, protein turnover and receptor binding in the organ. The unique aspects of the model are the determination of elimination using receptor kinetics and generation using protein turnover. The model also predicts steady state concentrations of BMP2 in tissues in mice and may be used for possible scale-up of dosage regimens in humans.

  11. Prediction of pharmacokinetics and drug-drug interaction potential using physiologically based pharmacokinetic (PBPK) modeling approach: A case study of caffeine and ciprofloxacin

    Science.gov (United States)

    Park, Min-Ho; Shin, Seok-Ho; Byeon, Jin-Ju; Lee, Gwan-Ho; Yu, Byung-Yong

    2017-01-01

    Over the last decade, physiologically based pharmacokinetics (PBPK) application has been extended significantly not only to predicting preclinical/human PK but also to evaluating the drug-drug interaction (DDI) liability at the drug discovery or development stage. Herein, we describe a case study to illustrate the use of PBPK approach in predicting human PK as well as DDI using in silico, in vivo and in vitro derived parameters. This case was composed of five steps such as: simulation, verification, understanding of parameter sensitivity, optimization of the parameter and final evaluation. Caffeine and ciprofloxacin were used as tool compounds to demonstrate the “fit for purpose” application of PBPK modeling and simulation for this study. Compared to caffeine, the PBPK modeling for ciprofloxacin was challenging due to several factors including solubility, permeability, clearance and tissue distribution etc. Therefore, intensive parameter sensitivity analysis (PSA) was conducted to optimize the PBPK model for ciprofloxacin. Overall, the increase in Cmax of caffeine by ciprofloxacin was not significant. However, the increase in AUC was observed and was proportional to the administered dose of ciprofloxacin. The predicted DDI and PK results were comparable to observed clinical data published in the literatures. This approach would be helpful in identifying potential key factors that could lead to significant impact on PBPK modeling and simulation for challenging compounds. PMID:28066147

  12. A PHYSIOLOGICALLY BASED PHARMACOKINETIC/PHARMACODYNAMIC (PBPK/PD) MODEL FOR ESTIMATION OF CUMULATIVE RISK FROM EXPOSURE TO THREE N-METHYL CARBAMATES: CARBARYL, ALDICARB, AND CARBOFURAN

    Science.gov (United States)

    A physiologically-based pharmacokinetic (PBPK) model for a mixture of N-methyl carbamate pesticides was developed based on single chemical models. The model was used to compare urinary metabolite concentrations to levels from National Health and Nutrition Examination Survey (NHA...

  13. 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.

  14. Physiologically based pharmacokinetic (PB-PK) modeling of indoor air pollutant degradation by houseplants

    Energy Technology Data Exchange (ETDEWEB)

    Smith, E.K.; El-Masri, H.A.; Tessari, J.D.; Yang, R.S.H.; Reardon, K.F. [Colorado State Univ., Fort Collins, CO (United States)

    1994-12-31

    In the US, indoor air pollutant levels commonly exceed outdoor levels by a factor of 7 or more. Since people typically spend more than 90% percent of their time indoors, indoor air pollution has the potential for greater consequences on human health. A NASA researcher has reported that certain houseplants will reduce closed chamber concentrations of common indoor air pollutants by more than 75%. The authors are expanding this research; common houseplants and PB-PK modeling can be combined to predict the reduction rates of frequently detected indoor air pollutants, and be used as an environmental remediation approach. The approach to measuring plant gas uptake of indoor air pollutants provides a more quantitative and controlled approach than previous studies. Construction of the closed chamber system linked to a computerized gas chromatograph is complete. This system measures plant uptake of volatile organic chemicals. In experiments using initial concentrations of 21--2,100 ppm of the common indoor air pollutant trichloroethylene (TCE) with peace lily in soil, between 27--34% of TCE was removed during a 12-hour test period. In similar experiments, plants in abiotic potting media removed only 4--13% of TCE from the closed system, suggesting that microbial degradation or soil adsorption of TCE are significant factors.

  15. 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......, oxychlordane, HCHs, HCB, PBDEs and PFOS in East Greenland polar bears based on known OHC pharmacokinetics and dynamics in laboratory rats (Rattus rattus). The results showed that subcutaneous adipose tissue concentrations of dieldrin (range: 79–1271 ng g−1 lw) and PCBs (range: 4128–53 923 ng g−1 lw) reported...... and for dieldrin (range: 43–640 ng g−1 lw), PCBs (range: 3491–13 243 ng g−1 lw) and PFOS (range: 1332–6160 ng g−1 ww) in the year 2006. The concentrations of oxychlordane, DDTs, HCB and HCHs in polar bears resulted in RQs

  16. MEGen: A Physiologically Based Pharmacokinetic Model Generator

    Directory of Open Access Journals (Sweden)

    George D Loizou

    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.

  17. Application of Bayesian population physiologically based pharmacokinetic (PBPK) modeling and Markov chain Monte Carlo simulations to pesticide kinetics studies in protected marine mammals: DDT, DDE, and DDD in harbor porpoises.

    Science.gov (United States)

    Weijs, Liesbeth; Yang, Raymond S H; Das, Krishna; Covaci, Adrian; Blust, Ronny

    2013-05-01

    Physiologically based pharmacokinetic (PBPK) modeling in marine mammals is a challenge because of the lack of parameter information and the ban on exposure experiments. To minimize uncertainty and variability, parameter estimation methods are required for the development of reliable PBPK models. The present study is the first to develop PBPK models for the lifetime bioaccumulation of p,p'-DDT, p,p'-DDE, and p,p'-DDD in harbor porpoises. In addition, this study is also the first to apply the Bayesian approach executed with Markov chain Monte Carlo simulations using two data sets of harbor porpoises from the Black and North Seas. Parameters from the literature were used as priors for the first "model update" using the Black Sea data set, the resulting posterior parameters were then used as priors for the second "model update" using the North Sea data set. As such, PBPK models with parameters specific for harbor porpoises could be strengthened with more robust probability distributions. As the science and biomonitoring effort progress in this area, more data sets will become available to further strengthen and update the parameters in the PBPK models for harbor porpoises as a species anywhere in the world. Further, such an approach could very well be extended to other protected marine mammals.

  18. 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

  19. Optimizing nanomedicine pharmacokinetics using physiologically based pharmacokinetics modelling.

    Science.gov (United States)

    Moss, Darren Michael; Siccardi, Marco

    2014-09-01

    The delivery of therapeutic agents is characterized by numerous challenges including poor absorption, low penetration in target tissues and non-specific dissemination in organs, leading to toxicity or poor drug exposure. Several nanomedicine strategies have emerged as an advanced approach to enhance drug delivery and improve the treatment of several diseases. Numerous processes mediate the pharmacokinetics of nanoformulations, with the absorption, distribution, metabolism and elimination (ADME) being poorly understood and often differing substantially from traditional formulations. Understanding how nanoformulation composition and physicochemical properties influence drug distribution in the human body is of central importance when developing future treatment strategies. A helpful pharmacological tool to simulate the distribution of nanoformulations is represented by physiologically based pharmacokinetics (PBPK) modelling, which integrates system data describing a population of interest with drug/nanoparticle in vitro data through a mathematical description of ADME. The application of PBPK models for nanomedicine is in its infancy and characterized by several challenges. The integration of property-distribution relationships in PBPK models may benefit nanomedicine research, giving opportunities for innovative development of nanotechnologies. PBPK modelling has the potential to improve our understanding of the mechanisms underpinning nanoformulation disposition and allow for more rapid and accurate determination of their kinetics. This review provides an overview of the current knowledge of nanomedicine distribution and the use of PBPK modelling in the characterization of nanoformulations with optimal pharmacokinetics.

  20. Human physiologically based pharmacokinetic model for propofol

    Directory of Open Access Journals (Sweden)

    Schnider Thomas W

    2005-04-01

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

  1. Physiologically based pharmacokinetic modeling in drug discovery and development: a pharmaceutical industry perspective.

    Science.gov (United States)

    Jones, H M; Chen, Y; Gibson, C; Heimbach, T; Parrott, N; Peters, S A; Snoeys, J; Upreti, V V; Zheng, M; Hall, S D

    2015-03-01

    The application of physiologically based pharmacokinetic (PBPK) modeling has developed rapidly within the pharmaceutical industry and is becoming an integral part of drug discovery and development. In this study, we provide a cross pharmaceutical industry position on "how PBPK modeling can be applied in industry" focusing on the strategies for application of PBPK at different stages, an associated perspective on the confidence and challenges, as well as guidance on interacting with regulatory agencies and internal best practices.

  2. 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...

  3. Development of Multi-Route Physiologically-based Pharmacokinetic Models for Ethanol in the Adult, Pregnant, and Neonatal Rat

    Science.gov (United States)

    Biofuel blends of 10% ethanol (EtOH) and gasoline are common in the United States, and higher EtOH concentrations are being considered (15-85%). Currently, no physiologically-based pharmacokinetic (PBPK) models are available to describe the kinetics of EtOH-based biofuels. PBPK...

  4. DEVELOPMENT OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR DELTAMETHRIN IN DEVELOPING SPRAGUE-DAWLEY RATS

    Science.gov (United States)

    This work describes the development of a physiologically based pharmacokinetic (PBPK) model of deltamethrin, a type II pyrethroid, in the developing male Sprague-Dawley rat. Generalized Michaelis-Menten equations were used to calculate metabolic rate constants and organ weights ...

  5. 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”.

  6. Comparison of the use of a physiologically based pharmacokinetic model and a classical pharmacokinetic model for dioxin exposure assessments.

    Science.gov (United States)

    Emond, Claude; Michalek, Joel E; Birnbaum, Linda S; DeVito, Michael J

    2005-12-01

    In epidemiologic studies, exposure assessments of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) assume a fixed elimination rate. Recent data suggest a dose-dependent elimination rate for TCDD. A physiologically based pharmacokinetic (PBPK) model, which uses a body-burden-dependent elimination rate, was developed previously in rodents to describe the pharmacokinetics of TCDD and has been extrapolated to human exposure for this study. Optimizations were performed using data from a random selection of veterans from the Ranch Hand cohort and data from a human volunteer who was exposed to TCDD. Assessment of this PBPK model used additional data from the Ranch Hand cohort and a clinical report of two women exposed to TCDD. This PBPK model suggests that previous exposure assessments may have significantly underestimated peak blood concentrations, resulting in potential exposure misclassifications. Application of a PBPK model that incorporates an inducible elimination of TCDD may improve the exposure assessments in epidemiologic studies of TCDD.

  7. Clinical pharmacokinetic/pharmacodynamic and physiologically based pharmacokinetic modeling in new drug development: the capecitabine experience.

    Science.gov (United States)

    Blesch, Karen S; Gieschke, Ronald; Tsukamoto, Yuko; Reigner, Bruno G; Burger, Hans U; Steimer, Jean-Louis

    2003-05-01

    Preclinical studies, along with Phase I, II, and III clinical trials demonstrate the pharmacokinetics, pharmacodynamics, safety and efficacy of a new drug under well controlled circumstances in relatively homogeneous populations. However, these types of studies generally do not answer important questions about variability in specific factors that predict pharmacokinetic and pharmacodynamic (PKPD) activity, in turn affecting safety and efficacy. Semi-physiological and clinical PKPD modeling and simulation offer the possibility of utilizing data obtained in the laboratory and the clinic to make accurate characterizations and predictions of PKPD activity in the target population, based on variability in predictive factors. Capecitabine is an orally administered pro-drug of 5-fluorouracil (5-FU), designed to exploit tissue-specific differences in metabolic enzyme activities in order to enhance efficacy and safety. It undergoes extensive metabolism in multiple physiologic compartments, and presents particular challenges for predicting pharmacokinetic and pharmacodynamic activity in humans. Clinical and physiologically based pharmacokinetic (PBPK) and pharmacodynamic models were developed to characterize the activity of capecitabine and its metabolites, and the clinical consequences under varying physiological conditions such as creatinine clearance or activity of key metabolic enzymes. The results of the modeling investigations were consistent with capecitabine's rational design as a triple pro-drug of 5-FU. This paper reviews and discusses the PKPD and PBPK modeling approaches used in capecitabine development to provide a more thorough understanding of what the key predictors of its PBPK activity are, and how variability in these predictors may affect its PKPD, and ultimately, clinical outcomes.

  8. Development of a Physiologically-Based Pharmacokinetic Model for Preterm Neonates: Evaluation with In Vivo Data.

    Science.gov (United States)

    Claassen, Karina; Thelen, Kirstin; Coboeken, Katrin; Gaub, Thomas; Lippert, Jorg; Allegaert, Karel; Willmann, Stefan

    2015-01-01

    Among pediatric patients, preterm neonates and newborns are the most vulnerable subpopulation. Rapid developmental changes of physiological factors affecting the pharmacokinetics of drug substances in newborns require extreme care in dose and dose regimen decisions. These decisions could be supported by in silico methods such as physiologically-based pharmacokinetic (PBPK) modeling. In a comprehensive literature search, the physiological information of preterm neonates that is required to establish a PBPK model has been summarized and implemented into the database of a generic PBPK software. Physiological parameters include the organ weights and blood flow rates, tissue composition, as well as ontogeny information about metabolic and elimination processes in the liver and kidney. The aim of this work is to evaluate the model's accuracy in predicting the pharmacokinetics following intravenous administration of two model drugs with distinct physicochemical properties and elimination pathways based on earlier reported in vivo data. To this end, PBPK models of amikacin and paracetamol have been set up to predict their plasma levels in preterm neonates. Predicted plasma concentration-time profiles were compared to experimentally obtained in vivo data. For both drugs, plasma concentration time profiles following single and multiple dosing were appropriately predicted for a large range gestational and postnatal ages. In summary, PBPK simulations in preterm neonates appear feasible and might become a useful tool in the future to support dosing decisions in this special patient population.

  9. Physiologically Based Pharmacokinetic Modeling for 1-Bromopropane in F344 Rats Using Gas Uptake Inhalation Experiments

    OpenAIRE

    2015-01-01

    1-Bromopropane (1-BP) was introduced into the workplace as an alternative to ozone-depleting solvents and increasingly used in manufacturing industry. The potential exposure to 1-BP and the current reports of adverse effects associated with occupational exposure to high levels of 1-BP have increased the need to understand the mechanism of 1-BP toxicity in animal models as a mean of understanding risk in workers. Physiologically based pharmacokinetic (PBPK) model for 1-BP has been developed to...

  10. DEVELOPMENT OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR DELTAMETHRIN IN ADULT AND DEVELOPING SPRAGUE-DAWLEY RATS

    Science.gov (United States)

    This work describes the development of a physiologically based pharmacokinetic (PBPK) model of deltamethrin, a type II pyrethroid, in the developing male Sprague-Dawley rat. Generalized Michaelis-Menten equations were used to calculate metabolic rate constants and organ weights ...

  11. PKQuest_Java: free, interactive physiologically based pharmacokinetic software package and tutorial

    Directory of Open Access Journals (Sweden)

    Levitt David G

    2009-08-01

    Full Text Available Abstract Background Physiologically based pharmacokinetics (PBPK uses a realistic organ model to describe drug kinetics. The blood-tissue exchange of each organ is characterized by its volume, perfusion, metabolism, capillary permeability and blood/tissue partition coefficient. PBPK applications require both sophisticated mathematical modeling software and a reliable complete set of physiological parameters. Currently there are no software packages available that combine ease of use with the versatility that is required of a general PBPK program. Findings The program is written in Java and is available for free download at http://www.pkquest.com/. Included in the download is a detailed tutorial that discusses the pharmacokinetics of 6 solutes (D2O, amoxicillin, desflurane, propofol, ethanol and thiopental illustrated using experimental human pharmacokinetic data. The complete PBPK description for each solute is stored in Excel spreadsheets that are included in the download. The main features of the program are: 1 Intuitive and versatile interactive interface; 2 Absolute and semi-logarithmic graphical output; 3 Pre-programmed optimized human parameter data set (but, arbitrary values can be input; 4 Time dependent changes in the PBPK parameters; 5 Non-linear parameter optimization; 6 Unique approach to determine the oral "first pass metabolism" of non-linear solutes (e.g. ethanol; 7 Pulmonary perfusion/ventilation heterogeneity for volatile solutes; 8 Input and output of Excel spreadsheet data; 9 Antecubital vein sampling. Conclusion PKQuest_Java is a free, easy to use, interactive PBPK software routine. The user can either directly use the pre-programmed optimized human or rat data set, or enter an arbitrary data set. It is designed so that drugs that are classified as "extracellular" or "highly fat soluble" do not require information about tissue/blood partition coefficients and can be modeled by a minimum of user input parameters. PKQuest

  12. PKQuest_Java: free, interactive physiologically based pharmacokinetic software package and tutorial.

    Science.gov (United States)

    Levitt, David G

    2009-08-05

    Physiologically based pharmacokinetics (PBPK) uses a realistic organ model to describe drug kinetics. The blood-tissue exchange of each organ is characterized by its volume, perfusion, metabolism, capillary permeability and blood/tissue partition coefficient. PBPK applications require both sophisticated mathematical modeling software and a reliable complete set of physiological parameters. Currently there are no software packages available that combine ease of use with the versatility that is required of a general PBPK program. The program is written in Java and is available for free download at http://www.pkquest.com/. Included in the download is a detailed tutorial that discusses the pharmacokinetics of 6 solutes (D2O, amoxicillin, desflurane, propofol, ethanol and thiopental) illustrated using experimental human pharmacokinetic data. The complete PBPK description for each solute is stored in Excel spreadsheets that are included in the download. The main features of the program are: 1) Intuitive and versatile interactive interface; 2) Absolute and semi-logarithmic graphical output; 3) Pre-programmed optimized human parameter data set (but, arbitrary values can be input); 4) Time dependent changes in the PBPK parameters; 5) Non-linear parameter optimization; 6) Unique approach to determine the oral "first pass metabolism" of non-linear solutes (e.g. ethanol); 7) Pulmonary perfusion/ventilation heterogeneity for volatile solutes; 8) Input and output of Excel spreadsheet data; 9) Antecubital vein sampling. PKQuest_Java is a free, easy to use, interactive PBPK software routine. The user can either directly use the pre-programmed optimized human or rat data set, or enter an arbitrary data set. It is designed so that drugs that are classified as "extracellular" or "highly fat soluble" do not require information about tissue/blood partition coefficients and can be modeled by a minimum of user input parameters. PKQuest_Java, along with the included tutorial, could be

  13. A Simplified PBPK Modeling Approach for Prediction of Pharmacokinetics of Four Primarily Renally Excreted and CYP3A Metabolized Compounds During Pregnancy

    OpenAIRE

    Xia, Binfeng; Heimbach, Tycho; Gollen, Rakesh; Nanavati, Charvi; He, Handan

    2013-01-01

    During pregnancy, a drug’s pharmacokinetics may be altered and hence anticipation of potential systemic exposure changes is highly desirable. Physiologically based pharmacokinetics (PBPK) models have recently been used to influence clinical trial design or to facilitate regulatory interactions. Ideally, whole-body PBPK models can be used to predict a drug’s systemic exposure in pregnant women based on major physiological changes which can impact drug clearance (i.e., in the kidney and liver) ...

  14. Characterizing the Effects of Race/Ethnicity on Acetaminophen Pharmacokinetics Using Physiologically Based Pharmacokinetic Modeling.

    Science.gov (United States)

    Zurlinden, Todd J; Reisfeld, Brad

    2017-02-01

    Acetaminophen (APAP, paracetamol) is currently the principal cause of acute liver failure in both the USA and the UK. However, relatively little is known about the influence of genes and race/ethnicity on the disposition of APAP and the extent to which genetic variation and ethnicity may predispose individuals to a higher risk of APAP-induced hepatotoxicity. The objective of this research was to develop subpopulation-specific physiologically based pharmacokinetic (PBPK) models for two genetically different groups (Western Europeans and East Asians) and then use the models to quantify the difference in absorption, distribution, metabolism, and excretion (ADME) of APAP between these groups. A comprehensive set of human pharmacokinetic data mined from the literature was divided into two groups based on ethnicity as an indicator of the expected abundance of phenol-metabolizing alleles. Using these datasets and a Bayesian hierarchical framework, subpopulation-specific physiologically based pharmacokinetic models for APAP were developed and tested for the two groups. Model simulations were in good agreement with experimental data for both time-dependent parent and metabolite concentrations and summary pharmacokinetic parameters. In addition, simulations were conducted to characterize the difference between ADME in these groups with regard to urinary excretion and APAP area under the curve (AUC) in the liver. Although not dramatic at therapeutic dosing levels, these results demonstrated the divergence in the liver-specific APAP concentrations and AUC between the two groups and suggested that differences in glucuronidation capacity may play a role in this disparity. Overall, the models developed in this study, and others created using this type of hierarchical methodology, are expected to be useful in quantifying ADME in a subpopulation-specific manner and reducing prediction uncertainty compared to that from generalized PBPK modeling approaches.

  15. Physiologically-based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women.

    Science.gov (United States)

    De Sousa Mendes, Maïlys; Hirt, Deborah; Urien, Saik; Valade, Elodie; Bouazza, Naïm; Foissac, Frantz; Blanche, Stephane; Treluyer, Jean-Marc; Benaboud, Sihem

    2015-11-01

    Physiological changes during pregnancy can affect drug disposition. Anticipating these changes will help to maximize drug efficacy and safety in pregnant women. Our objective was to determine if physiologically-based pharmacokinetics (PBPK) can accurately predict changes in the disposition of renally excreted antiretroviral drugs during pregnancy. Whole body PBPK models were developed for three renally excreted antiretroviral drugs, tenofovir (TFV), emtricitabine (FTC) and lamivudine (3TC). To assess the impact of pregnancy on PK, time-varying pregnancy-related physiological parameters available within the p-PBPK Simcyp software package were used. Renal clearance during pregnancy followed glomerular filtration changes with or without alterations in secretion. PK profiles were simulated and compared with observed data, i.e. area under the curves (AUC), peak plasma concentrations (Cmax ) and oral clearances (CL/F). PBPK models successfully predicted TFV, FTC and 3TC disposition for non-pregnant and pregnant populations. Both renal secretion and filtration changed during pregnancy. Changes in renal clearance secretion were related to changes in renal plasma flow. The maximum clearance increases were approximately 30% (TFV 33%, FTC 31%, 3TC 29%). Pregnancy PBPK models are useful tools to quantify a priori the drug exposure changes during pregnancy for renally excreted drugs. These models can be applied to evaluate alternative dosing regimens to optimize drug therapy during pregnancy. © 2015 The British Pharmacological Society.

  16. Estimating marbofloxacin withdrawal time in broiler chickens using a population physiologically based pharmacokinetics model.

    Science.gov (United States)

    Yang, F; Yang, Y R; Wang, L; Huang, X H; Qiao, G; Zeng, Z L

    2014-12-01

    Residue depletion of marbofloxacin in broiler chicken after oral administration at 5 mg/kg/day for three consecutive days was studied in this study. The areas under the concentration-time curve from 0 h to ∞ (AUC0-∞ s) of marbofloxacin in tissues and plasma were used to calculate tissue/plasma partition coefficients (PX s). Based on PX s and the other parameters derived from published studies, a flow-limited physiologically based pharmacokinetics (PBPK) model was developed to predict marbofloxacin concentrations, which were then compared with those derived from the residue depletion study so as to validate this model. Considering individual difference in drug disposition, a Monte Carlo simulation included 1000 iterations was further incorporated into the validated model to generate a population PBPK model and to estimate the marbofloxacin residue withdrawal times in edible tissues. The withdrawal periods were compared to those derived from linear regression analysis. The PBPK model presented here successfully predicted the measured concentrations in all tissues. The withdrawal times in all edible tissues derived from the population PBPK model were longer than those from linear regression analysis, and based on the residues in kidney, a withdrawal time of 4 days was estimated for marbofloxacin after oral administration at 5 mg/kg/day for three consecutive days. It was shown that population PBPK model could be used to accurately predict marbofloxacin residue withdrawal time in edible tissues in broiler chickens.

  17. Human plasma concentrations of cytochrome P450 probes extrapolated from pharmacokinetics in cynomolgus monkeys using physiologically based pharmacokinetic modeling.

    Science.gov (United States)

    Shida, Satomi; Utoh, Masahiro; Murayama, Norie; Shimizu, Makiko; Uno, Yasuhiro; Yamazaki, Hiroshi

    2015-01-01

    1. Cynomolgus monkeys are widely used in preclinical studies as non-human primate species. Pharmacokinetics of human cytochrome P450 probes determined in cynomolgus monkeys after single oral or intravenous administrations were extrapolated to give human plasma concentrations. 2. Plasma concentrations of slowly eliminated caffeine and R-/S-warfarin and rapidly eliminated omeprazole and midazolam previously observed in cynomolgus monkeys were scaled to human oral biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Results of the simplified human PBPK models were consistent with reported experimental PK data in humans or with values simulated by a fully constructed population-based simulator (Simcyp). 3. Oral administrations of metoprolol and dextromethorphan (human P450 2D probes) in monkeys reportedly yielded plasma concentrations similar to their quantitative detection limits. Consequently, ratios of in vitro hepatic intrinsic clearances of metoprolol and dextromethorphan determined in monkeys and humans were used with simplified PBPK models to extrapolate intravenous PK in monkeys to oral PK in humans. 4. These results suggest that cynomolgus monkeys, despite their rapid clearance of some human P450 substrates, could be a suitable model for humans, especially when used in conjunction with simple PBPK models.

  18. Physiologically based Pharmacokinetic Modeling of 1,4-Dioxane in Rats, Mice, and Humans

    Energy Technology Data Exchange (ETDEWEB)

    Sweeney, Lisa M.; Thrall, Karla D.; Poet, Torka S.; Corley, Rick; Weber, Thomas J.; Locey, B. J.; Clarkson, Jacquelyn; Sager, S.; Gargas, M. L.

    2008-01-01

    ABSTRACT 1,4-Dioxane (CAS No. 123-91-1) is used primarily as a solvent or as a solvent stabilizer. It can cause lung, liver and kidney damage at sufficiently high exposure levels. Two physiologically-based pharmacokinetic (PBPK) models of 1,4-dioxane and its major metabolite, hydroxyethoxyacetic acid (HEAA), were published in 1990. These models have uncertainties and deficiencies that could be addressed and the model strengthened for use in a contemporary cancer risk assessment for 1,4-dioxane. Studies were performed to fill data gaps and reduce uncertainties pertaining to the pharmacokinetics of 1,4-dioxane and HEAA in rats, mice, and humans. Three types of studies were performed:partition coefficient measurements, blood time course in mice, and in vitro pharmacokinetics using rat, mouse, and human hepatocytes. Updated PBPK models were developed based on these new data and previously available data. The optimized rate of metabolism for the mouse was significantly higher than the value previously estimated. The optimized rat kinetic parameters were similar to those in the 1990 models. Only two human studies were identified. Model predictions were consistent with one study, but did not fit the second as well. In addition, a rat nasal exposure was completed. The results confirmed water directly contacts rat nasal tissues during drinking water under bioassays. Consistent with previous PBPK models, nasal tissues were not specifically included in the model. Use of these models will reduce the uncertainty in future 1,4-dioxane risk assessments.

  19. Physiologically based pharmacokinetic modeling of 1,4-Dioxane in rats, mice, and humans.

    Science.gov (United States)

    Sweeney, Lisa M; Thrall, Karla D; Poet, Torka S; Corley, Richard A; Weber, Thomas J; Locey, Betty J; Clarkson, Jacquelyn; Sager, Shawn; Gargas, Michael L

    2008-01-01

    1,4-Dioxane (CAS No. 123-91-1) is used primarily as a solvent or as a solvent stabilizer. It can cause lung, liver, and kidney damage at sufficiently high exposure levels. Two physiologically based pharmacokinetic (PBPK) models of 1,4-dioxane and its major metabolite, hydroxyethoxyacetic acid (HEAA), were published in 1990. These models have uncertainties and deficiencies that could be addressed and the model strengthened for use in a contemporary cancer risk assessment for 1,4-dioxane. Studies were performed to fill data gaps and reduce uncertainties pertaining to the pharmacokinetics of 1,4-dioxane and HEAA in rats, mice, and humans. Three types of studies were performed: partition coefficient measurements, blood time course in mice, and in vitro pharmacokinetics using rat, mouse, and human hepatocytes. Updated PBPK models were developed based on these new data and previously available data. The optimized rate of metabolism for the mouse was significantly higher than the value previously estimated. The optimized rat kinetic parameters were similar to those in the 1990 models. Only two human studies were identified. Model predictions were consistent with one study, but did not fit the second as well. In addition, a rat nasal exposure was completed. The results confirmed water directly contacts rat nasal tissues during drinking water under bioassay conditions. Consistent with previous PBPK models, nasal tissues were not specifically included in the model. Use of these models will reduce the uncertainty in future 1,4-dioxane risk assessments.

  20. 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.

  1. 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.

  2. Development of Physiologically Based Pharmacokinetic/Pharmacodynamic Model for Indomethacin Disposition in Pregnancy.

    Directory of Open Access Journals (Sweden)

    Saeed Alqahtani

    Full Text Available Findings of a recent clinical study showed indomethacin has lower plasma levels and higher steady-state apparent clearance in pregnant subjects when compared to those in non-pregnant subjects reported in separate studies. Thus, in the current work we developed a pregnancy physiological based pharmacokinetic/pharmacodynamic (PBPK/PD model for indomethacin to explain the differences in indomethacin pharmacokinetics between pregnancy and non-pregnancy. A whole-body PBPK model with key pregnancy-related physiological changes was developed to characterize indomethacin PK in pregnant women and compare these parameters to those in non-pregnant subjects. Data related to maternal physiological and biological changes were obtained from literature and incorporated into the structural PBPK model that describes non-pregnant PK data. Changes in indomethacin area under the curve (AUC, maximum concentration (Cmax and average steady-state concentration (Cave in pregnant women were predicted. Model-simulated PK profiles were in agreement with observed data. The predicted mean ratio (non-pregnant:second trimester (T2 of indomethacin Cave was 1.6 compared to the observed value of 1.59. In addition, the predicted steady-state apparent clearance (CL/Fss ratio was almost similar to the observed value (0.46 vs. 0.42. Sensitivity analysis suggested changes in CYP2C9 activity, and to a lesser extent UGT2B7, as the primary factor contributing to differences in indomethacin disposition between pregnancy and non-pregnancy. The developed PBPK model which integrates prior physiological knowledge, in vitro and in vivo data, allowed the successful prediction of indomethacin disposition during T2. Our PBPK/PD model suggested a higher indomethacin dosing requirement during pregnancy.

  3. Physiologically based pharmacokinetics joined with in vitro-in vivo extrapolation of ADME: a marriage under the arch of systems pharmacology.

    Science.gov (United States)

    Rostami-Hodjegan, A

    2012-07-01

    Classic pharmacokinetics (PK) rarely takes into account the full knowledge of physiology and biology of the human body. However, physiologically based PK (PBPK) is built mainly from drug-independent "system" information. PBPK is not a new concept, but it has shown a very rapid rise in recent years. This has been attributed to a greater connectivity to in vitro-in vivo extrapolation (IVIVE) techniques for predicting drug absorption, distribution, metabolism, and excretion (ADME) and their variability in humans. The marriage between PBPK and IVIVE under the overarching umbrella of "systems biology" has removed many constraints related to cutoff approaches on prediction of ADME. PBPK-IVIVE linked models have repeatedly shown their value in guiding decisions when predicting the effects of intrinsic and extrinsic factors on PK of drugs. A review of the achievements and shortcomings of the models might suggest better strategies in extending the success of PBPK-IVIVE to pharmacodynamics (PD) and drug safety.

  4. 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...

  5. Integration of Life-Stage Physiologically Based Pharmacokinetic Models with Adverse Outcome Pathways and Environmental Exposure Models to Screen for Environmental Hazards

    Science.gov (United States)

    A Life-stage Physiologically-Based Pharmacokinetic (PBPK) model was developed to include descriptions of several life-stage events such as pregnancy, fetal development, the neonate and child growth. The overall modeling strategy was used for in vitro to in vivo (IVIVE) extrapolat...

  6. 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 <1.00E-03, although larger differences involving very small values were noted after exposure transitions. For vinyl chloride and methylene chloride, 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.

  7. Physiologically based pharmacokinetic modeling for 1-bromopropane in F344 rats using gas uptake inhalation experiments.

    Science.gov (United States)

    Garner, C Edwin; Liang, Shenxuan; Yin, Lei; Yu, Xiaozhong

    2015-05-01

    1-Bromopropane (1-BP) was introduced into the workplace as an alternative to ozone-depleting solvents and increasingly used in manufacturing industry. The potential exposure to 1-BP and the current reports of adverse effects associated with occupational exposure to high levels of 1-BP have increased the need to understand the mechanism of 1-BP toxicity in animal models as a mean of understanding risk in workers. Physiologically based pharmacokinetic (PBPK) model for 1-BP has been developed to examine 2 metabolic pathway assumptions for gas-uptake inhalation study. Based on previous gas-uptake experiments in the Fischer 344 rat, the PBPK model was developed by simulating the 1-BP concentration in a closed chamber. In the model, we tested the hypothesis that metabolism responsibilities were shared by the p450 CYP2E1 and glutathione (GSH) conjugation. The results showed that 2 metabolic pathways adequately simulated 1-BP closed chamber concentration. Furthermore, the above model was tested by simulating the gas-uptake data of the female rats pretreated with 1-aminobenzotrizole, a general P450 suicide inhibitor, or d,l-buthionine (S,R)-sulfoximine, an inhibitor of GSH synthesis, prior to exposure to 800 ppm 1-BP. The comparative investigation on the metabolic pathway of 1-BP through the PBPK modeling in both sexes provides critical information for understanding the role of p450 and GSH in the metabolism of 1-BP and eventually helps to quantitatively extrapolate current animal studies to human.

  8. 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.

  9. Retracted: Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans.

    Science.gov (United States)

    Bae, Soo Hyeon; Park, Wan-Su; Han, Seunghoon; Park, Gab-Jin; Lee, Jongtae; Hong, Taegon; Jeon, Sangil; Yim, Dong-Seok

    2017-07-01

    'Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans' by Soo Hyeon Bae, Wan-Su Park, Seunghoon Han, Gab-jin Park, Jongtae Lee, Taegon Hong, Sangil Jeon and Dong-Seok Yim The above article, published online on 06 February 2017 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor in Chief, K. Sandy Pang, and John Wiley & Sons, Ltd. The authors retracted the paper due to errors associated with use of log D vs. log P of telmisartan as inputs of the PBPK model. The authors concluded that there are too many changes in the article to be resolved by an Erratum, and had requested a retraction. Reference Bae, S. H., Park, W.-S., Han, S., Park, G., Lee, J., Hong, T., Jeon, S., and Yim, D.-S. (2016) Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans. Biopharm. Drug Dispos., doi: 10.1002/bdd.2060. Copyright © 2016 John Wiley & Sons, Ltd.

  10. Virtual population pharmacokinetic using physiologically based pharmacokinetic model for evaluating bioequivalence of oral lacidipine formulations in dogs

    Directory of Open Access Journals (Sweden)

    Bin Yang

    2017-01-01

    Full Text Available The aim of the present study was to investigate virtual population pharmacokinetic using physiologically based pharmacokinetic (PBPK model for evaluating bioequivalence of oral lacidipine formulations in dogs. The dissolution behaviors of three lacidipine formulations including one commercial product and two self-made amorphous solid dispersions (ASDs capsules were determined in 0.07% Tween 80 media. A randomized 3-period crossover design in 6 healthy beagle dogs after oral administration of the three formulations at a single dose of 4 mg was conducted. The PBPK modeling was utilized for the virtual bioequivalence study. In vitro dissolution experiment showed that the dissolution behaviors of lacidipine amorphous solid dispersions (ASDs capsules, which was respectively prepared by HPMC-E5 or Soluplus, as polymer displayed similar curves compared with the reference formulation in 0.07% Tween 80 media. In vivo pharmacokinetics experiments showed that three formulations had comparable maximum plasma drug concentration (Cmax, and the time (Tmax to reach Cmax of lacidipine tablet, which was prepared by Soluplus, as polymer was slower than other two formulations in consistency with the in vitro dissolution rate. The 90% confidence interval (CI for the Cmax, AUC0–24 h and AUC0–∞ of the ratio of the test drug to the referencedrug exceeded the acceptable bioequivalence (BE limits (0.80–1.25. However, the 90% CI of the AUC0–24 h, AUC0–∞ and Cmax of the ratio of test to reference drug were within the BE limit, calculated using PBPK modeling when the virtual subjects reached 24 dogs. The results all demonstrated that virtual bioequivalence study can overcome the inequivalence caused by inter-subject variability of the 6 beagle dogs involved in in vivo experiments.

  11. Use of partition coefficients in flow-limited physiologically-based pharmacokinetic modeling.

    Science.gov (United States)

    Thompson, Matthew D; Beard, Daniel A; Wu, Fan

    2012-08-01

    Permeability-limited two-subcompartment and flow-limited, well-stirred tank tissue compartment models are routinely used in physiologically-based pharmacokinetic modeling. Here, the permeability-limited two-subcompartment model is used to derive a general flow-limited case of a two-subcompartment model with the well-stirred tank being a specific case where tissue fractional blood volume approaches zero. The general flow-limited two-subcompartment model provides a clear distinction between two partition coefficients typically used in PBPK: a biophysical partition coefficient and a well-stirred partition coefficient. Case studies using diazepam and cotinine demonstrate that, when the well-stirred tank is used with a priori predicted biophysical partition coefficients, simulations overestimate or underestimate total organ drug concentration relative to flow-limited two-subcompartment model behavior in tissues with higher fractional blood volumes. However, whole-body simulations show predicted drug concentrations in plasma and lower fractional blood volume tissues are relatively unaffected. These findings point to the importance of accurately determining tissue fractional blood volume for flow-limited PBPK modeling. Simulations using biophysical and well-stirred partition coefficients optimized with flow-limited two-subcompartment and well-stirred models, respectively, lead to nearly identical fits to tissue drug distribution data. Therefore, results of whole-body PBPK modeling with diazepam and cotinine indicate both flow-limited models are appropriate PBPK tissue models as long as the correct partition coefficient is used: the biophysical partition coefficient is for use with two-subcompartment models and the well-stirred partition coefficient is for use with the well-stirred tank model.

  12. 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

  13. 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.

  14. 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.

  15. Physiologically-based pharmacokinetic simulation modelling.

    Science.gov (United States)

    Grass, George M; Sinko, Patrick J

    2002-03-31

    Drug selection is now widely viewed as an important and relatively new, yet largely unsolved, bottleneck in the drug discovery and development process. In order to achieve an efficient selection process, high quality, rapid, predictive and correlative ADME models are required in order for them to be confidently used to support critical financial decisions. Systems that can be relied upon to accurately predict performance in humans have not existed, and decisions have been made using tools whose capabilities could not be verified until candidates went to clinical trial, leading to the high failure rates historically observed. However, with the sequencing of the human genome, advances in proteomics, the anticipation of the identification of a vastly greater number of potential targets for drug discovery, and the potential of pharmacogenomics to require individualized evaluation of drug kinetics as well as drug effects, there is an urgent need for rapid and accurately computed pharmacokinetic properties.

  16. Reduction of a Whole-Body Physiologically Based Pharmacokinetic Model to Stabilise the Bayesian Analysis of Clinical Data.

    Science.gov (United States)

    Wendling, Thierry; Tsamandouras, Nikolaos; Dumitras, Swati; Pigeolet, Etienne; Ogungbenro, Kayode; Aarons, Leon

    2016-01-01

    Whole-body physiologically based pharmacokinetic (PBPK) models are increasingly used in drug development for their ability to predict drug concentrations in clinically relevant tissues and to extrapolate across species, experimental conditions and sub-populations. A whole-body PBPK model can be fitted to clinical data using a Bayesian population approach. However, the analysis might be time consuming and numerically unstable if prior information on the model parameters is too vague given the complexity of the system. We suggest an approach where (i) a whole-body PBPK model is formally reduced using a Bayesian proper lumping method to retain the mechanistic interpretation of the system and account for parameter uncertainty, (ii) the simplified model is fitted to clinical data using Markov Chain Monte Carlo techniques and (iii) the optimised reduced PBPK model is used for extrapolation. A previously developed 16-compartment whole-body PBPK model for mavoglurant was reduced to 7 compartments while preserving plasma concentration-time profiles (median and variance) and giving emphasis to the brain (target site) and the liver (elimination site). The reduced model was numerically more stable than the whole-body model for the Bayesian analysis of mavoglurant pharmacokinetic data in healthy adult volunteers. Finally, the reduced yet mechanistic model could easily be scaled from adults to children and predict mavoglurant pharmacokinetics in children aged from 3 to 11 years with similar performance compared with the whole-body model. This study is a first example of the practicality of formal reduction of complex mechanistic models for Bayesian inference in drug development.

  17. Optimizing the Clinical Use of Carvedilol in Liver Cirrhosis Using a Physiologically Based Pharmacokinetic Modeling Approach.

    Science.gov (United States)

    Rasool, Muhammad Fawad; Khalil, Feras; Läer, Stephanie

    2017-06-01

    Liver cirrhosis is a complex pathophysiological condition that can affect the pharmacokinetics (PK) and hereby dosing of administered drugs. The physiologically based pharmacokinetic (PBPK) models are a valuable tool to explore PK of drugs in cirrhosis patients. The objective of this study was to develop and evaluate a PBPK-carvedilol-cirrhosis model with the available clinical data in liver cirrhosis patients and to recommend model-based drug dosing after exploring the underlying differences in unbound and total (bound and unbound) systemic carvedilol concentrations with the different disease stages. A whole body PBPK model was developed using the population-based PBPK simulator, Simcyp(®). After model development and evaluation in healthy adults, system parameters were modified according to the pathophysiological changes that occur in liver cirrhosis, and predictions were compared to available experimental data from liver cirrhosis Child-Pugh [CP]-C patients. A two-fold error range for the observed/predicted ratios (ratioObs/Pred) of the pharmacokinetic parameters was used for model evaluation. Simulations were then extended to cirrhosis CP-A and CP-B populations were no experimental data that are available to explore changes in drug disposition in these patients. Finally, drug unbound and total (bound and unbound) exposure were predicted in cirrhotic patients of different disease severity, and the results were compared to those of healthy adults. The developed model has successfully described carvedilol PK in healthy and cirrhosis CP-C patients. The model predictions showed that, there was an ~13-fold increase in unbound and ~7-fold increase in total (bound and unbound) systemic exposure of carvedilol between healthy and CP-C populations. To have comparable predicted unbound drug exposure in cirrhosis CP-A, CP-B, and CP-C populations as in healthy subjects receiving a dose of 25 mg, reductions of administered doses to 9.375 mg in CP-A, 4.68 mg in CP-B, and 2

  18. Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model for aldicarb and its metabolites in rats and human using exposure-related dose Estimating Model (ERDEM)%应用ERDEM模型为涕灭威及其代谢物构建大鼠和人的PBPK/PD模型研究

    Institute of Scientific and Technical Information of China (English)

    巢迎妍; 张辉; 张晓菲

    2012-01-01

    Objective To construct the PBPK/PD models for aldicarb in rats and humans to help understandits disposition in both species in order to use the models for risk assessment purposes due to aldicarb exposure. MethodsThe PBPK/PD models were constructed using the ERDEM ( Exposure-related dose estimating model ) platform. Themodel structures for both species included a full gastrointestinal compartment, liver metabolism, urinary excretion, fecalelimination,and bimolecular acetylcholinesterase ( AChE ) inhibition by aldicarb and its two oxidized metabolites, aldi-carb sulfoxide and aldicarb sulfone. Experimentally reported values or estimation of physiological, biochemical, and physicochemical parameters were obtained from the open literature or optimized by fitting to the experimental data. Results The rat model simulation of oral exposure of 0. 4 mg/kg aldicarb indicated that aldicarb had an overall half-life of 1. 35 h,and 96. 6% of the dose was excreted in urine compared to the measured 91. 6% at 144 h after oral exposure. AChE activity in blood was inhibited to 31 % of the control level at 0. 35 h in the rat model compared to the measured 42. 5% at 0. 5 h after oral exposure of 0. 33 mg/kg aldicarb. In the human model,the simulation showed that the minimum blood AChE activity was 76. 9% at 1 h compared to the measured 75. 3% after a 0. 05 mg/kg dose of aldicarb. Conclusion The ERDEM model simulations for both species were consistent with the experimental data. Therefore, the models constructed in the ERDEM platform may be helpful in evaluating human health risk due to aldicarb exposure.%目的 为构建涕灭威在大鼠和人的生理药代动力学/药效学(PBPK/PD)模型,以进一步了解涕灭威在两物种体内的转化过程,从而用于其风险评估.方法 采用暴露相关的剂量估算模型(Exposure-related dose estimating model,ERDEM)的构建平台进行模型构建.两个物种的模型结构均包括完整的胃肠道、肝脏代谢、尿排泄

  19. Setting safe acute exposure limits for halon replacement chemicals using physiologically based pharmacokinetic modeling.

    Science.gov (United States)

    Vinegar, A; Jepson, G W; Cisneros, M; Rubenstein, R; Brock, W J

    2000-08-01

    Most proposed replacements for Halon 1301 as a fire suppressant are halogenated hydrocarbons. The acute toxic endpoint of concern for these agents is cardiac sensitization. An approach is described that links the cardiac endpoint as assessed in dogs to a target arterial concentration in humans. Linkage was made using a physiologically based pharmacokinetic (PBPK) model. Monte Carlo simulations, which account for population variability, were used to establish safe exposure times at different exposure concentrations for Halon 1301 (bromotrifluoromethane), CF(3)I (trifluoroiodomethane), HFC-125 (pentafluoroethane), HFC-227ea (1,1,1,2,3,3,3-heptafluoropropane), and HFC-236fa (1,1,1,3,3,3-hexafluoropropane). Application of the modeling technique described here not only makes use of the conservative cardiac sensitization endpoint, but also uses an understanding of the pharmacokinetics of the chemical agents to better establish standards for safe exposure. The combined application of cardiac sensitization data and physiologically based modeling provides a quantitative approach, which can facilitate the selection and effective use of halon replacement candidates.

  20. Physiologically Based Pharmacokinetic Modeling Framework for Quantitative Prediction of an Herb–Drug Interaction

    Science.gov (United States)

    Brantley, S J; Gufford, B T; Dua, R; Fediuk, D J; Graf, T N; Scarlett, Y V; Frederick, K S; Fisher, M B; Oberlies, N H; Paine, M F

    2014-01-01

    Herb–drug interaction predictions remain challenging. Physiologically based pharmacokinetic (PBPK) modeling was used to improve prediction accuracy of potential herb–drug interactions using the semipurified milk thistle preparation, silibinin, as an exemplar herbal product. Interactions between silibinin constituents and the probe substrates warfarin (CYP2C9) and midazolam (CYP3A) were simulated. A low silibinin dose (160 mg/day × 14 days) was predicted to increase midazolam area under the curve (AUC) by 1%, which was corroborated with external data; a higher dose (1,650 mg/day × 7 days) was predicted to increase midazolam and (S)-warfarin AUC by 5% and 4%, respectively. A proof-of-concept clinical study confirmed minimal interaction between high-dose silibinin and both midazolam and (S)-warfarin (9 and 13% increase in AUC, respectively). Unexpectedly, (R)-warfarin AUC decreased (by 15%), but this is unlikely to be clinically important. Application of this PBPK modeling framework to other herb–drug interactions could facilitate development of guidelines for quantitative prediction of clinically relevant interactions. PMID:24670388

  1. 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

  2. Validation of human physiologically based pharmacokinetic model for vinyl acetate against human nasal dosimetry data.

    Science.gov (United States)

    Hinderliter, P M; Thrall, K D; Corley, R A; Bloemen, L J; Bogdanffy, M S

    2005-05-01

    Vinyl acetate has been shown to induce nasal lesions in rodents in inhalation bioassays. A physiologically based pharmacokinetic (PBPK) model for vinyl acetate has been used in human risk assessment, but previous in vivo validation was conducted only in rats. Controlled human exposures to vinyl acetate were conducted to provide validation data for the application of the model in humans. Five volunteers were exposed to 1, 5, and 10 ppm 13C1,13C2 vinyl acetate via inhalation. A probe inserted into the nasopharyngeal region sampled both 13C1,13C2 vinyl acetate and the major metabolite 13C1,13C2 acetaldehyde during rest and light exercise. Nasopharyngeal air concentrations were analyzed in real time by ion trap mass spectrometry (MS/MS). Experimental concentrations of both vinyl acetate and acetaldehyde were then compared to predicted concentrations calculated from the previously published human model. Model predictions of vinyl acetate nasal extraction compared favorably with measured values of vinyl acetate, as did predictions of nasopharyngeal acetaldehyde when compared to measured acetaldehyde. The results showed that the current PBPK model structure and parameterization are appropriate for vinyl acetate. These analyses were conducted from 1 to 10 ppm vinyl acetate, a range relevant to workplace exposure standards but which would not be expected to saturate vinyl acetate metabolism. Risk assessment based on this model further concluded that 24 h per day exposures up to 1 ppm do not present concern regarding cancer or non-cancer toxicity. Validation of the vinyl acetate human PBPK model provides support for these conclusions.

  3. A Novel Method for Assessing Drug Degradation Product Safety Using Physiologically-Based Pharmacokinetic Models and Stochastic Risk Assessment.

    Science.gov (United States)

    Nguyen, Hoa Q; Stamatis, Stephen D; Kirsch, Lee E

    2015-09-01

    Patient safety risk due to toxic degradation products is a potentially critical quality issue for a small group of useful drug substances. Although the pharmacokinetics of toxic drug degradation products may impact product safety, these data are frequently unavailable. The objective of this study is to incorporate the prediction capability of physiologically based pharmacokinetic (PBPK) models into a rational drug degradation product risk assessment procedure using a series of model drug degradants (substituted anilines). The PBPK models were parameterized using a combination of experimental and literature data and computational methods. The impact of model parameter uncertainty was incorporated into stochastic risk assessment procedure for estimating human safe exposure levels based on the novel use of a statistical metric called "PROB" for comparing probability that a human toxicity-target tissue exposure exceeds the rat exposure level at a critical no-observed-adverse-effect level. When compared with traditional risk assessment calculations, this novel PBPK approach appeared to provide a rational basis for drug instability risk assessment by focusing on target tissue exposure and leveraging physiological, biochemical, biophysical knowledge of compounds and species.

  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. 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

  6. 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.

  7. 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

  8. 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.

  9. Mathematical modeling and simulation in animal health - Part II: principles, methods, applications, and value of physiologically based pharmacokinetic modeling in veterinary medicine and food safety assessment.

    Science.gov (United States)

    Lin, Z; Gehring, R; Mochel, J P; Lavé, T; Riviere, J E

    2016-10-01

    This review provides a tutorial for individuals interested in quantitative veterinary pharmacology and toxicology and offers a basis for establishing guidelines for physiologically based pharmacokinetic (PBPK) model development and application in veterinary medicine. This is important as the application of PBPK modeling in veterinary medicine has evolved over the past two decades. PBPK models can be used to predict drug tissue residues and withdrawal times in food-producing animals, to estimate chemical concentrations at the site of action and target organ toxicity to aid risk assessment of environmental contaminants and/or drugs in both domestic animals and wildlife, as well as to help design therapeutic regimens for veterinary drugs. This review provides a comprehensive summary of PBPK modeling principles, model development methodology, and the current applications in veterinary medicine, with a focus on predictions of drug tissue residues and withdrawal times in food-producing animals. The advantages and disadvantages of PBPK modeling compared to other pharmacokinetic modeling approaches (i.e., classical compartmental/noncompartmental modeling, nonlinear mixed-effects modeling, and interspecies allometric scaling) are further presented. The review finally discusses contemporary challenges and our perspectives on model documentation, evaluation criteria, quality improvement, and offers solutions to increase model acceptance and applications in veterinary pharmacology and toxicology.

  10. 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.

  11. A physiologically based pharmacokinetic model for quinoxaline-2-carboxylic acid in rats, extrapolation to pigs.

    Science.gov (United States)

    Yang, X; Zhou, Y-F; Yu, Y; Zhao, D-H; Shi, W; Fang, B-H; Liu, Y-H

    2015-02-01

    A multi-compartment physiologically based pharmacokinetic (PBPK) model to describe the disposition of cyadox (CYX) and its metabolite quinoxaline-2-carboxylic acid (QCA) after a single oral administration was developed in rats (200 mg/kg b.w. of CYX). Considering interspecies differences in physiology and physiochemistry, the model efficiency was validated by pharmacokinetic data set in swine. The model included six compartments that were blood, muscle, liver, kidney, adipose, and a combined compartment for the rest of tissues. The model was parameterized using rat plasma and tissue concentration data that were generated from this study. Model simulations were achieved using a commercially available software program (ACSLXL ibero version 3.0.2.1). Results supported the validity of the model with simulated tissue concentrations within the range of the observations. The correlation coefficients of the predicted and experimentally determined values for plasma, liver, kidney, adipose, and muscles in rats were 0.98, 0.98, 0.98, 0.99, and 0.95, respectively. The rat model parameters were then extrapolated to pigs to estimate QCA disposition in tissues and validated by tissue concentration of QCA in swine. The correlation coefficients between the predicted and observed values were over 0.90. This model could provide a foundation for developing more reliable pig models once more data are available.

  12. Performance Assessment and Translation of Physiologically Based Pharmacokinetic Models from acslX™ to Berkeley Madonna™, MATLAB®, and R language: Oxytetracycline and Gold Nanoparticles as Case Examples.

    Science.gov (United States)

    Lin, Zhoumeng; Jaberi-Douraki, Majid; He, Chunla; Jin, Shiqiang; Yang, Raymond S H; Fisher, Jeffrey W; Riviere, Jim E

    2017-04-08

    Many physiologically based pharmacokinetic (PBPK) models for environmental chemicals, drugs, and nanomaterials have been developed to aid risk and safety assessments using acslXTM. However, acslXTM has been rendered sunset since November 2015. Alternative modeling tools and tutorials are needed for future PBPK applications. This forum article aimed to: (1) demonstrate the performance of four PBPK modeling software packages (acslXTM, Berkeley MadonnaTM, MATLAB®, and R language) tested using two existing models (oxytetracycline and gold nanoparticles); (2) provide a tutorial of PBPK model code conversion from acslXTM to Berkeley MadonnaTM, MATLAB®, and R language; (3) discuss the advantages and disadvantages of each software package in the implementation of PBPK models in toxicology, and (4) share our perspective about future direction in this field. Simulation results of plasma/tissue concentrations/amounts of oxytetracycline and gold from different models were compared visually and statistically with linear regression analyses. Simulation results from the original models were correlated well with results from the recoded models, with time-concentration/amount curves nearly superimposable and determination coefficients of 0.86-1.00. Step-by-step explanations of the recoding of the models in different software programs are provided in the Supplementary Data. In summary, this article presents a tutorial of PBPK model code conversion for a small molecule and a nanoparticle among four software packages, and a performance comparison of these software packages in PBPK model implementation. This tutorial helps beginners learn PBPK modeling, provides suggestions for selecting a suitable tool for future projects, and may lead to the transition from acslXTM to alternative modeling tools. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  13. A physiologically based model for tramadol pharmacokinetics in horses.

    Science.gov (United States)

    Abbiati, Roberto Andrea; Cagnardi, Petra; Ravasio, Giuliano; Villa, Roberto; Manca, Davide

    2017-09-21

    This work proposes an application of a minimal complexity physiologically based pharmacokinetic model to predict tramadol concentration vs time profiles in horses. Tramadol is an opioid analgesic also used for veterinary treatments. Researchers and medical doctors can profit from the application of mathematical models as supporting tools to optimize the pharmacological treatment of animal species. The proposed model is based on physiology but adopts the minimal compartmental architecture necessary to describe the experimental data. The model features a system of ordinary differential equations, where most of the model parameters are either assigned or individualized for a given horse, using literature data and correlations. Conversely, residual parameters, whose value is unknown, are regressed exploiting experimental data. The model proved capable of simulating pharmacokinetic profiles with accuracy. In addition, it provides further insights on un-observable tramadol data, as for instance tramadol concentration in the liver or hepatic metabolism and renal excretion extent. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. UNCERTAINTIES IN TRICHLOROETHYLENE PHARMACOKINETIC MODELS

    Science.gov (United States)

    Understanding the pharmacokinetics of a chemical¯its absorption, distribution, metabolism, and excretion in humans and laboratory animals ¯ is critical to the assessment of its human health risks. For trichloroethylene (TCE), numerous physiologically-based pharmacokinetic (PBPK)...

  15. 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

  16. Predicting lung dosimetry of inhaled particleborne benzo[a]pyrene using physiologically based pharmacokinetic modeling

    Science.gov (United States)

    Campbell, Jerry; Franzen, Allison; Van Landingham, Cynthia; Lumpkin, Michael; Crowell, Susan; Meredith, Clive; Loccisano, Anne; Gentry, Robinan; Clewell, Harvey

    2016-01-01

    Abstract Benzo[a]pyrene (BaP) is a by-product of incomplete combustion of fossil fuels and plant/wood products, including tobacco. A physiologically based pharmacokinetic (PBPK) model for BaP for the rat was extended to simulate inhalation exposures to BaP in rats and humans including particle deposition and dissolution of absorbed BaP and renal elimination of 3-hydroxy benzo[a]pyrene (3-OH BaP) in humans. The clearance of particle-associated BaP from lung based on existing data in rats and dogs suggest that the process is bi-phasic. An initial rapid clearance was represented by BaP released from particles followed by a slower first-order clearance that follows particle kinetics. Parameter values for BaP-particle dissociation were estimated using inhalation data from isolated/ventilated/perfused rat lungs and optimized in the extended inhalation model using available rat data. Simulations of acute inhalation exposures in rats identified specific data needs including systemic elimination of BaP metabolites, diffusion-limited transfer rates of BaP from lung tissue to blood and the quantitative role of macrophage-mediated and ciliated clearance mechanisms. The updated BaP model provides very good prediction of the urinary 3-OH BaP concentrations and the relative difference between measured 3-OH BaP in nonsmokers versus smokers. This PBPK model for inhaled BaP is a preliminary tool for quantifying lung BaP dosimetry in rat and humans and was used to prioritize data needs that would provide significant model refinement and robust internal dosimetry capabilities. PMID:27569524

  17. Physiologically Based Pharmacokinetic Modeling to Predict Drug-Drug Interactions with Efavirenz Involving Simultaneous Inducing and Inhibitory Effects on Cytochromes.

    Science.gov (United States)

    Marzolini, Catia; Rajoli, Rajith; Battegay, Manuel; Elzi, Luigia; Back, David; Siccardi, Marco

    2017-04-01

    Antiretroviral drugs are among the therapeutic agents with the highest potential for drug-drug interactions (DDIs). In the absence of clinical data, DDIs are mainly predicted based on preclinical data and knowledge of the disposition of individual drugs. Predictions can be challenging, especially when antiretroviral drugs induce and inhibit multiple cytochrome P450 (CYP) isoenzymes simultaneously. This study predicted the magnitude of the DDI between efavirenz, an inducer of CYP3A4 and inhibitor of CYP2C8, and dual CYP3A4/CYP2C8 substrates (repaglinide, montelukast, pioglitazone, paclitaxel) using a physiologically based pharmacokinetic (PBPK) modeling approach integrating concurrent effects on CYPs. In vitro data describing the physicochemical properties, absorption, distribution, metabolism, and elimination of efavirenz and CYP3A4/CYP2C8 substrates as well as the CYP-inducing and -inhibitory potential of efavirenz were obtained from published literature. The data were integrated in a PBPK model developed using mathematical descriptions of molecular, physiological, and anatomical processes defining pharmacokinetics. Plasma drug-concentration profiles were simulated at steady state in virtual individuals for each drug given alone or in combination with efavirenz. The simulated pharmacokinetic parameters of drugs given alone were compared against existing clinical data. The effect of efavirenz on CYP was compared with published DDI data. The predictions indicate that the overall effect of efavirenz on dual CYP3A4/CYP2C8 substrates is induction of metabolism. The magnitude of induction tends to be less pronounced for dual CYP3A4/CYP2C8 substrates with predominant CYP2C8 metabolism. PBPK modeling constitutes a useful mechanistic approach for the quantitative prediction of DDI involving simultaneous inducing or inhibitory effects on multiple CYPs as often encountered with antiretroviral drugs.

  18. Application of physiologically based pharmacokinetic modeling in predicting drug–drug interactions for sarpogrelate hydrochloride in humans

    Directory of Open Access Journals (Sweden)

    Min JS

    2016-09-01

    Full Text Available Jee Sun Min,1 Doyun Kim,1 Jung Bae Park,1 Hyunjin Heo,1 Soo Hyeon Bae,2 Jae Hong Seo,1 Euichaul Oh,1 Soo Kyung Bae1 1Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, 2Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, South Korea Background: Evaluating the potential risk of metabolic drug–drug interactions (DDIs is clinically important. Objective: To develop a physiologically based pharmacokinetic (PBPK model for sarpogrelate hydrochloride and its active metabolite, (R,S-1-{2-[2-(3-methoxyphenylethyl]-phenoxy}-3-(dimethylamino-2-propanol (M-1, in order to predict DDIs between sarpogrelate and the clinically relevant cytochrome P450 (CYP 2D6 substrates, metoprolol, desipramine, dextromethorphan, imipramine, and tolterodine. Methods: The PBPK model was developed, incorporating the physicochemical and pharmacokinetic properties of sarpogrelate hydrochloride, and M-1 based on the findings from in vitro and in vivo studies. Subsequently, the model was verified by comparing the predicted concentration-time profiles and pharmacokinetic parameters of sarpogrelate and M-1 to the observed clinical data. Finally, the verified model was used to simulate clinical DDIs between sarpogrelate hydrochloride and sensitive CYP2D6 substrates. The predictive performance of the model was assessed by comparing predicted results to observed data after coadministering sarpogrelate hydrochloride and metoprolol. Results: The developed PBPK model accurately predicted sarpogrelate and M-1 plasma concentration profiles after single or multiple doses of sarpogrelate hydrochloride. The simulated ratios of area under the curve and maximum plasma concentration of metoprolol in the presence of sarpogrelate hydrochloride to baseline were in good agreement with the observed ratios. The predicted fold-increases in the area under the curve ratios of metoprolol

  19. PBPK modeling and simulation in drug research and development

    OpenAIRE

    Xiaomei Zhuang; Chuang Lu

    2016-01-01

    Physiologically based pharmacokinetic (PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data. It can also explore the effects of various physiologic parameters such as age, ethnicity, or disease status on human pharmacokinetics, as well as guide dose and dose regiment selection and aid drug–drug interaction risk assessment. PBPK modeling has developed rapidly in the last decade within both the field of academia and the phar...

  20. Use of a physiologically based pharmacokinetic model to simulate drug-drug interactions between antineoplastic and antiretroviral drugs.

    Science.gov (United States)

    Moltó, José; Rajoli, Rajith; Back, David; Valle, Marta; Miranda, Cristina; Owen, Andrew; Clotet, Bonaventura; Siccardi, Marco

    2017-03-01

    Co-administration of antineoplastics with ART is challenging due to potential drug-drug interactions (DDIs). However, trials specifically assessing such DDIs are lacking. Our objective was to simulate DDIs between the antineoplastics erlotinib and gefitinib with key antiretroviral drugs and to predict dose adjustments using a physiologically based pharmacokinetic (PBPK) model. In vitro data describing chemical properties and pharmacokinetic processes of each drug and their effect on cytochrome P450 isoforms were obtained from the literature. Plasma drug-concentration profiles were simulated in a virtual population of 50 individuals receiving erlotinib or gefitinib alone or with darunavir/ritonavir, efavirenz or etravirine. Simulated pharmacokinetic parameters and the magnitude of DDIs with probe drugs (midazolam, maraviroc) were compared with literature values. Erlotinib and gefitinib pharmacokinetics with and without antiretrovirals were compared and dose-adjustment strategies were evaluated. Simulated parameters of each drug and the magnitude of DDIs with probe drugs were in agreement with reference values. Darunavir/ritonavir increased erlotinib and gefitinib exposure, while efavirenz and etravirine decreased erlotinib and gefitinib concentrations. Based on our predictions, dose-adjustment strategies may consist of once-daily dosing erlotinib at 25 mg and gefitinib at 125 mg with darunavir/ritonavir; or erlotinib at 200 mg and gefitinib at 375 mg with etravirine. The interaction with efavirenz was not overcome even after doubling erlotinib or gefitinib doses. PBPK models predicted the in vivo pharmacokinetics of erlotinib, gefitinib and the antiretrovirals darunavir/ritonavir, efavirenz and etravirine, and the DDIs between them. The simulated dose-adjustments may represent valuable strategies to optimize antineoplastic therapy in HIV-infected patients.

  1. Human Blood Concentrations of Cotinine, a Biomonitoring Marker for Tobacco Smoke, Extrapolated from Nicotine Metabolism in Rats and Humans and Physiologically Based Pharmacokinetic Modeling

    Directory of Open Access Journals (Sweden)

    Masato Kitajima

    2010-09-01

    Full Text Available The present study defined a simplified physiologically based pharmacokinetic (PBPK model for nicotine and its primary metabolite cotinine in humans, based on metabolic parameters determined in vitro using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and an established rat PBPK model. The model consists of an absorption compartment, a metabolizing compartment, and a central compartment for nicotine and three equivalent compartments for cotinine. Evaluation of a rat model was performed by making comparisons with predicted concentrations in blood and in vivo experimental pharmacokinetic values obtained from rats after oral treatment with nicotine (1.0 mg/kg, a no-observed-adverse-effect level for 14 days. Elimination rates of nicotine in vitro were established from data from rat liver microsomes and from human pooled liver microsomes. Human biomonitoring data (17 ng nicotine and 150 ng cotinine per mL plasma 1 h after smoking from pooled five male Japanese smokers (daily intake of 43 mg nicotine by smoking revealed that these blood concentrations could be calculated using a human PBPK model. These results indicate that a simplified PBPK model for nicotine/cotinine is useful for a forward dosimetry approach in humans and for estimating blood concentrations of other related compounds resulting from exposure to low chemical doses.

  2. Development of a Physiologically Based Pharmacokinetic and Pharmacodynamic Model to Determine Dosimetry and Cholinesterase Inhibition for a Binary Mixture of Chlorpyrifos and Diazinon in the Rat

    Energy Technology Data Exchange (ETDEWEB)

    Timchalk, Chuck; Poet, Torka S.

    2008-05-01

    Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models have been developed and validated for the organophosphorus (OP) insecticides chlorpyrifos (CPF) and diazinon (DZN). Based on similar pharmacokinetic and mode of action properties it is anticipated that these OPs could interact at a number of important metabolic steps including: CYP450 mediated activation/detoxification, and blood/tissue cholinesterase (ChE) binding/inhibition. We developed a binary PBPK/PD model for CPF, DZN and their metabolites based on previously published models for the individual insecticides. The metabolic interactions (CYP450) between CPF and DZN were evaluated in vitro and suggests that CPF is more substantially metabolized to its oxon metabolite than is DZN. These data are consistent with their observed in vivo relative potency (CPF>DZN). Each insecticide inhibited the other’s in vitro metabolism in a concentration-dependent manner. The PBPK model code used to described the metabolism of CPF and DZN was modified to reflect the type of inhibition kinetics (i.e. competitive vs. non-competitive). The binary model was then evaluated against previously published rodent dosimetry and ChE inhibition data for the mixture. The PBPK/PD model simulations of the acute oral exposure to single- (15 mg/kg) vs. binary-mixtures (15+15 mg/kg) of CFP and DZN at this lower dose resulted in no differences in the predicted pharmacokinetics of either the parent OPs or their respective metabolites; whereas, a binary oral dose of CPF+DZN at 60+60 mg/kg did result in observable changes in the DZN pharmacokinetics. Cmax was more reasonably fit by modifying the absorption parameters. It is anticipated that at low environmentally relevant binary doses, most likely to be encountered in occupational or environmental related exposures, that the pharmacokinetics are expected to be linear, and ChE inhibition dose-additive.

  3. Physiologically based pharmacokinetic model of amphotericin B disposition in rats following administration of deoxycholate formulation (Fungizone®): pooled analysis of published data.

    Science.gov (United States)

    Kagan, Leonid; Gershkovich, Pavel; Wasan, Kishor M; Mager, Donald E

    2011-06-01

    The time course of tissue distribution of amphotericin B (AmB) has not been sufficiently characterized despite its therapeutic importance and an apparent disconnect between plasma pharmacokinetics and clinical outcomes. The goals of this work were to develop and evaluate a physiologically based pharmacokinetic (PBPK) model to characterize the disposition properties of AmB administered as deoxycholate formulation in healthy rats and to examine the utility of the PBPK model for interspecies scaling of AmB pharmacokinetics. AmB plasma and tissue concentration-time data, following single and multiple intravenous administration of Fungizone® to rats, from several publications were combined for construction of the model. Physiological parameters were fixed to literature values. Various structural models for single organs were evaluated, and the whole-body PBPK model included liver, spleen, kidney, lung, heart, gastrointestinal tract, plasma, and remainder compartments. The final model resulted in a good simultaneous description of both single and multiple dose data sets. Incorporation of three subcompartments for spleen and kidney tissues was required for capturing a prolonged half-life in these organs. The predictive performance of the final PBPK model was assessed by evaluating its utility in predicting pharmacokinetics of AmB in mice and humans. Clearance and permeability-surface area terms were scaled with body weight. The model demonstrated good predictions of plasma AmB concentration-time profiles for both species. This modeling framework represents an important basis that may be further utilized for characterization of formulation- and disease-related factors in AmB pharmacokinetics and pharmacodynamics.

  4. Overview of Dioxin Kinetics and Application of Dioxin Physiologically Based Phannacokinetic (PBPK) Models to Risk Assessment

    Science.gov (United States)

    The available data on the pharmacokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in animals and humans have been thoroughly reviewed in literature. It is evident based on these reviews and other analyses that three distinctive features of TCDD play important roles in dete...

  5. Overview of Dioxin Kinetics and Application of Dioxin Physiologically Based Phannacokinetic (PBPK) Models to Risk Assessment

    Science.gov (United States)

    The available data on the pharmacokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in animals and humans have been thoroughly reviewed in literature. It is evident based on these reviews and other analyses that three distinctive features of TCDD play important roles in dete...

  6. Prediction of Deoxypodophyllotoxin Disposition in Mouse, Rat, Monkey and Dog by Physiologically-based Pharmacokinetic Model and the Extrapolation to Human

    Directory of Open Access Journals (Sweden)

    Yang Chen

    2016-12-01

    Full Text Available Deoxypodophyllotoxin (DPT is a potential anti-tumor candidate prior to its clinical phase. The aim of the study was to develop a physiologically-based pharmacokinetic (PBPK model consisting of 13 tissue compartments to predict DPT disposition in mouse, rat, monkey and dog based on in vitro and in silico inputs. Since large interspecies difference was found in unbound fraction of DPT in plasma, we assumed that Kt:pl,u (unbound tissue-to-plasma concentration ratio was identical across species. The predictions of our model were then validated by in vivo data of corresponding preclinical species, along with visual predictive checks. Reasonable matches were found between observed and predicted plasma concentrations and pharmacokinetic parameters in all four animal species. The prediction in the related seven tissues of mouse was also desirable. We also attempted to predict human pharmacokinetic profile by both the developed PBPK model and interspecies allometric scaling across mouse, rat and monkey, while dog was excluded from the scaling. The two approaches reached similar results. We hope the study will help in the efficacy and safety assessment of DPT in future clinical studies and provide a reference to the preclinical screening of similar compounds by PBPK model.

  7. Prediction and evaluation of route dependent dosimetry of BPA in rats at different life stages using a physiologically based pharmacokinetic model

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Xiaoxia, E-mail: Xiaoxia.Yang@fda.hhs.gov; Doerge, Daniel R.; Fisher, Jeffrey W.

    2013-07-01

    Bisphenol A (BPA) has received considerable attention throughout the last decade due to its widespread use in consumer products. For the first time a physiologically based pharmacokinetic (PBPK) model was developed in neonatal and adult rats to quantitatively evaluate age-dependent pharmacokinetics of BPA and its phase II metabolites. The PBPK model was calibrated in adult rats using studies on BPA metabolism and excretion in the liver and gastrointestinal tract, and pharmacokinetic data with BPA in adult rats. For immature rats the hepatic and gastrointestinal metabolism of BPA was inferred from studies on the maturation of phase II enzymes coupled with serum time course data in pups. The calibrated model predicted the measured serum concentrations of BPA and BPA conjugates after administration of 100 μg/kg of d6-BPA in adult rats (oral gavage and intravenous administration) and postnatal days 3, 10, and 21 pups (oral gavage). The observed age-dependent BPA serum concentrations were partially attributed to the immature metabolic capacity of pups. A comparison of the dosimetry of BPA across immature rats and monkeys suggests that dose adjustments would be necessary to extrapolate toxicity studies from neonatal rats to infant humans. - Highlights: • A PBPK model predicts the kinetics of bisphenol A (BPA) in young and adult rats. • BPA metabolism within enterocytes is required for fitting of oral BPA kinetic data. • BPA dosimetry in young rats is different than adult rats and young monkeys.

  8. Use of Physiologically-Based Pharmacokinetic Modeling to Simulate the Profiles of 3-Hydroxybenzo(a)pyrene in Workers Exposed to Polycyclic Aromatic Hydrocarbons

    OpenAIRE

    Roberto Heredia Ortiz; Anne Maître; Damien Barbeau; Michel Lafontaine; Michèle Bouchard

    2014-01-01

    Biomathematical modeling has become an important tool to assess xenobiotic exposure in humans. In the present study, we have used a human physiologically-based pharmacokinetic (PBPK) model and an simple compartmental toxicokinetic model of benzo(a)pyrene (BaP) kinetics and its 3-hydroxybenzo(a)pyrene (3-OHBaP) metabolite to reproduce the time-course of this biomarker of exposure in the urine of industrially exposed workers and in turn predict the most plausible exposure scenarios. The models ...

  9. Scale-up of a physiologically-based pharmacokinetic model to predict the disposition of monoclonal antibodies in monkeys.

    Science.gov (United States)

    Glassman, Patrick M; Chen, Yang; Balthasar, Joseph P

    2015-10-01

    Preclinical assessment of monoclonal antibody (mAb) disposition during drug development often includes investigations in non-human primate models. In many cases, mAb exhibit non-linear disposition that relates to mAb-target binding [i.e., target-mediated disposition (TMD)]. The goal of this work was to develop a physiologically-based pharmacokinetic (PBPK) model to predict non-linear mAb disposition in plasma and in tissues in monkeys. Physiological parameters for monkeys were collected from several sources, and plasma data for several mAbs associated with linear pharmacokinetics were digitized from prior literature reports. The digitized data displayed great variability; therefore, parameters describing inter-antibody variability in the rates of pinocytosis and convection were estimated. For prediction of the disposition of individual antibodies, we incorporated tissue concentrations of target proteins, where concentrations were estimated based on categorical immunohistochemistry scores, and with assumed localization of target within the interstitial space of each organ. Kinetics of target-mAb binding and target turnover, in the presence or absence of mAb, were implemented. The model was then employed to predict concentration versus time data, via Monte Carlo simulation, for two mAb that have been shown to exhibit TMD (2F8 and tocilizumab). Model predictions, performed a priori with no parameter fitting, were found to provide good prediction of dose-dependencies in plasma clearance, the areas under plasma concentration versu time curves, and the time-course of plasma concentration data. This PBPK model may find utility in predicting plasma and tissue concentration versus time data and, potentially, the time-course of receptor occupancy (i.e., mAb-target binding) to support the design and interpretation of preclinical pharmacokinetic-pharmacodynamic investigations in non-human primates.

  10. Prediction of Ketoconazole absorption using an updated in vitro transfer model coupled to physiologically based pharmacokinetic modelling.

    Science.gov (United States)

    Ruff, Aaron; Fiolka, Tom; Kostewicz, Edmund S

    2017-03-30

    The aim of this study was to optimize the in vitro transfer model and to increase its biorelevance to more accurately mimic the in vivo supersaturation and precipitation behaviour of weak basic drugs. Therefore, disintegration of the formulation, volumes of the stomach and intestinal compartments, transfer rate, bile salt concentration, pH range and paddle speed were varied over a physiological relevant range. The supersaturation and precipitation data from these experiments for Ketoconazole (KTZ) were coupled to physiologically based pharmacokinetic (PBPK) model using Stella® software, which also incorporated the disposition kinetics of KTZ taken from the literature, in order to simulate the oral absorption and plasma profile in humans. As expected for a poorly soluble weak base, KTZ demonstrated supersaturation followed by precipitation under various in vitro conditions simulating the proximal small intestine with the results influenced by transfer rate, hydrodynamics, volume, bile salt concentration and pH values. When the in vitro data representing the "average" GI conditions was coupled to the PBPK model, the simulated profiles came closest to the observed mean plasma profiles for KTZ. In line with the high permeability of KTZ, the simulated profiles were highly influenced by supersaturation whilst precipitation was not predicted to occur in vivo. A physiological relevant in vitro "standard" transfer model setup to investigate supersaturation and precipitation was established. For translating the in vitro data to the in vivo setting, it is important that permeability is considered which can be achieved by coupling the in vitro data to PBPK modelling. Copyright © 2016. Published by Elsevier B.V.

  11. Physiologically-Based Pharmacokinetic/Toxicokinetic Modeling in Risk Assessment

    Science.gov (United States)

    2005-03-01

    thyroid stroma, follicular membrane and lumen after perchlorate (C10 4 ) dosing (Chow and Woodbury, 1970). Electrical potential differences can be...concentration in blood. In addition, some of the chemical will be reabsorbed from bile and result in an increase of parent or metabolite(s) concentration...misleading as it is usually not suggested that there is an actual membrane barrier to the diffusion process. PBPK/PD models These models include a

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

    Science.gov (United States)

    Bachler, Gerald; von Goetz, Natalie; Hungerbühler, Konrad

    2013-01-01

    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 (nano)silver 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 different exposure scenarios, namely dietary intake, use of three separate consumer products, and occupational exposure. PMID:24039420

  13. Physiologically-Based Pharmacokinetic and Pharmacodynamic Modeling for the Inhibition of Acetylcholinesterase by Acotiamide, A Novel Gastroprokinetic Agent for the Treatment of Functional Dyspepsia, in Rat Stomach.

    Science.gov (United States)

    Yoshii, Kazuyoshi; Iikura, Minami; Hirayama, Masamichi; Toda, Ryoko; Kawabata, Yoshihiro

    2016-02-01

    Acotiamide, a gastroprokinetic agent used to treat functional dyspepsia, is transported to at least two compartments in rat stomach. However, the role of these stomach compartments in pharmacokinetics and pharmacodynamics of acotiamide remains unclear. Thus, the purpose of this study was to elucidate the relationship of the blood and stomach concentration of acotiamide with its inhibitory effect on acetylcholinesterase (AChE). Concentration profiles of acotiamide and acetylcholine (ACh) were determined after intravenous administration to rats and analyzed by physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD) model containing vascular space, precursor pool and deep pool of stomach. Acotiamide was eliminated from the blood and stomach in a biexponential manner. Our PBPK/PD model estimated that acotiamide concentration in the precursor pool exceeded 2 μM at approximately 2 h after administration. Acotiamide inhibited AChE activity in vitro with a 50% inhibitory concentration of 1.79 μM. ACh reached the maximum concentration at 2 h after administration. Our PBPK model well described the profile of acotiamide and ACh concentration in the stomach in the assumption that acotiamide was distributed by carrier mediated process and inhibited AChE in the precursor pool of stomach. Thus, Acotiamide in the precursor pool plays an important role for producing the pharmacological action.

  14. Human plasma concentrations of herbicidal carbamate molinate extrapolated from the pharmacokinetics established in in vivo experiments with chimeric mice with humanized liver and physiologically based pharmacokinetic modeling.

    Science.gov (United States)

    Yamashita, Masanao; Suemizu, Hiroshi; Murayama, Norie; Nishiyama, Sayako; Shimizu, Makiko; Yamazaki, Hiroshi

    2014-10-01

    To predict concentrations in humans of the herbicidal carbamate molinate, used exclusively in rice cultivation, a forward dosimetry approach was carried out using data from lowest-observed-adverse-effect-level doses orally administered to rats, wild type mice, and chimeric mice with humanized liver and from in vitro human and rodent experiments. Human liver microsomes preferentially mediated hydroxylation of molinate, but rat livers additionally produced molinate sulfoxide and an unidentified metabolite. Adjusted animal biomonitoring equivalents for molinate and its primary sulfoxide from animal studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and human metabolic data with a simple physiologically based pharmacokinetic (PBPK) model. The slower disposition of molinate and accumulation of molinate sulfoxide in humans were estimated by modeling after single and multiple doses compared with elimination in rodents. The results from simplified PBPK modeling in combination with chimeric mice with humanized liver suggest that ratios of estimated parameters of molinate sulfoxide exposure in humans to those in rats were three times as many as general safety factor of 10 for species difference in toxicokinetics. Thus, careful regulatory decision is needed when evaluating the human risk resulting from exposure to low doses of molinate and related carbamates based on data obtained from rats.

  15. A physiologically based pharmacokinetic model to predict the pharmacokinetics of highly protein-bound drugs and the impact of errors in plasma protein binding.

    Science.gov (United States)

    Ye, Min; Nagar, Swati; Korzekwa, Ken

    2016-04-01

    Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data were often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding and the blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate the model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for the terminal elimination half-life (t1/2 , 100% of drugs), peak plasma concentration (Cmax , 100%), area under the plasma concentration-time curve (AUC0-t , 95.4%), clearance (CLh , 95.4%), mean residence time (MRT, 95.4%) and steady state volume (Vss , 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. Copyright © 2016 John Wiley & Sons, Ltd.

  16. 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.

  17. Physiologically Based Pharmacokinetic Predictions of Tramadol Exposure Throughout Pediatric Life: an Analysis of the Different Clearance Contributors with Emphasis on CYP2D6 Maturation.

    Science.gov (United States)

    T'jollyn, Huybrecht; Snoeys, Jan; Vermeulen, An; Michelet, Robin; Cuyckens, Filip; Mannens, Geert; Van Peer, Achiel; Annaert, Pieter; Allegaert, Karel; Van Bocxlaer, Jan; Boussery, Koen

    2015-11-01

    This paper focuses on the retrospective evaluation of physiologically based pharmacokinetic (PBPK) techniques used to mechanistically predict clearance throughout pediatric life. An intravenous tramadol retrograde PBPK model was set up in Simcyp® using adult clearance values, qualified for CYP2D6, CYP3A4, CYP2B6, and renal contributions. Subsequently, the model was evaluated for mechanistic prediction of total, CYP2D6-related, and renal clearance predictions in very early life. In two in vitro pediatric human liver microsomal (HLM) batches (1 and 3 months), O-desmethyltramadol and N-desmethyltramadol formation rates were compared with CYP2D6 and CYP3A4 activity, respectively. O-desmethyltramadol formation was mediated only by CYP2D6, while N-desmethyltramadol was mediated in part by CYP3A4. Additionally, the clearance maturation of the PBPK model predictions was compared to two in vivo maturation models (Hill and exponential) based on plasma concentration data, and to clearance estimations from a WinNonlin® fit of plasma concentration and urinary excretion data. Maturation of renal and CYP2D6 clearance is captured well in the PBPK model predictions, but total tramadol clearance is underpredicted. The most pronounced underprediction of total and CYP2D6-mediated clearance was observed in the age range of 2-13 years. In conclusion, the PBPK technique showed to be a powerful mechanistic tool capable of predicting maturation of CYP2D6 and renal tramadol clearance in early infancy, although some underprediction occurs between 2 and 13 years for total and CYP2D6-mediated tramadol clearance.

  18. Physiologically based pharmacokinetic modeling of a homologous series of barbiturates in the rat: a sensitivity analysis.

    Science.gov (United States)

    Nestorov, I A; Aarons, L J; Rowland, M

    1997-08-01

    Sensitivity analysis studies the effects of the inherent variability and uncertainty in model parameters on the model outputs and may be a useful tool at all stages of the pharmacokinetic modeling process. The present study examined the sensitivity of a whole-body physiologically based pharmacokinetic (PBPK) model for the distribution kinetics of nine 5-n-alkyl-5-ethyl barbituric acids in arterial blood and 14 tissues (lung, liver, kidney, stomach, pancreas, spleen, gut, muscle, adipose, skin, bone, heart, brain, testes) after i.v. bolus administration to rats. The aims were to obtain new insights into the model used, to rank the model parameters involved according to their impact on the model outputs and to study the changes in the sensitivity induced by the increase in the lipophilicity of the homologues on ascending the series. Two approaches for sensitivity analysis have been implemented. The first, based on the Matrix Perturbation Theory, uses a sensitivity index defined as the normalized sensitivity of the 2-norm of the model compartmental matrix to perturbations in its entries. The second approach uses the traditional definition of the normalized sensitivity function as the relative change in a model state (a tissue concentration) corresponding to a relative change in a model parameter. Autosensitivity has been defined as sensitivity of a state to any of its parameters; cross-sensitivity as the sensitivity of a state to any other states' parameters. Using the two approaches, the sensitivity of representative tissue concentrations (lung, liver, kidney, stomach, gut, adipose, heart, and brain) to the following model parameters: tissue-to-unbound plasma partition coefficients, tissue blood flows, unbound renal and intrinsic hepatic clearance, permeability surface area product of the brain, have been analyzed. Both the tissues and the parameters were ranked according to their sensitivity and impact. The following general conclusions were drawn: (i) the overall

  19. A Detailed Physiologically Based Model to Simulate the Pharmacokinetics and Hormonal Pharmacodynamics of Enalapril on the Circulating Endocrine Renin-Angiotensin-Aldosterone System

    Science.gov (United States)

    Claassen, Karina; Willmann, Stefan; Eissing, Thomas; Preusser, Tobias; Block, Michael

    2013-01-01

    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 with 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. PMID:23404365

  20. Physiologically based pharmacokinetic-pharmacodynamic modeling to predict concentrations and actions of sodium-dependent glucose transporter 2 inhibitor canagliflozin in human intestines and renal tubules.

    Science.gov (United States)

    Mori, Kazumi; Saito, Ryuta; Nakamaru, Yoshinobu; Shimizu, Makiko; Yamazaki, Hiroshi

    2016-11-01

    Canagliflozin is a recently developed sodium-glucose cotransporter (SGLT) 2 inhibitor that promotes renal glucose excretion and is considered to inhibit renal SGLT2 from the luminal side of proximal tubules. Canagliflozin reportedly inhibits SGLT1 weakly and suppresses postprandial plasma glucose, suggesting that it also inhibits intestinal SGLT1. However, it is difficult to measure the drug concentrations of these assumed sites of action directly. The pharmacokinetic-pharmacodynamic (PK/PD) relationships of canagliflozin remain poorly characterized. Therefore, a physiologically based pharmacokinetic (PBPK) model of canagliflozin was developed based on clinical data from healthy volunteers and it was used to simulate luminal concentrations in intestines and renal tubules. In small intestine simulations, the inhibition ratios for SGLT1 were predicted to be 40%-60% after the oral administration of clinical doses (100-300 mg/day). In contrast, inhibition ratios of canagliflozin for renal SGLT2 and SGLT1 were predicted to be approximately 100% and 0.2%-0.4%, respectively. These analyses suggest that canagliflozin only inhibits SGLT2 in the kidney. Using the simulated proximal tubule luminal concentrations of canagliflozin, the urinary glucose excretion rates in canagliflozin-treated diabetic patients were accurately predicted using the renal glucose reabsorption model as a PD model. Because the simulation of canagliflozin pharmacokinetics was successful, this PBPK methodology was further validated by successfully simulating the pharmacokinetics of dapagliflozin, another SGLT2 inhibitor. The present results suggest the utility of this PBPK/PD model for predicting canagliflozin concentrations at target sites and help to elucidate the pharmacological effects of SGLT1/2 inhibition in humans. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  1. 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

  2. Use of physiologically based pharmacokinetic models coupled with pharmacodynamic models to assess the clinical relevance of current bioequivalence criteria for generic drug products containing Ibuprofen.

    Science.gov (United States)

    Cristofoletti, Rodrigo; Dressman, Jennifer B

    2014-10-01

    Physiologically based pharmacokinetic models coupled with pharmacodynamic (PBPK/PD) models can be useful to identify whether current bioequivalence criteria is overly conservative or venturesome for different drugs. A PBPK model constructed with Simcyp Simulator(®) using reported biopharmaceutics parameters for ibuprofen was coupled with two published PD models: one for antipyresis and one for dental pain relief. Using products with doses of 400 mg and 10 mg/kg as "reference (R)" drug products, virtual products with doses of 280 mg and 7 mg/kg, respectively, could be interpreted as representing bioinequivalent test (T) drug products, as the point estimate for the ratios T/R are well below the bioequivalence limits. Despite being bioinequivalent in terms of PK, these lower doses were shown to be therapeutically equivalent to the higher doses because of the flat dose-response relationship of ibuprofen. Sensitivity analysis of the PBPK/PD models demonstrated that gastric emptying time, dissolution rate and small intestine pH are variables that influence ibuprofen PK, but do not seem to significantly affect its PD. It was concluded that current bioequivalent guidance might be unnecessarily restrictive for ibuprofen products.

  3. 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

  4. USE OF EXPOSURE RELATED DOSE ESTIMATING MODEL ( ERDEM ) TO CONSTRUCT A PBPK /MODEL FOR CARBOFURAN WITH THE REPORTED EXPERIMENTAL DATA IN THE RAT

    Science.gov (United States)

    To better understand the relationships among carbofuran exposure, dose, and effects, a physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed for the rat using the Exposure Related Dose Estimating Model (ERDEM) framework.

  5. 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

  6. 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

  7. 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.

  8. Elucidating the Plasma and Liver Pharmacokinetics of Simeprevir in Special Populations Using Physiologically Based Pharmacokinetic Modelling.

    Science.gov (United States)

    Snoeys, Jan; Beumont, Maria; Monshouwer, Mario; Ouwerkerk-Mahadevan, Sivi

    2016-11-29

    The disposition of simeprevir (SMV) in humans is characterised by cytochrome P450 3A4 metabolism and hepatic uptake by organic anion transporting polypeptide 1B1/3 (OATP1B1/3). This study was designed to investigate SMV plasma and liver exposure upon oral administration in subjects infected with hepatitis C virus (HCV), in subjects of Japanese or Chinese origin, subjects with organ impairment and subjects with OATP genetic polymorphisms, using physiologically based pharmacokinetic modelling. Simulations showed that compared with healthy Caucasian subjects, SMV plasma exposure was 2.4-, 1.7-, 2.2- and 2.0-fold higher, respectively, in HCV-infected Caucasian subjects, in healthy Japanese, healthy Chinese and subjects with severe renal impairment. Further simulations showed that compared with HCV-infected Caucasian subjects, SMV plasma exposure was 1.6-fold higher in HCV-infected Japanese subjects. In subjects with OATP1B1 genetic polymorphisms, no noteworthy changes in SMV pharmacokinetics were observed. Simulations suggested that liver concentrations in Caucasians with HCV are 18 times higher than plasma concentrations.

  9. Characterization of preclinical in vitro and in vivo ADME properties and prediction of human PK using a physiologically based pharmacokinetic model for YQA-14, a new dopamine D3 receptor antagonist candidate for treatment of drug addiction.

    Science.gov (United States)

    Liu, Fei; Zhuang, Xiaomei; Yang, Cuiping; Li, Zheng; Xiong, Shan; Zhang, Zhiwei; Li, Jin; Lu, Chuang; Zhang, Zhenqing

    2014-07-01

    YQA-14 is a novel and selective dopamine D3 receptor antagonist, with potential for the treatment of drug addiction. However, earlier compounds in its structural class tend to have poor oral bioavailability. The objectives of this study were to characterize the preclinical absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK) of YQA-14, then to simulate the clinical PK of YQA-14 using a physiologically based pharmacokinetics (PBPK) model to assess the likelihood of developing YQA-14 as a clinical candidate. For human PK prediction, PBPK models were first built in preclinical species, rats and dogs, for validation purposes. The model was then modified by input of human in vitro ADME data obtained from in vitro studies. The study data showed that YQA-14 is a basic lipophilic compound, with rapid absorption (Tmax ~ 1 h) in both rats and dogs. Liver microsomal clearances and in vivo clearances were moderate in rats and dogs consistent with the moderate bioavailability observed in both species. The PBPK models built for rats and dogs simulated the observed PK data well in both species. The PBPK model refined with human data predicted that YQA-14 would have a clearance of 8.0 ml/min/kg, a volume distribution of 1.7 l/kg and a bioavailability of 16.9%. These acceptable PK properties make YQA-14 an improved candidate for further research and development as a potential dopamine D3R antagonism for the treatment of drug addiction in the clinic.

  10. Physiologically based pharmacokinetic toolkit to evaluate environmental exposures: Applications of the dioxin model to study real life exposures.

    Science.gov (United States)

    Emond, Claude; Ruiz, Patricia; Mumtaz, Moiz

    2017-01-15

    Chlorinated dibenzo-p-dioxins (CDDs) are a series of mono- to octa-chlorinated homologous chemicals commonly referred to as polychlorinated dioxins. One of the most potent, well-known, and persistent member of this family is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). As part of translational research to make computerized models accessible to health risk assessors, we present a Berkeley Madonna recoded version of the human physiologically based pharmacokinetic (PBPK) model used by the U.S. Environmental Protection Agency (EPA) in the recent dioxin assessment. This model incorporates CYP1A2 induction, which is an important metabolic vector that drives dioxin distribution in the human body, and it uses a variable elimination half-life that is body burden dependent. To evaluate the model accuracy, the recoded model predictions were compared with those of the original published model. The simulations performed with the recoded model matched well with those of the original model. The recoded model was then applied to available data sets of real life exposure studies. The recoded model can describe acute and chronic exposures and can be useful for interpreting human biomonitoring data as part of an overall dioxin and/or dioxin-like compounds risk assessment. Copyright © 2016. Published by Elsevier Inc.

  11. An Extended Minimal Physiologically Based Pharmacokinetic Model: Evaluation of Type II Diabetes Mellitus and Diabetic Nephropathy on Human IgG Pharmacokinetics in Rats.

    Science.gov (United States)

    Chadha, Gurkishan S; Morris, Marilyn E

    2015-11-01

    Although many studies have evaluated the effects of type 2 diabetes mellitus (T2DM) on the pharmacokinetics (PK) of low molecular weight molecules, there is limited information regarding effects on monoclonal antibodies. Our previous studies have reported significant increases in total (2-4 fold) and renal (100-300 fold) clearance of human IgG, an antibody isotype, in Zucker diabetic fatty (ZDF) rats. Pioglitazone treatment incompletely reversed the disease-related PK changes. The objective of this study was to construct a mechanistic model for simultaneous fitting plasma and urine data, to yield physiologically relevant PK parameters. We propose an extended minimal physiologically based PK (mPBPK) model specifically for IgG by classifying organs as either leaky or tight vascular tissues, and adding a kidney compartment. The model incorporates convection as the primary mechanism of IgG movement from plasma into tissues, interstitial fluid (ISF) in extravascular distribution space, and glomerular filtration rate (GFR), sieving coefficient and fraction reabsorbed in the kidney. The model captured the plasma and urine PK profiles well, and simulated concentrations in ISF. The model estimated a 2-4 fold increase in nonrenal clearance from plasma and 30-120 fold increase in renal clearance with T2DM, consistent with the experimental findings, and these differences in renal clearance were related to changes in GFR, sieving coefficient, and proximal tubular reabsorption. In conclusion, the mPBPK model offers a more relevant approach for analyzing plasma and urine IgG concentration-time data than conventional models and provides insight regarding alterations in distributional and elimination parameters occurring with T2DM.

  12. Human biofluid concentrations of mono(2-ethylhexyl)phthalate extrapolated from pharmacokinetics in chimeric mice with humanized liver administered with di(2-ethylhexyl)phthalate and physiologically based pharmacokinetic modeling.

    Science.gov (United States)

    Adachi, Koichiro; Suemizu, Hiroshi; Murayama, Norie; Shimizu, Makiko; Yamazaki, Hiroshi

    2015-05-01

    Di(2-ethylhexyl)phthalate (DEHP) is a reproductive toxicant in male rodents. The aim of the current study was to extrapolate the pharmacokinetics and toxicokinetics of mono(2-ethylhexyl)phthalate (MEHP, a primary metabolite of DEHP) in humans by using data from oral administration of DEHP to chimeric mice transplanted with human hepatocytes. MEHP and its glucuronide were detected in plasma from control mice and chimeric mice after single oral doses of 250mg DEHP/kg body weight. Biphasic plasma concentration-time curves of MEHP and its glucuronide were seen only in control mice. MEHP and its glucuronide were extensively excreted in urine within 24h in mice with humanized liver. In contrast, fecal excretion levels of MEHP glucuronide were high in control mice compared with those with humanized liver. Adjusted animal biomonitoring equivalents from chimeric mice studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Estimated urine MEHP concentrations in humans were consistent with reported concentrations. This research illustrates how chimeric mice transplanted with human hepatocytes in combination with a simple PBPK model can assist evaluations of pharmacokinetics or toxicokinetics of the primary or secondary metabolites of DEHP.

  13. A semi-physiologically based pharmacokinetic pharmacodynamic model for glycyrrhizin-induced pseudoaldosteronism and prediction of the dose limit causing hypokalemia in a virtual elderly population.

    Directory of Open Access Journals (Sweden)

    Ruijuan Xu

    Full Text Available Glycyrrhizin (GL is a widely used food additive which can cause severe pseudoaldosteronism at high doses or after a long period of consumption. The aim of the present study was to develop a physiologically based pharmacokinetic (PBPK pharmacodynamic (PD model for GL-induced pseudoaldosteronism to improve the safe use of GL. Since the major metabolite of GL, glycyrrhetic acid (GA, is largely responsible for pseudoaldosteronism via inhibition of the kidney enzyme 11β-hydroxysteroiddehydrogenase 2 (11β-HSD 2, a semi-PBPK model was first developed in rat to predict the systemic pharmacokinetics of and the kidney exposure to GA. A human PBPK model was then developed using parameters either from the rat model or from in vitro studies in combination with essential scaling factors. Kidney exposure to GA was further linked to an Imax model in the 11β-HSD 2 module of the PD model to predict the urinary excretion of cortisol and cortisone. Subsequently, activation of the mineralocorticoid receptor in the renin-angiotensin-aldosterone-electrolyte system was associated with an increased cortisol level. Experimental data for various scenarios were used to optimize and validate the model which was finally able to predict the plasma levels of angiotensin II, aldosterone, potassium and sodium. The Monte Carlo method was applied to predict the probability distribution of the individual dose limits of GL causing pseudoaldosteronism in the elderly according to the distribution of sensitivity factors using serum potassium as an indicator. The critical value of the dose limit was found to be 101 mg with a probability of 3.07%.

  14. The Application of Global Sensitivity Analysis in the Development of a Physiologically Based Pharmacokinetic Model for m-Xylene and Ethanol Co-Exposure in Humans

    Directory of Open Access Journals (Sweden)

    George D Loizou

    2015-06-01

    Full Text Available Global sensitivity analysis (SA was used during the development phase of a binary chemical physiologically based pharmacokinetic (PBPK model used for the analysis of m-xylene and ethanol co-exposure in humans. SA was used to identify those parameters which had the most significant impact on variability of venous blood and exhaled m-xylene and urinary excretion of the major metabolite of m-xylene metabolism, 3-methyl hippuric acid. This information informed the selection of parameters for estimation/calibration by fitting to measured biological monitoring (BM data in a Bayesian framework using Markov chain Monte Carlo (MCMC simulation. Data generated in controlled human studies were shown to be useful for investigating the structure and quantitative outputs of PBPK models as well as the biological plausibility and variability of parameters for which measured values were not available. This approach ensured that a priori knowledge in the form of prior distributions was ascribed only to those parameters that were identified as having the greatest impact on variability. This is an efficient approach which helps reduce computational cost.

  15. Development and application of a population physiologically based pharmacokinetic model for penicillin G in swine and cattle for food safety assessment.

    Science.gov (United States)

    Li, Miao; Gehring, Ronette; Riviere, Jim E; Lin, Zhoumeng

    2017-09-01

    Penicillin G is a widely used antimicrobial in food-producing animals, and one of the most predominant drug residues in animal-derived food products. Due to reduced sensitivity of bacteria to penicillin, extralabel use of penicillin G is common, which may lead to violative residues in edible tissues and cause adverse reactions in consumers. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict drug residues in edible tissues and estimate extended withdrawal intervals for penicillin G in swine and cattle. A flow-limited PBPK model was developed with data from Food Animal Residue Avoidance Databank using Berkeley Madonna. The model predicted observed drug concentrations in edible tissues, including liver, muscle, and kidney for penicillin G both in swine and cattle well, including data not used in model calibration. For extralabel use (5× and 10× label dose) of penicillin G, Monte Carlo sampling technique was applied to predict times needed for tissue concentrations to fall below established tolerances for the 99th percentile of the population. This model provides a useful tool to predict tissue residues of penicillin G in swine and cattle to aid food safety assessment, and also provide a framework for extrapolation to other food animal species. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. A physiologically based pharmacokinetic/pharmacodynamic model for carbofuran in Sprague-Dawley rats using the exposure-related dose estimating model.

    Science.gov (United States)

    Zhang, Xiaofei; Tsang, Andy M; Okino, Miles S; Power, Frederick W; Knaak, James B; Harrison, Lynda S; Dary, Curtis C

    2007-12-01

    Carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl-N-methylcarbamate), a broad spectrum N-methyl carbamate insecticide, and its metabolite, 3-hydroxycarbofuran, exert their toxicity by reversibly inhibiting acetylcholinesterase (AChE). To characterize AChE inhibition from carbofuran exposure, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was developed in the Exposure-Related Dose Estimating Model (ERDEM) platform for the Sprague-Dawley (SD) rat. Experimental estimates of physiological, biochemical, and physicochemical model parameters were obtained or based on data from the open literature. The PBPK/PD model structure included carbofuran metabolism in the liver to 16 known metabolites, enterohepatic circulation of glucuronic acid conjugates, and excretion in urine and feces. Bolus doses by ingestion of 50 microg/kg and 0.5 mg/kg carbofuran were simulated for the blood and brain AChE activity. The carbofuran ERDEM simulated a half-life of 5.2 h for urinary clearance, and the experimental AChE activity data were reproduced for the blood and brain. Thirty model parameters were found influential to the model outputs and were chosen for perturbation in Monte Carlo simulations to evaluate the impact of their variability on the model predictions. Results of the simulation runs indicated that the minimum AChE activity in the blood ranged from 29.3 to 79.0% (as 5th and 95th percentiles) of the control level with a mean of 55.9% (standard deviation = 15.1%) compared to an experimental value of 63%. The constructed PBPK/PD model for carbofuran in the SD rat provides a foundation for extrapolating to a human model that can be used for future risk assessment.

  17. 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

  18. Application of physiologically based pharmacokinetic (PBPK) model of trichloroethylene in rats for estimation of internal dose

    Science.gov (United States)

    Potential human health risk from chemical exposure must often be assessed for conditions for which suitable human or animal data are not available, requiring extrapolation across duration and concentration. The default method for exposure-duration adjustment is based on Haber's r...

  19. Physiologically Based Pharmacokinetic (PBPK) Modeling of Interstrain Variability in Trichloroethylene Metabolism in the Mouse

    Science.gov (United States)

    Background: Quantitative estimation of toxicokinetic variability in the human population is a persistent challenge in risk assessment of environmental chemicals. Traditionally, inter-individual differences in the population are accounted for by default assumptions or, in rare cas...

  20. Physiologically Based Pharmacokinetic Modeling of Tamoxifen and its Metabolites in Women of Different CYP2D6 Phenotypes Provides New Insight into the Tamoxifen Mass Balance

    Science.gov (United States)

    Dickschen, Kristin; Willmann, Stefan; Thelen, Kirstin; Lippert, Jörg; Hempel, Georg; Eissing, Thomas

    2012-01-01

    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 exert a pronounced decrease in endoxifen steady-state plasma concentrations compared to CYP2D6 extensive metabolizers. 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 study, physiologically based pharmacokinetic (PBPK)-modeling was applied to mechanistically investigate the impact of CYP2D6 phenotype on endoxifen formation in female breast cancer patients undergoing tamoxifen therapy. A PBPK-model of tamoxifen and its pharmacologically important metabolites N-desmethyltamoxifen (NDM-TAM), 4-hydroxytamoxifen (4-OH-TAM), and endoxifen was developed and validated. This model is able to simulate the pharmacokinetics (PK) after single and repeated oral tamoxifen doses in female breast cancer patients in dependence of the CYP2D6 phenotype. A detailed model-based analysis of the mass balance offered support for a recent hypothesis stating a more prominent role for endoxifen formation from 4-OH-TAM. In the future this model provides 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. PMID:22661948

  1. Application of a physiologically based pharmacokinetic model for the evaluation of single-point plasma phenotyping method of CYP2D6.

    Science.gov (United States)

    Chen, Rui; Rostami-Hodjegan, Amin; Wang, Haotian; Berk, David; Shi, Jun; Hu, Pei

    2016-09-20

    Determining metabolic ratio from single-point plasma is potentially a good phenotyping method of CYP2D6 to reduce the required time interval and increase the reliability of data. It is difficult to conduct large sample size clinical trials to evaluate this phenotyping method for multiple plasma points. A physiologically based pharmacokinetic (PBPK) model can be developed to do simulations based on the large virtual Chinese population and evaluate single-point plasma phenotyping method of CYP2D6. Pharmacokinetic data of dextromethorphan (DM) and its metabolite dextrorphan (DX) after oral administration were used for model development. The SimCYP® model incorporating Chinese demographic, physiological, and enzyme data was used to simulate DM and DX pharmacokinetics in different phenotype groups. The ratios of the simulated to the observed mean AUC and Cmax of DM were 1.01 and 0.81 for extensive metabolizers (EMs), 0.90 and 0.81 for intermediate metabolizers (IMs), and 1.12 and 0.84 for poor metabolizers (PMs). The ratios of the simulated to the observed mean AUC and Cmax of DX were 1.12 and 0.89 for EMs, 0.66 and 0.62 for IMs. All ratios were within the predefined criterion of 0.5-2. The simulations of DM and DX pharmacokinetic profiles in 1000 virtual Chinese subjects with reported frequencies of different phenotypes indicated that statistically significant correlations were found between metabolic ratio of DM to DX (MRDM/DX) from AUC and from single-point plasma from 1 to 30h (all p-values phenotyping method of CYP2D6 for EMs, IMs, and PMs. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Using physiologically-based pharmacokinetic-guided "body-on-a-chip" systems to predict mammalian response to drug and chemical exposure.

    Science.gov (United States)

    Sung, Jong Hwan; Srinivasan, Balaji; Esch, Mandy Brigitte; McLamb, William T; Bernabini, Catia; Shuler, Michael L; Hickman, James J

    2014-09-01

    The continued development of in vitro systems that accurately emulate human response to drugs or chemical agents will impact drug development, our understanding of chemical toxicity, and enhance our ability to respond to threats from chemical or biological agents. A promising technology is to build microscale replicas of humans that capture essential elements of physiology, pharmacology, and/or toxicology (microphysiological systems). Here, we review progress on systems for microscale models of mammalian systems that include two or more integrated cellular components. These systems are described as a "body-on-a-chip", and utilize the concept of physiologically-based pharmacokinetic (PBPK) modeling in the design. These microscale systems can also be used as model systems to predict whole-body responses to drugs as well as study the mechanism of action of drugs using PBPK analysis. In this review, we provide examples of various approaches to construct such systems with a focus on their physiological usefulness and various approaches to measure responses (e.g. chemical, electrical, or mechanical force and cellular viability and morphology). While the goal is to predict human response, other mammalian cell types can be utilized with the same principle to predict animal response. These systems will be evaluated on their potential to be physiologically accurate, to provide effective and efficient platform for analytics with accessibility to a wide range of users, for ease of incorporation of analytics, functional for weeks to months, and the ability to replicate previously observed human responses. © 2014 by the Society for Experimental Biology and Medicine.

  3. 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.

  4. Use of Physiologically-Based Pharmacokinetic Modeling to Simulate the Profiles of 3-Hydroxybenzo(a)pyrene in Workers Exposed to Polycyclic Aromatic Hydrocarbons

    Science.gov (United States)

    Heredia Ortiz, Roberto; Maître, Anne; Barbeau, Damien; Lafontaine, Michel; Bouchard, Michèle

    2014-01-01

    Biomathematical modeling has become an important tool to assess xenobiotic exposure in humans. In the present study, we have used a human physiologically-based pharmacokinetic (PBPK) model and an simple compartmental toxicokinetic model of benzo(a)pyrene (BaP) kinetics and its 3-hydroxybenzo(a)pyrene (3-OHBaP) metabolite to reproduce the time-course of this biomarker of exposure in the urine of industrially exposed workers and in turn predict the most plausible exposure scenarios. The models were constructed from in vivo experimental data in rats and then extrapolated from animals to humans after assessing and adjusting the most sensitive model parameters as well as species specific physiological parameters. Repeated urinary voids from workers exposed to polycyclic aromatic hydrocarbons (PAHs) have been collected over the course of a typical workweek and during subsequent days off work; urinary concentrations of 3-OHBaP were then determined. Based on the information obtained for each worker (BaP air concentration, daily shift hours, tasks, protective equipment), the time courses of 3-OHBaP in the urine of the different workers have been simulated using the PBPK and toxicokinetic models, considering the various possible exposure routes, oral, dermal and inhalation. Both models were equally able to closely reproduce the observed time course of 3-OHBaP in the urine of workers and predicted similar exposure scenarios. Simulations of various scenarios suggest that the workers under study were exposed mainly by the dermal route. Comparison of measured air concentration levels of BaP with simulated values needed to obtain a good approximation of observed time course further pointed out that inhalation was not the main route of exposure for most of the studied workers. Both kinetic models appear as a useful tool to interpret biomonitoring data of PAH exposure on the basis of 3-OHBaP levels. PMID:25032692

  5. Human inhalation exposures to toluene, ethylbenzene, and m-xylene and physiologically based pharmacokinetic modeling of exposure biomarkers in exhaled air, blood, and urine.

    Science.gov (United States)

    Marchand, Axelle; Aranda-Rodriguez, Rocio; Tardif, Robert; Nong, Andy; Haddad, Sami

    2015-04-01

    Urinary biomarkers of exposure are used widely in biomonitoring studies. The commonly used urinary biomarkers for the aromatic solvents toluene (T), ethylbenzene (E), and m-xylene (X) are o-cresol, mandelic acid, and m-methylhippuric acid. The toxicokinetics of these biomarkers following inhalation exposure have yet to be described by physiologically based pharmacokinetic (PBPK) modeling. Five male volunteers were exposed for 6 h in an inhalation chamber to 1/8 or 1/4 of the time-weighted average exposure value (TWAEV) for each solvent: toluene, ethylbenzene, and m-xylene were quantified in blood and exhaled air and their corresponding urine biomarkers were measured in urine. Published PBPK model for parent compounds was used and simulations were compared with experimental blood and exhaled air concentration data. If discrepancies existed, Vmax and Km were optimized. Urinary excretion was modeled using parameters found in literature assuming simply stoichiometric yields from parent compound metabolism and first-order urinary excretion rate. Alternative models were also tested for (1) the possibility that CYP1A2 is the only enzyme implicated in o-cresol and (2) a 2-step model for describing serial metabolic steps for mandelic acid. Models adapted in this study for urinary excretion will be further used to interpret urinary biomarker kinetic data from mixed exposures of these solvents. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. Development of a Physiologically-Based Pharmacokinetic Model of the Rat Central Nervous System

    Directory of Open Access Journals (Sweden)

    Raj K. Singh Badhan

    2014-03-01

    Full Text Available Central nervous system (CNS drug disposition is dictated by a drug’s physicochemical properties and its ability to permeate physiological barriers. The blood–brain barrier (BBB, blood-cerebrospinal fluid barrier and centrally located drug transporter proteins influence drug disposition within the central nervous system. Attainment of adequate brain-to-plasma and cerebrospinal fluid-to-plasma partitioning is important in determining the efficacy of centrally acting therapeutics. We have developed a physiologically-based pharmacokinetic model of the rat CNS which incorporates brain interstitial fluid (ISF, choroidal epithelial and total cerebrospinal fluid (CSF compartments and accurately predicts CNS pharmacokinetics. The model yielded reasonable predictions of unbound brain-to-plasma partition ratio (Kpuu,brain and CSF:plasma ratio (CSF:Plasmau using a series of in vitro permeability and unbound fraction parameters. When using in vitro permeability data obtained from L-mdr1a cells to estimate rat in vivo permeability, the model successfully predicted, to within 4-fold, Kpuu,brain and CSF:Plasmau for 81.5% of compounds simulated. The model presented allows for simultaneous simulation and analysis of both brain biophase and CSF to accurately predict CNS pharmacokinetics from preclinical drug parameters routinely available during discovery and development pathways.

  7. 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

  8. Prediction of a potentially effective dose in humans for BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein (CETP) by allometric species scaling and combined pharmacodynamic and physiologically-based pharmacokinetic modelling

    Science.gov (United States)

    Weber, Olaf; Willmann, Stefan; Bischoff, Hilmar; Li, Volkhart; Vakalopoulos, Alexandros; Lustig, Klemens; Hafner, Frank-Thorsten; Heinig, Roland; Schmeck, Carsten; Buehner, Klaus

    2012-01-01

    AIMS The purpose of this work was to support the prediction of a potentially effective dose for the CETP-inhibitor, BAY 60–5521, in humans. METHODS A combination of allometric scaling of the pharmacokinetics of the CETP-inhibitor BAY 60–5521 with pharmacodynamic studies in CETP-transgenic mice and in human plasma with physiologically-based pharmacokinetic (PBPK) modelling was used to support the selection of the first-in-man dose. RESULTS The PBPK approach predicts a greater extent of distribution for BAY 60–5521 in humans compared with the allometric scaling method as reflected by a larger predicted volume of distribution and longer elimination half-life. The combined approach led to an estimate of a potentially effective dose for BAY 60–5521 of 51 mg in humans. CONCLUSION The approach described in this paper supported the prediction of a potentially effective dose for the CETP-inhibitor BAY 60–5521 in humans. Confirmation of the dose estimate was obtained in a first-in-man study. PMID:21762205

  9. 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.

  10. PBPK modeling and simulation in drug research and development

    Directory of Open Access Journals (Sweden)

    Xiaomei Zhuang

    2016-09-01

    Full Text Available Physiologically based pharmacokinetic (PBPK modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data. It can also explore the effects of various physiologic parameters such as age, ethnicity, or disease status on human pharmacokinetics, as well as guide dose and dose regiment selection and aid drug–drug interaction risk assessment. PBPK modeling has developed rapidly in the last decade within both the field of academia and the pharmaceutical industry, and has become an integral tool in drug discovery and development. In this mini-review, the concept and methodology of PBPK modeling are briefly introduced. Several case studies were discussed on how PBPK modeling and simulation can be utilized through various stages of drug discovery and development. These case studies are from our own work and the literature for better understanding of the absorption, distribution, metabolism and excretion (ADME of a drug candidate, and the applications to increase efficiency, reduce the need for animal studies, and perhaps to replace clinical trials. The regulatory acceptance and industrial practices around PBPK modeling and simulation is also discussed.

  11. 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

  12. Quantitative Analysis of Complex Drug-Drug Interactions Between Repaglinide and Cyclosporin A/Gemfibrozil Using Physiologically Based Pharmacokinetic Models With In Vitro Transporter/Enzyme Inhibition Data.

    Science.gov (United States)

    Kim, Soo-Jin; Toshimoto, Kota; Yao, Yoshiaki; Yoshikado, Takashi; Sugiyama, Yuichi

    2017-09-01

    Quantitative analysis of transporter- and enzyme-mediated complex drug-drug interactions (DDIs) is challenging. Repaglinide (RPG) is transported into the liver by OATP1B1 and then is metabolized by CYP2C8 and CYP3A4. The purpose of this study was to describe the complex DDIs of RPG quantitatively based on unified physiologically based pharmacokinetic (PBPK) models using in vitro Ki values for OATP1B1, CYP3A4, and CYP2C8. Cyclosporin A (CsA) or gemfibrozil (GEM) increased the blood concentrations of RPG. The time profiles of RPG and the inhibitors were analyzed by PBPK models, considering the inhibition of OATP1B1 and CYP3A4 by CsA or OATP1B1 inhibition by GEM and its glucuronide and the mechanism-based inhibition of CYP2C8 by GEM glucuronide. RPG-CsA interaction was closely predicted using a reported in vitro Ki,OATP1B1 value in the presence of CsA preincubation. RPG-GEM interaction was underestimated compared with observed data, but the simulation was improved with the increase of fm,CYP2C8. These results based on in vitro Ki values for transport and metabolism suggest the possibility of a bottom-up approach with in vitro inhibition data for the prediction of complex DDIs using unified PBPK models and in vitro fm value of a substrate for multiple enzymes should be considered carefully for the prediction. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  13. 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.

  14. Assessment of Bioequivalence of Weak Base Formulations Under Various Dosing Conditions Using Physiologically Based Pharmacokinetic Simulations in Virtual Populations. Case Examples: Ketoconazole and Posaconazole.

    Science.gov (United States)

    Cristofoletti, Rodrigo; Patel, Nikunjkumar; Dressman, Jennifer B

    2017-02-01

    Postabsorptive factors which can affect systemic drug exposure are assumed to be dependent on the active pharmaceutical ingredient (API), and thus independent of formulation. In contrast, preabsorptive factors, for example, hypochlorhydria, might affect systemic exposure in both an API and a formulation-dependent way. The aim of this study was to evaluate whether the oral absorption of 2 poorly soluble, weakly basic APIs, ketoconazole (KETO) and posaconazole (POSA), would be equally sensitive to changes in dissolution rate under the following dosing conditions-coadministration with water, with food, with carbonated drinks, and in drug-induced hypochlorhydria. The systems-components of validated absorption and PBPK models for KETO and POSA were modified to simulate the above-mentioned clinical scenarios. Virtual bioequivalence studies were then carried out to investigate whether formulation effects on the plasma profile vary with the dosing conditions. The slow precipitation of KETO upon reaching the upper part of the small intestine renders its absorption more sensitive to the completeness of gastric dissolution and thus to the gastric environment than POSA, which is subject to extensive precipitation in response to a pH shift. The virtual bioequivalence studies showed that hypothetical test and reference formulations containing KETO would be bioequivalent only if the microenvironment in the stomach enables complete gastric dissolution. We conclude that physiologically based pharmacokinetic modeling and simulation has excellent potential to address issues close to bedside such as optimizing dosing conditions. By studying virtual populations adapted to various clinical situations, clinical strategies to reduce therapeutic failures can be identified.

  15. Physiologically based pharmacokinetic modeling of human exposure to perfluorooctanoic acid suggests historical non drinking-water exposures are important for predicting current serum concentrations.

    Science.gov (United States)

    Worley, Rachel Rogers; Yang, Xiaoxia; Fisher, Jeffrey

    2017-09-01

    Manufacturing of perfluorooctanoic acid (PFOA), a synthetic chemical with a long half-life in humans, peaked between 1970 and 2002, and has since diminished. In the United States, PFOA is detected in the blood of >99% of people tested, but serum concentrations have decreased since 1999. Much is known about exposure to PFOA in drinking water; however, the impact of non-drinking water PFOA exposure on serum PFOA concentrations is not well characterized. The objective of this research is to apply physiologically based pharmacokinetic (PBPK) modeling and Monte Carlo analysis to evaluate the impact of historic non-drinking water PFOA exposure on serum PFOA concentrations. In vitro to in vivo extrapolation was utilized to inform descriptions of PFOA transport in the kidney. Monte Carlo simulations were incorporated to evaluate factors that account for the large inter-individual variability of serum PFOA concentrations measured in individuals from North Alabama in 2010 and 2016, and the Mid-Ohio River Valley between 2005 and 2008. Predicted serum PFOA concentrations were within two-fold of experimental data. With incorporation of Monte Carlo simulations, the model successfully tracked the large variability of serum PFOA concentrations measured in populations from the Mid-Ohio River Valley. Simulation of exposure in a population of 45 adults from North Alabama successfully predicted 98% of individual serum PFOA concentrations measured in 2010 and 2016, respectively, when non-drinking water ingestion of PFOA exposure was included. Variation in serum PFOA concentrations may be due to inter-individual variability in the disposition of PFOA and potentially elevated historical non-drinking water exposures. Published by Elsevier Inc.

  16. The Role of Extracellular Binding Proteins in the Cellular Uptake of Drugs: Impact on Quantitative In Vitro-to-In Vivo Extrapolations of Toxicity and Efficacy in Physiologically Based Pharmacokinetic-Pharmacodynamic Research.

    Science.gov (United States)

    Poulin, Patrick; Burczynski, Frank J; Haddad, Sami

    2016-02-01

    A critical component in the development of physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) models for estimating target organ dosimetry in pharmacology and toxicology studies is the understanding of the uptake kinetics and accumulation of drugs and chemicals at the cellular level. Therefore, predicting free drug concentrations in intracellular fluid will contribute to our understanding of concentrations at the site of action in cells in PBPK/PD research. Some investigators believe that uptake of drugs in cells is solely driven by the unbound fraction; conversely, others argue that the protein-bound fraction contributes a significant portion of the total amount delivered to cells. Accordingly, the current literature suggests the existence of a so-called albumin-mediated uptake mechanism(s) for the protein-bound fraction (i.e., extracellular protein-facilitated uptake mechanisms) at least in hepatocytes and cardiac myocytes; however, such mechanism(s) and cells from other organs deserve further exploration. Therefore, the main objective of this present study was to discuss further the implication of potential protein-facilitated uptake mechanism(s) on drug distribution in cells under in vivo conditions. The interplay between the protein-facilitated uptake mechanism(s) and the effects of a pH gradient, metabolism, transport, and permeation limitation potentially occurring in cells was also discussed, as this should violate the basic assumption on similar free drug concentration in cells and plasma. This was made because the published equations used to calculate drug concentrations in cells in a PBPK/PD model did not consider potential protein-facilitated uptake mechanism(s). Consequently, we corrected some published equations for calculating the free drug concentrations in cells compared with plasma in PBPK/PD modeling studies, and we proposed a refined strategy for potentially performing more accurate quantitative in vitro-to-in vivo extrapolations

  17. Enabling PBPK model development through the application of freely available techniques for the creation of a chemically-annotatedcollection of literature

    Science.gov (United States)

    The creation of Physiologically Based Pharmacokinetic (PBPK) models for a new chemical requires the selection of an appropriate model structure and the collection of a large amount of data for parameterization. Commonly, a large proportion of the needed information is collected ...

  18. The contribution of protein binding in the liver to the body burden of dibenzo-p-docins and dibenzo-p-furans: Analysis by means of PBPK modeling

    NARCIS (Netherlands)

    Zeilmaker MJ; Fiolet DCM; Cuijpers CEJ; LBM

    1999-01-01

    In a previous study "Physiologically Based PharmacoKinetic" (PBPK) modeling was used to estimate the amount of dibenzo-p-dioxins and dibenzo-p-furans in mother's milk. This amount is considered to reflect the total amount of dibenzo-p-dioxins and dibenzo-p-furans in the body (body burden). In the PB

  19. A Physiologically Based Pharmacokinetic (PB/PK) Model for Multiple Exposure Routes of Soman in Multiple Species

    Science.gov (United States)

    2006-01-01

    per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing...Although the beagle is extensively used susceptible to the neurotoxicity induced by ivermectin , a in the safety assessment studies of new drug candidates...tissueainto CYP isozyme polymorphism in dogs. Recently, a single ivermectin not to be extruded from the brain tissue into nucleotide polymorphism

  20. Providing a Theoretical Basis for Nanotoxicity Risk Analysis Departing from Traditional Physiologically-Based Pharmacokinetic (PBPK) Modeling

    Science.gov (United States)

    2010-09-01

    perfused tissue representation in STELLA R⃝ 131 Aspt u14SPT to Venous Cvspt P Qspt Arterial to SPT Vspt Cspt Ca Slowly Perfused Tissue - 15 - (a...5 - Cintra 5/Pintra2extra) Active Transp 5 =Vmaxe2i× Cextra 5 / (Kme2i + Cextra 5) 153 SPT ODEs Aspt u14SPT to Venous Cvspt P Qspt Arterial to SPT...Kme2i Vintraspt Cintra 6 Pintra2extra Vmaxi2e Kmi2e SPT - 16 - (b) SPT expanded Figure 74. SPT IE and expanded models in STELLA R⃝ SPT IE. d( Aspt u14

  1. Development of a PBPK model for monoclonal antibodies and simulation of human and mice PBPK of a radiolabelled monoclonal antibody.

    Science.gov (United States)

    Heiskanen, Tomi; Heiskanen, Tomas; Kairemo, Kalevi

    2009-01-01

    Physiology based pharmacokinetic (PBPK) modeling and simulation is a useful method for prediction of biodistribution of both macromolecules and small molecules. It can enhance our understanding of the underlying mechanisms of biodistribution and hence may help in rational design of macromolecules used as diagnostic and therapeutic agents. In this review we discuss PBPK modeling and simulation of a radiolabelled Monoclonal Antibody ((111)In-DOTA-hAFP31 IgG) ("MAB") in mice without tumor and in a human with tumor. This study is part of Xemet Co.'s effort to develop a more accurate and reliable PBPK model and simulation platform, which is applicable both for small molecules and macromolecules. The simulated results were fitted to experimental time series data by varying parameters which were not fixed a priori. It was demonstrated that the PBPK model describes the main features of the pharmacokinetics of the studied systems. It was also shown that simulation can be used for evaluating the parameters of the system and scaling up the pharmacokinetics of MAB from mice to man. We identified several areas of improvement and further development needed to improve the accuracy of PBPK simulation for MAB and other macromolecules. It was concluded that the transvascular permeabilities are the most important parameters and more research is needed to enable prediction of permeabilities from molecular characteristics of macromolecules. It would also be necessary to understand better and describe with a more detailed model the microstructure of the tumor and to measure or predict the antigen concentration in tumor. Non-specific, non-saturable binding in other organs/tissues should be understood better and the kinetic constants of the binding should be measured experimentally. Although the metabolism and clearance were neglected in this study they need to be included in more detailed studies. Also the intracellular trafficking of macromolecules, which was not included in this study

  2. 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

  3. THE ESTABLISHMENT OF THE PHYSIOLOGICAL BASED PHARMACOKINETIC MODEL FOR QUINOCETONE IN GRASS CARP (CTENOPHARYNGODON IDELLUS)%喹烯酮在草鱼体内生理药动模型的建立

    Institute of Scientific and Technical Information of China (English)

    胥宁; 刘永涛; 杨秋红; 艾晓辉

    2015-01-01

    为了预测喹烯酮在草鱼体内药物残留, 建立其在草鱼体内生理药动学模型.通过搜集大量文献获得鱼的生理解剖参数, 采用已有的喹烯酮试验数据拟合得到药物特异性参数.基于 acslXtreme 生理药动学软件,进行模型假设、血流图设计、质量平衡方程的建立和模型拟合.喹烯酮为小分子药物, 其分布服从血流限速型, 在肝脏代谢, 从肾脏消除.喹烯酮通过口服进入肠道, 然后经肝脏代谢进入血液循环, 因此设定 5 个房室, 即肝、肾、肌肉、肠和其他组织.经过一系列的计算和调试, 最终建立喹烯酮在草体内5室生理药动模型, 成功拟合连续饲喂药物 60d之后的药物残留消除曲线, 其中肝脏中的预测结果比肾脏和肌肉高, 与实测数据一致.因此, 喹烯酮在鱼体内生理药动模型具有一定的应用价值, 将是药物残留检测的新亮点.%An effective physiological-based pharmacokinetic (PB-PK) model can be used to analogize and extrapolate the in vivo drug concentrations in different administrations and environments, as well as in different species of animals, hence it has become more and more popular in the drug residual prediction in aquatic animals. In order to predict drug residues of quinocetone in grass carp (Ctenopharyngodon idellus), we established the PB-PK model of quinocetone in this study. We obtained the physiological and anatomical parameters of fish from literatures, and estimated the drug-specific parameters of quinocetone by fitting the existing data. We used the physiological pharmacokinetic soft-ware, asclXtreme, to make the model assumptions, to design the blood flow chart, to generate the mass balance equa-tions and to complete the model fitting. Quinocetone was a small molecule drug, and itsin vivo disposition was blood flow-limited. It was metabolized by the liver and excreted by the kidney. Quinocetone entered the intestine through oral administration and

  4. Integration of Life-Stage Physiologically Based ...

    Science.gov (United States)

    A Life-stage Physiologically-Based Pharmacokinetic (PBPK) model was developed to include descriptions of several life-stage events such as pregnancy, fetal development, the neonate and child growth. The overall modeling strategy was used for in vitro to in vivo (IVIVE) extrapolation to help contextualize activity in ToxCast assays that were mapped to an adverse outcome pathway (AOP) for embryonic vascular disruption. Using life-stage PBPK models, we estimated maternal exposures that would yield fetal blood levels equivalent to in vitro activity from ToxCast assays with critical vascular signaling targets. The resulting in vivo dose estimates were then compared to life-time exposures using literature data or exposure models (SHEDS-LITE) to derive AOP-based Margins of Exposure (ME). This computational framework was applied to a list of five chemicals with varying activity against the putative Vascular Disruption AOP. The idea of linking biological information related to toxicity (using AOPs), high throughput in vitro data (ToxCast), and age-varying physiological and biochemical information to estimate AOP-based MEs is novel and can be used to help regulators in realistically assessing chemicals based on toxicity, dosimetry, and real-life exposures. Developing fetuses and infants are especially sensitive to toxicity caused by exposure to xenobiotics. The time and dose to which a developing target tissue is exposed during pregnancy or via lactation after birth are c

  5. Mechanistic understanding of the nonlinear pharmacokinetics and intersubject variability of simeprevir: A PBPK-guided drug development approach.

    Science.gov (United States)

    Snoeys, J; Beumont, M; Monshouwer, M; Ouwerkerk-Mahadevan, S

    2016-02-01

    Simeprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, displays nonlinear pharmacokinetics (PK) at therapeutic doses. Using physiologically based PK modeling, various drug-drug interactions were simulated with simeprevir as victim drug to identify whether saturation of the predominant metabolic enzyme (CYP3A4) or the active hepatic transporters (organic anion-transporting polypeptide (OATP)1B1/3) could account for the nonlinear PK. Interactions with ritonavir, a strong CYP3A4 inhibitor that does not affect OATP (at 100 mg dose), erythromycin, a moderate CYP3A4 inhibitor, and efavirenz, a moderate CYP3A inducer that does not affect OATP, demonstrated the involvement of CYP3A4. Interaction studies with low-dose cyclosporine confirmed the role of OATP. The interplay between hepatic uptake and CYP3A4 metabolism was verified by simulations with rifampicin, a potent CYP3A4 inducer and OATP1B1/3 inhibitor, and maintenance doses of cyclosporine. Saturation of gut and liver metabolism by CYP3A4, and saturation of hepatic uptake by OATP1B1/3, seem to account for the observed nonlinear PK of simeprevir.

  6. 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).

  7. Gestation-Specific Changes in the Anatomy and Physiology of Healthy Pregnant Women: An Extended Repository of Model Parameters for Physiologically Based Pharmacokinetic Modeling in Pregnancy.

    Science.gov (United States)

    Dallmann, André; Ince, Ibrahim; Meyer, Michaela; Willmann, Stefan; Eissing, Thomas; Hempel, Georg

    2017-04-11

    In the past years, several repositories for anatomical and physiological parameters required for physiologically based pharmacokinetic modeling in pregnant women have been published. While providing a good basis, some important aspects can be further detailed. For example, they did not account for the variability associated with parameters or were lacking key parameters necessary for developing more detailed mechanistic pregnancy physiologically based pharmacokinetic models, such as the composition of pregnancy-specific tissues. The aim of this meta-analysis was to provide an updated and extended database of anatomical and physiological parameters in healthy pregnant women that also accounts for changes in the variability of a parameter throughout gestation and for the composition of pregnancy-specific tissues. A systematic literature search was carried out to collect study data on pregnancy-related changes of anatomical and physiological parameters. For each parameter, a set of mathematical functions was fitted to the data and to the standard deviation observed among the data. The best performing functions were selected based on numerical and visual diagnostics as well as based on physiological plausibility. The literature search yielded 473 studies, 302 of which met the criteria to be further analyzed and compiled in a database. In total, the database encompassed 7729 data. Although the availability of quantitative data for some parameters remained limited, mathematical functions could be generated for many important parameters. Gaps were filled based on qualitative knowledge and based on physiologically plausible assumptions. The presented results facilitate the integration of pregnancy-dependent changes in anatomy and physiology into mechanistic population physiologically based pharmacokinetic models. Such models can ultimately provide a valuable tool to investigate the pharmacokinetics during pregnancy in silico and support informed decision making regarding

  8. PBPK models for the prediction of in vivo performance of oral dosage forms.

    Science.gov (United States)

    Kostewicz, Edmund S; Aarons, Leon; Bergstrand, Martin; Bolger, Michael B; Galetin, Aleksandra; Hatley, Oliver; Jamei, Masoud; Lloyd, Richard; Pepin, Xavier; Rostami-Hodjegan, Amin; Sjögren, Erik; Tannergren, Christer; Turner, David B; Wagner, Christian; Weitschies, Werner; Dressman, Jennifer

    2014-06-16

    Drug absorption from the gastrointestinal (GI) tract is a highly complex process dependent upon numerous factors including the physicochemical properties of the drug, characteristics of the formulation and interplay with the underlying physiological properties of the GI tract. The ability to accurately predict oral drug absorption during drug product development is becoming more relevant given the current challenges facing the pharmaceutical industry. Physiologically-based pharmacokinetic (PBPK) modeling provides an approach that enables the plasma concentration-time profiles to be predicted from preclinical in vitro and in vivo data and can thus provide a valuable resource to support decisions at various stages of the drug development process. Whilst there have been quite a few successes with PBPK models identifying key issues in the development of new drugs in vivo, there are still many aspects that need to be addressed in order to maximize the utility of the PBPK models to predict drug absorption, including improving our understanding of conditions in the lower small intestine and colon, taking the influence of disease on GI physiology into account and further exploring the reasons behind population variability. Importantly, there is also a need to create more appropriate in vitro models for testing dosage form performance and to streamline data input from these into the PBPK models. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the current status of PBPK models available. The current challenges in PBPK set-ups for oral drug absorption including the composition of GI luminal contents, transit and hydrodynamics, permeability and intestinal wall metabolism are discussed in detail. Further, the challenges regarding the appropriate integration of results from in vitro models, such as consideration of appropriate integration/estimation of solubility and the complexity of the in vitro release and precipitation data

  9. Characteristics and Research Progress of Physiologically Based Pharmacokinetic Model%生理药代动力学模型的特征及其国内外研究进展

    Institute of Scientific and Technical Information of China (English)

    董宇; 赵兰英; 吴萍; 王阶

    2012-01-01

    Introduce the characteristic and research status for physiologically based phannacokinetic model ( PBPK) . This article systemized and analysed the construction, features and application status of the PBPK model by reference 21 literatures from Pubmed. Currently, PBPK model has been widely used in the safety evaluation of toxic compounds, drug metabolism research, the influence of the drug by the enzymes and transport proteins, drug-drug interaction, and the research and development of new drugs. Although PBPK model has many advantages, and won the most encouraged evaluate results, but it need support of mathematics and computers, and cooperate of a multidisciplinary professionals, which including systems biology, medicine chemistry, pharmacology and statistic, etc, to further exploration and perfect.%介绍生理药代动力学(PBPK)模型的特征及其研究现状.通过Pubmed检索工具,查询国内外相关文献21篇,对PBPK模型的构建、模型特征和应用现状进行了文献整理和分析.目前PBPK模型已经广泛应用于有毒化合物的安全性评价、药物代谢过程研究、代谢酶和转运蛋白对药物代谢的影响、药物-药物相互作用以及新药的研发过程等研究之中.尽管PBPK模型有很多优势,获得了令人鼓舞的评价结果,但其构建需要数学和计算机的支持以及系统生物学、药物化学、药理学和数学、统计学等多学科专业人员合作,做进一步的探索和完善.

  10. Quantitative Property-Property Relationship for Screening-Level Prediction of Intrinsic Clearance of Volatile Organic Chemicals in Rats and Its Integration within PBPK Models to Predict Inhalation Pharmacokinetics in Humans

    Directory of Open Access Journals (Sweden)

    Thomas Peyret

    2012-01-01

    Full Text Available The objectives of this study were (i to develop a screening-level Quantitative property-property relationship (QPPR for intrinsic clearance (CLint obtained from in vivo animal studies and (ii to incorporate it with human physiology in a PBPK model for predicting the inhalation pharmacokinetics of VOCs. CLint, calculated as the ratio of the in vivo Vmax (μmol/h/kg bw rat to the Km (μM, was obtained for 26 VOCs from the literature. The QPPR model resulting from stepwise linear regression analysis passed the validation step (R2=0.8; leave-one-out cross-validation Q2=0.75 for CLint normalized to the phospholipid (PL affinity of the VOCs. The QPPR facilitated the calculation of CLint (L PL/h/kg bw rat from the input data on log Pow, log blood: water PC and ionization potential. The predictions of the QPPR as lower and upper bounds of the 95% mean confidence intervals (LMCI and UMCI, resp. were then integrated within a human PBPK model. The ratio of the maximum (using LMCI for CLint to minimum (using UMCI for CLint AUC predicted by the QPPR-PBPK model was 1.36±0.4 and ranged from 1.06 (1,1-dichloroethylene to 2.8 (isoprene. Overall, the integrated QPPR-PBPK modeling method developed in this study is a pragmatic way of characterizing the impact of the lack of knowledge of CLint in predicting human pharmacokinetics of VOCs, as well as the impact of prediction uncertainty of CLint on human pharmacokinetics of VOCs.

  11. Development of a Physiologically Based Pharmacokinetic Model for the Anesthetics Halothane, Isoflurane, and Desflurane in the Pig (SUS SCROFA)

    Science.gov (United States)

    1999-08-01

    HALOTHANE, ISOFLURANE, AND DESFLURANE IN THE PIG ( SUS SCROFA ) / Allen Vinegar MANTECH-GEO CENTER JOINT VENTURE PO BOX 31009 ~ DAYTON, OH 45437-0009...Pharmacokinetic Model for the Anesthetics Contract F41624-96-C-9010 Halothane, Isoflurane, and Desfiurane in the Pig ( Sus Scrofa ) PE 62202F PR 7757 6. AUTHOR(S) TA...PFA) " CA Figure I - Physiologicallly Based Pharmacokinetic Model of the Pig ( Sus scrofa ). Abbreviations: CA, arterial concentration; CX, exhaled

  12. DEVELOPMENT OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR DELTAMETHRIN IN THE ADULT MALE SPRAGUE-DAWLEY RAT

    Science.gov (United States)

    Deltamethrin (DLT) is a Type II pyrethroid insecticide widely used in agriculture and public health. DLT is a potent neurotoxin that is primarily cleared from the body by metabolism. To better understand the dosimetry of DLT in the central nervous system, a physiologically based ...

  13. Availability of Acute and/or Subacute Toxicokinetic Data for Select Compounds for the Rat and Physiologically Based Pharmacokinetic (PBPK) Models for Rats and Humans for Those Compounds

    Science.gov (United States)

    2017-05-04

    represents a compilation of comparable data for 18 metals collected using a consistent protocol . The radiolabeled forms were arsenic trichloride...using a consistent protocol . A listing of the other tested metals may be found in Table A12. In urinary and fecal excretion studies, excreta were...mice, humans Species details Adult male and female Wistar, Sprague Dawley, and F344 rats; male Wistar Kyoto , Albino, Zucker, and unspecified rats

  14. CONSTRUCTION OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC/PHARMACODYNAMIC (PBPK/PD) MODEL FOR CARBOFURAN USING THE EXPOSURE RELATED DOSE ESTIMATING MODEL (ERDEM)

    Science.gov (United States)

    Carbofuran, known as 2, 3-dihydro-2, 2-dimethyl-7-benzofuranyl-N-methylcarbamate, is a broad spectrum N-methyl carbamate pesticide. Carbofuran and its metabolite, 3-hydroxycarbofuran, exert their toxicity by reversibly inhibiting acetylcholinesterase (AChE). Carbofuran is widel...

  15. 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

    and for dieldrin (range: 43–640 ng g−1 lw), PCBs (range: 3491–13 243 ng g−1 lw) and PFOS (range: 1332–6160 ng g−1 ww) in the year 2006. The concentrations of oxychlordane, DDTs, HCB and HCHs in polar bears resulted in RQs

  16. IN VITRO ESTIMATES OF METABOLIC PARAMETERS AND THEIR USE IN PREDICTIVE PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING (PBPK) OF THE TYPE I PYRETHROIDS PERMETHRIN AND BIFENTHRIN

    Science.gov (United States)

    Pyrethroids are a class of neurotoxic insecticides that are used in a variety of agricultural and household activities. Hepatic clearance of the Type I pyrethroids permethrin and bifenthrin may be a critical determinant of their toxic effect. Rat LD50s reported in the literatur...

  17. DEVELOPMENT OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODEL FOR THE INHALATION OF 2,2,4-TRIMETHYLPENTANE (TMP) IN LONG EVANS RATS.

    Science.gov (United States)

    TMP (2,2,4-trimethylpentane,“isooctane”) is a colorless liquid used primarily in the alkylation of isobutene and butylene reactions to derive high-octane fuels. TMP is released in the environment through the manufacture, use, and disposal of products associated with the gasoline ...

  18. Physiologically-based pharmacokinetic (PBPK) modeling of two binary mixtures: metabolic activation of carbon tetrachloride by trichloroethylene and metabolic inhibition of chloroform by trichloroethylene.

    Science.gov (United States)

    The interaction between trichloroethylene (TCE) and chloroform (CHCI3) has been described as less than additive, with co-exposure to TCE and CHC13 resulting in less hepatic and renal toxicity than observed with CHCl3 alone. In contrast, the nonadditive interaction between TCE and...

  19. 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.

  20. A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam.

    Science.gov (United States)

    Maharaj, A R; Barrett, J S; Edginton, A N

    2013-04-01

    The use of physiologically based pharmacokinetic (PBPK) models in the field of pediatric drug development has garnered much interest of late due to a recent Food and Drug Administration recommendation. The purpose of this study is to illustrate the developmental processes involved in creation of a pediatric PBPK model incorporating existing adult drug data. Lorazepam, a benzodiazepine utilized in both adults and children, was used as an example. A population-PBPK model was developed in PK-Sim v4.2® and scaled to account for age-related changes in size and composition of tissue compartments, protein binding, and growth/maturation of elimination processes. Dose (milligrams per kilogram) requirements for children aged 0-18 years were calculated based on simulations that achieved targeted exposures based on adult references. Predictive accuracy of the PBPK model for producing comparable plasma concentrations among 63 pediatric subjects was assessed using average-fold error (AFE). Estimates of clearance (CL) and volume of distribution (V(ss)) were compared with observed values for a subset of 15 children using fold error (FE). Pediatric dose requirements in young children (1-3 years) exceeded adult levels on a linear weight-adjusted (milligrams per kilogram) basis. AFE values for model-derived concentration estimates were within 1.5- and 2-fold deviation from observed values for 73% and 92% of patients, respectively. For CL, 60% and 80% of predictions were within 1.5 and 2 FE, respectively. Comparatively, predictions of V(ss) were more accurate with 80% and 100% of estimates within 1.5 and 2 FE, respectively. Using the presented workflow, the developed pediatric model estimated lorazepam pharmacokinetics in children as a function of age.

  1. Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model.

    Science.gov (United States)

    Lin, Wen; Ji, Tao; Einolf, Heidi; Ayalasomayajula, Surya; Lin, Tsu-Han; Hanna, Imad; Heimbach, Tycho; Breen, Christopher; Jarugula, Venkateswar; He, Handan

    2017-01-13

    Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of organic anion-transporting polypeptides (OATPs). In clinical studies, LCZ696 increased atorvastatin Cmax by 1.7-fold and area under the plasma concentration-time curve by 1.3-fold, but had little or no effect on simvastatin or simvastatin acid exposure. A physiologically based pharmacokinetics modeling approach was applied to explore the underlying mechanisms behind the statin-specific LCZ696 drug interaction observations. The model incorporated OATP-mediated clearance (CLint,T) for simvastatin and simvastatin acid to successfully describe the pharmacokinetic profiles of either analyte in the absence or presence of LCZ696. Moreover, the model successfully described the clinically observed drug effect with atorvastatin. The simulations clarified the critical parameters responsible for the observation of a low, yet clinically relevant, drug-drug interaction DDI between sacubitril and atorvastatin and the lack of effect with simvastatin acid. Atorvastatin is administered in its active form and rapidly achieves Cmax that coincide with the low Cmax of sacubitril. In contrast, simvastatin requires a hydrolysis step to the acid form and therefore is not present at the site of interactions at sacubitril concentrations that are inhibitory. Similar models were used to evaluate the drug-drug interaction risk for additional OATP-transported statins which predicted to maximally result in a 1.5-fold exposure increase.

  2. Mechanistic PBPK Modeling of the Dissolution and Food Effect of a BCS IV Compound - the Venetoclax Story.

    Science.gov (United States)

    Emami Riedmaier, Arian; Lindley, David J; Hall, Jeffrey A; Castleberry, Steven; Slade, Russell T; Stuart, Patricia; Carr, Robert A; Borchardt, Thomas B; Bow, Daniel A J; Nijsen, Marjoleen

    2017-10-06

    Venetoclax, a selective B-cell lymphoma-2 inhibitor, is a biopharmaceutics classification system (BCS) class IV compound. The aim of this study was to develop a physiologically-based pharmacokinetic (PBPK) model to mechanistically describe absorption and disposition of an amorphous solid dispersion (ASD) formulation of venetoclax in humans. A mechanistic PBPK model was developed incorporating measured amorphous solubility, dissolution, metabolism and plasma protein binding. A middle-out approach was used to define permeability. Model predictions of oral venetoclax pharmacokinetics were verified against clinical studies of fed and fasted healthy volunteers, and clinical drug interaction studies with strong CYP3A inhibitor (ketoconazole) and inducer (rifampicin). Model verification demonstrated accurate prediction of the observed food effect following a low-fat diet. Ratios of predicted versus observed Cmax and AUC of venetoclax were within 0.8- to 1.25-fold of observed ratios for strong CYP3A inhibitor and inducer interactions, indicating that the venetoclax elimination pathway was correctly specified. The verified venetoclax PBPK model is one of the first examples mechanistically capturing absorption, food effect and exposure of an ASD formulated compound. This model allows evaluation of untested drug-drug interactions, especially those primarily occurring in the intestine, and paves the way for future modeling of BCS IV compounds. Copyright © 2017. Published by Elsevier Inc.

  3. Variation in predicted internal concentrations in relation to PBPK model complexity for rainbow trout

    Energy Technology Data Exchange (ETDEWEB)

    Salmina, E.S.; Wondrousch, D. [UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research, Permoserstr. 15, 04318 Leipzig (Germany); Institute for Organic Chemistry, Technical University Bergakademie Freiberg, Leipziger Str. 29, 09596 Freiberg (Germany); Kühne, R. [UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research, Permoserstr. 15, 04318 Leipzig (Germany); Potemkin, V.A. [Department of Chemistry, South Ural State Medical University, Vorovskogo 64, 454048, Chelyabinsk (Russian Federation); Schüürmann, G. [UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research, Permoserstr. 15, 04318 Leipzig (Germany); Institute for Organic Chemistry, Technical University Bergakademie Freiberg, Leipziger Str. 29, 09596 Freiberg (Germany)

    2016-04-15

    The present study is motivated by the increasing demand to consider internal partitioning into tissues instead of exposure concentrations for the environmental toxicity assessment. To this end, physiologically based pharmacokinetic (PBPK) models can be applied. We evaluated the variation in accuracy of PBPK model outcomes depending on tissue constituents modeled as sorptive phases and chemical distribution tendencies addressed by molecular descriptors. The model performance was examined using data from 150 experiments for 28 chemicals collected from US EPA databases. The simplest PBPK model is based on the “K{sub ow}-lipid content” approach as being traditional for environmental toxicology. The most elaborated one considers five biological sorptive phases (polar and non-polar lipids, water, albumin and the remaining proteins) and makes use of LSER (linear solvation energy relationship) parameters to describe the compound partitioning behavior. The “K{sub ow}-lipid content”-based PBPK model shows more than one order of magnitude difference in predicted and measured values for 37% of the studied exposure experiments while for the most elaborated model this happens only for 7%. It is shown that further improvements could be achieved by introducing corrections for metabolic biotransformation and compound transmission hindrance through a cellular membrane. The analysis of the interface distribution tendencies shows that polar tissue constituents, namely water, polar lipids and proteins, play an important role in the accumulation behavior of polar compounds with H-bond donating functional groups. For compounds without H-bond donating fragments preferable accumulation phases are storage lipids and water depending on compound polarity. - Highlights: • For reliable predictions, models of a certain complexity should be compared. • For reliable predictions non-lipid fish tissue constituents should be considered. • H-donor compounds preferably accumulate in water

  4. Analysis of biomarker utility using a PBPK/PD model for carbaryl

    Directory of Open Access Journals (Sweden)

    Martin Blake Phillips

    2014-11-01

    Full Text Available There are many types of biomarkers; the two common ones are biomarkers of exposure and biomarkers of effect. The utility of a biomarker for estimating exposures or predicting risks depends on the strength of the correlation between biomarker concentrations and exposure/effects. In the current study, a combined exposure and physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD model of carbaryl was used to demonstrate the use of computational modeling for providing insight into the selection of biomarkers for different purposes. The Cumulative and Aggregate Risk Evaluation System (CARES was used to generate exposure profiles, including magnitude and timing, for use as inputs to the PBPK/PD model. The PBPK/PD model was then used to predict blood concentrations of carbaryl and urine concentrations of its principal metabolite, 1-naphthol (1-N, as biomarkers of exposure. The PBPK/PD model also predicted acetylcholinesterase (AChE inhibition in red blood cells (RBC as a biomarker of effect. The correlations of these simulated biomarker concentrations with intake doses or brain AChE inhibition (as a surrogate of effects were analyzed using a linear regression model. Results showed that 1-N in urine is a better biomarker of exposure than carbaryl in blood, and that 1-N in urine is correlated with the dose averaged over the last two days of the simulation. They also showed that RBC AChE inhibition is an appropriate biomarker of effect. This computational approach can be applied to a wide variety of chemicals to facilitate quantitative analysis of biomarker utility.

  5. Investigation of an alternative generic model for predicting pharmacokinetic changes during physiological stress.

    Science.gov (United States)

    Peng, Henry T; Edginton, Andrea N; Cheung, Bob

    2013-10-01

    Physiologically based pharmacokinetic models were developed using MATLAB Simulink® and PK-Sim®. We compared the capability and usefulness of these two models by simulating pharmacokinetic changes of midazolam under exercise and heat stress to verify the usefulness of MATLAB Simulink® as a generic PBPK modeling software. Although both models show good agreement with experimental data obtained under resting condition, their predictions of pharmacokinetics changes are less accurate in the stressful conditions. However, MATLAB Simulink® may be more flexible to include physiologically based processes such as oral absorption and simulate various stress parameters such as stress intensity, duration and timing of drug administration to improve model performance. Further work will be conducted to modify algorithms in our generic model developed using MATLAB Simulink® and to investigate pharmacokinetics under other physiological stress such as trauma. © The Author(s) 2013.

  6. Assessing human variability in kinetics for exposures to multiple environmental chemicals: a physiologically based pharmacokinetic modeling case study with dichloromethane, benzene, toluene, ethylbenzene, and m-xylene.

    Science.gov (United States)

    Valcke, Mathieu; Haddad, Sami

    2015-01-01

    The objective of this study was to compare the magnitude of interindividual variability in internal dose for inhalation exposure to single versus multiple chemicals. Physiologically based pharmacokinetic models for adults (AD), neonates (NEO), toddlers (TODD), and pregnant women (PW) were used to simulate inhalation exposure to "low" (RfC-like) or "high" (AEGL-like) air concentrations of benzene (Bz) or dichloromethane (DCM), along with various levels of toluene alone or toluene with ethylbenzene and xylene. Monte Carlo simulations were performed and distributions of relevant internal dose metrics of either Bz or DCM were computed. Area under the blood concentration of parent compound versus time curve (AUC)-based variability in AD, TODD, and PW rose for Bz when concomitant "low" exposure to mixtures of increasing complexities occurred (coefficient of variation (CV) = 16-24%, vs. 12-15% for Bz alone), but remained unchanged considering DCM. Conversely, AUC-based CV in NEO fell (15 to 5% for Bz; 12 to 6% for DCM). Comparable trends were observed considering production of metabolites (AMET), except for NEO's CYP2E1-mediated metabolites of Bz, where an increased CV was observed (20 to 71%). For "high" exposure scenarios, Cmax-based variability of Bz and DCM remained unchanged in AD and PW, but decreased in NEO (CV= 11-16% to 2-6%) and TODD (CV= 12-13% to 7-9%). Conversely, AMET-based variability for both substrates rose in every subpopulation. This study analyzed for the first time the impact of multiple exposures on interindividual variability in toxicokinetics. Evidence indicates that this impact depends upon chemical concentrations and biochemical properties, as well as the subpopulation and internal dose metrics considered.

  7. Clinical Exposure Boost Predictions by Integrating Cytochrome P450 3A4-Humanized Mouse Studies With PBPK Modeling.

    Science.gov (United States)

    Zhang, Jin; Heimbach, Tycho; Scheer, Nico; Barve, Avantika; Li, Wenkui; Lin, Wen; He, Handan

    2016-04-01

    NVS123 is a poorly water-soluble protease 56 inhibitor in clinical development. Data from in vitro hepatocyte studies suggested that NVS123 is mainly metabolized by CYP3A4. As a consequence of limited solubility, NVS123 therapeutic plasma exposures could not be achieved even with high doses and optimized formulations. One approach to overcome NVS123 developability issues was to increase plasma exposure by coadministrating it with an inhibitor of CYP3A4 such as ritonavir. A clinical boost effect was predicted by using physiologically based pharmacokinetic (PBPK) modeling. However, initial boost predictions lacked sufficient confidence because a key parameter, fraction of drug metabolized by CYP3A4 (fmCYP3A4), could not be estimated with accuracy on account of disconnects between in vitro and in vivo preclinical data. To accurately estimate fmCYP3A4 in human, an in vivo boost effect study was conducted using CYP3A4-humanized mouse model which showed a 33- to 56-fold exposure boost effect. Using a top-down approach, human fmCYP3A4 for NVS123 was estimated to be very high and included in the human PBPK modeling to support subsequent clinical study design. The combined use of the in vivo boost study in CYP3A4-humanized mouse model mice along with PBPK modeling accurately predicted the clinical outcome and identified a significant NVS123 exposure boost (∼42-fold increase) with ritonavir.

  8. 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

  9. Organophosphorus Insecticide Pharmacokinetics

    Energy Technology Data Exchange (ETDEWEB)

    Timchalk, Charles

    2010-01-01

    This chapter highlights a number of current and future applications of pharmacokinetics to assess organophosphate (OP) insecticide dosimetry, biological response and risk in humans exposed to these agents. Organophosphates represent a large family of pesticides where insecticidal as well as toxicological mode of action is associated with their ability to target and inhibit acetylcholinesterase (AChE). Pharmacokinetics entails the quantitative integration of physiological and metabolic processes associated with the absorption, distribution, metabolism and excretion (ADME) of drugs and xenobiotics. Pharmacokinetic studies provide important data on the amount of toxicant delivered to a target site as well as species-, age-, gender-specific and dose-dependent differences in biological response. These studies have been conducted with organophosphorus insecticides in multiple species, at various dose levels, and across different routes of exposure to understand their in vivo pharmacokinetics and how they contribute to the observed toxicological response. To access human exposure to organophosphorus insecticides, human pharmacokinetic studies have been conducted and used to develop biological monitoring strategies based on the quantitation of key metabolites in biological fluids. Pharmacokinetic studies with these insecticides are also useful to facilitate extrapolation of dosimetry and biological response from animals to humans and for the assessment of human health risk. In this regard, physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models are being utilized to assess risk and understand the toxicological implications of known or suspected exposures to various insecticides. In this chapter a number of examples are presented that illustrate the utility and limitation of pharmacokinetic studies to address human health concerns associated with organophosphorus insecticides.

  10. Advances and challenges in PBPK modeling--Analysis of factors contributing to the oral absorption of atazanavir, a poorly soluble weak base.

    Science.gov (United States)

    Berlin, Mark; Ruff, Aaron; Kesisoglou, Filippos; Xu, Wei; Wang, Michael Hong; Dressman, Jennifer B

    2015-06-01

    Many active pharmaceutical ingredients (APIs) exhibit a highly variable pharmacokinetic (PK) profile. This behavior may be attributable to pre-absorptive, absorptive and/or post-absorptive factors. Pre-absorptive factors are those related to dosage form disintegration, drug dissolution, supersaturation, precipitation and gastric emptying. Absorptive factors are involved with drug absorption and efflux mechanisms, while drug distribution and clearance are post-absorptive factors. This study aimed to investigate the relative influence of the aforementioned parameters on the pharmacokinetic profile of atazanavir, a poorly soluble weakly basic compound with highly variable pharmacokinetics. The pre-absorptive behavior of the drug was examined by applying biorelevant in vitro tests to reflect upper gastrointestinal behavior in the fasted and fed states. The in vitro results were implemented, along with permeability and post-absorptive data obtained from the literature, into physiologically based pharmacokinetic (PBPK) models. Sensitivity analysis of the resulting plasma profiles revealed that the pharmacokinetic profile of atazanavir is affected by an array of factors rather than one standout factor. According to the in silico model, pre-absorptive and absorptive factors had less impact on atazanavir bioavailability compared to post-absorptive parameters, although active drug efflux and extraction appear to account for the sub-proportional pharmacokinetic response to lower atazanavir doses in the fasted state. From the PBPK models it was concluded that further enhancement of the formulation would bring little improvement in the pharmacokinetic response to atazanavir. This approach may prove useful in assessing the potential benefits of formulation enhancement of other existing drug products on the market.

  11. 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.

  12. PBPK-Based Probabilistic Risk Assessment for Total Chlorotriazines in Drinking Water.

    Science.gov (United States)

    Breckenridge, Charles B; Campbell, Jerry L; Clewell, Harvey J; Andersen, Melvin E; Valdez-Flores, Ciriaco; Sielken, Robert L

    2016-04-01

    The risk of human exposure to total chlorotriazines (TCT) in drinking water was evaluated using a physiologically based pharmacokinetic (PBPK) model. Daily TCT (atrazine, deethylatrazine, deisopropylatrazine, and diaminochlorotriazine) chemographs were constructed for 17 frequently monitored community water systems (CWSs) using linear interpolation and Krieg estimates between observed TCT values. Synthetic chemographs were created using a conservative bias factor of 3 to generate intervening peaks between measured values. Drinking water consumption records from 24-h diaries were used to calculate daily exposure. Plasma TCT concentrations were updated every 30 minutes using the PBPK model output for each simulated calendar year from 2006 to 2010. Margins of exposure (MOEs) were calculated (MOE = [Human Plasma TCTPOD] ÷ [Human Plasma TCTEXP]) based on the toxicological point of departure (POD) and the drinking water-derived exposure to TCT. MOEs were determined based on 1, 2, 3, 4, 7, 14, 28, or 90 days of rolling average exposures and plasma TCT Cmax, or the area under the curve (AUC). Distributions of MOE were determined and the 99.9th percentile was used for risk assessment. MOEs for all 17 CWSs were >1000 at the 99.9(th)percentile. The 99.9(th)percentile of the MOE distribution was 2.8-fold less when the 3-fold synthetic chemograph bias factor was used. MOEs were insensitive to interpolation method, the consumer's age, the water consumption database used and the duration of time over which the rolling average plasma TCT was calculated, for up to 90 days. MOEs were sensitive to factors that modified the toxicological, or hyphenated appropriately no-observed-effects level (NOEL), including rat strain, endpoint used, method of calculating the NOEL, and the pharmacokinetics of elimination, as well as the magnitude of exposure (CWS, calendar year, and use of bias factors).

  13. Calibration and validation of a physiologically based model for soman intoxication in the rat, marmoset, guinea pig and pig.

    Science.gov (United States)

    Chen, Kaizhen; Seng, Kok-Yong

    2012-09-01

    A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model has been developed for low, medium and high levels of soman intoxication in the rat, marmoset, guinea pig and pig. The primary objective of this model was to describe the pharmacokinetics of soman after intravenous, intramuscular and subcutaneous administration in the rat, marmoset, guinea pig, and pig as well as its subsequent pharmacodynamic effects on blood acetylcholinesterase (AChE) levels, relating dosimetry to physiological response. The reactions modelled in each physiologically realistic compartment are: (1) partitioning of C(±)P(±) soman from the blood into the tissue; (2) inhibition of AChE and carboxylesterase (CaE) by soman; (3) elimination of soman by enzymatic hydrolysis; (4) de novo synthesis and degradation of AChE and CaE; and (5) aging of AChE-soman and CaE-soman complexes. The model was first calibrated for the rat, then extrapolated for validation in the marmoset, guinea pig and pig. Adequate fits to experimental data on the time course of soman pharmacokinetics and AChE inhibition were achieved in the mammalian models. In conclusion, the present model adequately predicts the dose-response relationship resulting from soman intoxication and can potentially be applied to predict soman pharmacokinetics and pharmacodynamics in other species, including human.

  14. IMI - oral biopharmaceutics tools project - evaluation of bottom-up PBPK prediction success part 1: Characterisation of the OrBiTo database of compounds.

    Science.gov (United States)

    Margolskee, Alison; Darwich, Adam S; Pepin, Xavier; Pathak, Shriram M; Bolger, Michael B; Aarons, Leon; Rostami-Hodjegan, Amin; Angstenberger, Jonas; Graf, Franziska; Laplanche, Loic; Müller, Thomas; Carlert, Sara; Daga, Pankaj; Murphy, Dónal; Tannergren, Christer; Yasin, Mohammed; Greschat-Schade, Susanne; Mück, Wolfgang; Muenster, Uwe; van der Mey, Dorina; Frank, Kerstin Julia; Lloyd, Richard; Adriaenssen, Lieve; Bevernage, Jan; De Zwart, Loeckie; Swerts, Dominique; Tistaert, Christophe; Van Den Bergh, An; Van Peer, Achiel; Beato, Stefania; Nguyen-Trung, Anh-Thu; Bennett, Joanne; McAllister, Mark; Wong, Mei; Zane, Patricia; Ollier, Céline; Vicat, Pascale; Kolhmann, Markus; Marker, Alexander; Brun, Priscilla; Mazuir, Florent; Beilles, Stéphane; Venczel, Marta; Boulenc, Xavier; Loos, Petra; Lennernäs, Hans; Abrahamsson, Bertil

    2017-01-01

    Predicting oral bioavailability (Foral) is of importance for estimating systemic exposure of orally administered drugs. Physiologically-based pharmacokinetic (PBPK) modelling and simulation have been applied extensively in biopharmaceutics recently. The Oral Biopharmaceutical Tools (OrBiTo) project (Innovative Medicines Initiative) aims to develop and improve upon biopharmaceutical tools, including PBPK absorption models. A large-scale evaluation of PBPK models may be considered the first step. Here we characterise the OrBiTo active pharmaceutical ingredient (API) database for use in a large-scale simulation study. The OrBiTo database comprised 83 APIs and 1475 study arms. The database displayed a median logP of 3.60 (2.40-4.58), human blood-to-plasma ratio of 0.62 (0.57-0.71), and fraction unbound in plasma of 0.05 (0.01-0.17). The database mainly consisted of basic compounds (48.19%) and Biopharmaceutics Classification System class II compounds (55.81%). Median human intravenous clearance was 16.9L/h (interquartile range: 11.6-43.6L/h; n=23), volume of distribution was 80.8L (54.5-239L; n=23). The majority of oral formulations were immediate release (IR: 87.6%). Human Foral displayed a median of 0.415 (0.203-0.724; n=22) for IR formulations. The OrBiTo database was found to be largely representative of previously published datasets. 43 of the APIs were found to satisfy the minimum inclusion criteria for the simulation exercise, and many of these have significant gaps of other key parameters, which could potentially impact the interpretability of the simulation outcome. However, the OrBiTo simulation exercise represents a unique opportunity to perform a large-scale evaluation of the PBPK approach to predicting oral biopharmaceutics.

  15. Using PBPK guided “Body-on-a-Chip” Systems to Predict Mammalian Response to Drug and Chemical Exposure

    Science.gov (United States)

    Sung, Jong Hwan; Srinivasan, Balaji; Esch, Mandy Brigitte; McLamb, William T.; Bernabini, Catia; Shuler, Michael L.; Hickman, James J.

    2014-01-01

    The continued development of in vitro systems that accurately emulate human response to drugs or chemical agents will impact drug development, our understanding of chemical toxicity, and enhance our ability to respond to threats from chemical or biological agents. A promising technology is to build microscale replicas of humans that capture essential elements of physiology, pharmacology and/or toxicology (microphysiological systems). Here, we review progress on systems for microscale models of mammalian systems that include two or more integrated cellular components. These systems are described as a “Body-on-a-Chip.”, and utilize the concept of physiologically-based pharmacokinetic (PBPK) modeling in the design. These microscale systems can also be used as model systems to predict whole-body responses to drugs as well as study the mechanism of action of drugs using PBPK analysis. In this review, we provide examples of various approaches to construct such systems with a focus on their physiological usefulness and various approaches to measure responses (e.g. chemical, electrical, or mechanical force and cellular viability and morphology). While the goal is to predict human response, other mammalian cell types can be utilized with the same principle to predict animal response. These systems will be evaluated on their potential to be physiologically accurate, to provide effective and efficient platform for analytics with accessibility to a wide range of users, for ease of incorporation of analytics, functional for weeks to months, and the ability to replicate previously observed human responses. PMID:24951471

  16. Clinical pharmacokinetics of buffered propranolol sublingual tablet (Promptol™)-application of a new "physiologically based" model to assess absorption and disposition.

    Science.gov (United States)

    Wang, Yanfeng; Wang, Zhijun; Zuo, Zhong; Tomlinson, Brian; Lee, Benjamin T K; Bolger, Michael B; Chow, Moses S S

    2013-07-01

    Sublingual administration of certain buffered propranolol may improve the rate and extent of absorption compared to oral administration. The main objectives of this study were to (1) compare the plasma propranolol concentrations (Cp-prop) following sublingual administration of a specially buffered formulation (Promptol™) to that following oral administration of Inderal(®) and (2) evaluate the utility of a special pharmacokinetic model in describing the Cp-prop following sublingual administration. Eighteen healthy volunteers received 10 mg sublingual Promptol™ or oral Inderal(®). Multiple Cp-prop were determined and their pharmacokinetics compared. Additional data following sublingual 40 mg Promptol™ or Inderal(®) were utilized for evaluation of a special advanced compartmental absorption and transit (ACAT) model. For model simulation, the physicochemical parameters were imported from AMET predictor, whereas the pharmacokinetic parameters were calculated and optimized by Gastroplus(®). Based on this model, the quantity of drug absorbed via buccal/sublingual mucosa was estimated. Cp-prop was higher at earlier times with 3-fold greater relative bioavailability following sublingual Promptol™ compared to that from oral Inderal(®). The special ACAT model provided excellent goodness of fit of Cp-prop-time curve and estimated a 56.6% increase in absorption rate from Promptol™ and higher initial Cp-prop compared to the regular formulation. The modified ACAT model provided a useful approach to describe sublingual absorption of propranolol and clearly demonstrated an improvement of absorption of Promptol™. The sublingual 10 mg Promptol™ achieved not only a similar systemic exposure as 30 mg oral Inderal(®) but an earlier effective Cp-prop which may be advantageous for certain clinical conditions.

  17. 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.

  18. A calibrated human PBPK model for benzene inhalation with urinary bladder and bone marrow compartments.

    Science.gov (United States)

    Knutsen, Jeffrey S; Kerger, Brent D; Finley, Brent; Paustenbach, Dennis J

    2013-07-01

    A physiologically-based pharmacokinetic (PBPK) model of benzene inhalation based on a recent mouse model was adapted to include bone marrow (target organ) and urinary bladder compartments. Empirical data on human liver microsomal protein levels and linked CYP2E1 activities were incorporated into the model, and metabolite-specific conversion rate parameters were estimated by fitting to human biomonitoring data and adjusting for background levels of urinary metabolites. Human studies of benzene levels in blood and breath, and phenol levels in urine were used to validate the rate of human conversion of benzene to benzene oxide, and urinary benzene metabolites from Chinese benzene worker populations provided model validation for rates of human conversion of benzene to muconic acid (MA) and phenylmercapturic acid (PMA), phenol (PH), catechol (CA), hydroquinone (HQ), and benzenetriol (BT). The calibrated human model reveals that while liver microsomal protein and CYP2E1 activities are lower on average in humans compared to mice, the mouse also shows far lower rates of benzene conversion to MA and PMA, and far higher conversion of benzene to BO/PH, and of BO/PH to CA, HQ, and BT. The model also differed substantially from existing human PBPK models with respect to several metabolic rate parameters of importance to interpreting benzene metabolism and health risks in human populations associated with bone marrow doses. The model provides a new methodological paradigm focused on integrating linked human liver metabolism data and calibration using biomonitoring data, thus allowing for model uncertainty analysis and more rigorous validation. © 2012 Society for Risk Analysis.

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

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, Jeffrey W., E-mail: jeffrey.fisher@fda.hhs.gov; Twaddle, Nathan C.; Vanlandingham, Michelle; Doerge, Daniel R.

    2011-11-15

    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 {mu}g 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 (Voelkel et al., 2002). Voelkel 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 Voelkel 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: Black-Right-Pointing-Pointer A bisphenol A (BPA) PBPK model for the infant and adult monkey was constructed. Black-Right-Pointing-Pointer The hepatic metabolic rate of BPA increased with age of the monkey. Black-Right-Pointing-Pointer The systemic clearance rate of metabolites increased with age of the monkey. Black-Right-Pointing-Pointer Gut wall metabolism of orally administered BPA was substantial across all ages of monkeys. Black-Right-Pointing-Pointer Aglycone BPA plasma concentrations were predicted in humans orally given oral doses of deuterated BPA.

  20. 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.

  1. Delineating the Role of Various Factors in Renal Disposition of Digoxin through Application of Physiologically Based Kidney Model to Renal Impairment Populations

    Science.gov (United States)

    Scotcher, Daniel; Jones, Christopher R.; Galetin, Aleksandra

    2017-01-01

    Development of submodels of organs within physiologically-based pharmacokinetic (PBPK) principles and beyond simple perfusion limitations may be challenging because of underdeveloped in vitro-in vivo extrapolation approaches or lack of suitable clinical data for model refinement. However, advantage of such models in predicting clinical observations in divergent patient groups is now commonly acknowledged. Mechanistic understanding of altered renal secretion in renal impairment is one area that may benefit from such models, despite knowledge gaps in renal pathophysiology. In the current study, a PBPK kidney model was developed for digoxin, accounting for the roles of organic anion transporting peptide 4C1 (OATP4C1) and P-glycoprotein (P-gp) in its tubular secretion, with the aim to investigate the impact of age and renal impairment (moderate to severe) on renal drug disposition. Initial PBPK simulations based on changes in glomerular filtration rate (GFR) underestimated the observed reduction in digoxin renal excretion clearance (CLR) in subjects with moderately impaired renal function relative to healthy. Reduction in either proximal tubule cell number or the OATP4C1 abundance in the mechanistic kidney model successfully predicted 59% decrease in digoxin CLR, in particular when these changes were proportional to reduction in GFR. In contrast, predicted proximal tubule concentration of digoxin was only sensitive to changes in the transporter expression/ million proximal tubule cells. Based on the mechanistic modeling, reduced proximal tubule cellularity and OATP4C1 abundance, and inhibition of OATP4C1-mediated transport, are proposed as possible causes of reduced digoxin renal secretion in renally impaired patients. PMID:28057840

  2. Development of an updated PBPK model for trichloroethylene and metabolites in mice, and its application to discern the role of oxidative metabolism in TCE-induced hepatomegaly.

    Science.gov (United States)

    Evans, M V; Chiu, W A; Okino, M S; Caldwell, J C

    2009-05-01

    Trichloroethylene (TCE) is a lipophilic solvent rapidly absorbed and metabolized via oxidation and conjugation to a variety of metabolites that cause toxicity to several internal targets. Increases in liver weight (hepatomegaly) have been reported to occur quickly in rodents after TCE exposure, with liver tumor induction reported in mice after long-term exposure. An integrated dataset for gavage and inhalation TCE exposure and oral data for exposure to two of its oxidative metabolites (TCA and DCA) was used, in combination with an updated and more accurate physiologically-based pharmacokinetic (PBPK) model, to examine the question as to whether the presence of TCA in the liver is responsible for TCE-induced hepatomegaly in mice. The updated PBPK model was used to help discern the quantitative contribution of metabolites to this effect. The update of the model was based on a detailed evaluation of predictions from previously published models and additional preliminary analyses based on gas uptake inhalation data in mice. The parameters of the updated model were calibrated using Bayesian methods with an expanded pharmacokinetic database consisting of oral, inhalation, and iv studies of TCE administration as well as studies of TCE metabolites in mice. The dose-response relationships for hepatomegaly derived from the multi-study database showed that the proportionality of dose to response for TCE- and DCA-induced hepatomegaly is not observed for administered doses of TCA in the studied range. The updated PBPK model was used to make a quantitative comparison of internal dose of metabolized and administered TCA. While the internal dose of TCA predicted by modeling of TCE exposure (i.e., mg TCA/kg-d) showed a linear relationship with hepatomegaly, the slope of the relationship was much greater than that for directly administered TCA. Thus, the degree of hepatomegaly induced per unit of TCA produced through TCE oxidation is greater than that expected per unit of TCA

  3. Physiologically based pharmacokinetic model for ethyl tertiary-butyl ether and tertiary-butyl alcohol in rats: Contribution of binding to α2u-globulin in male rats and high-exposure nonlinear kinetics to toxicity and cancer outcomes.

    Science.gov (United States)

    Borghoff, Susan J; Ring, Caroline; Banton, Marcy I; Leavens, Teresa L

    2017-05-01

    In cancer bioassays, inhalation, but not drinking water exposure to ethyl tertiary-butyl ether (ETBE), caused liver tumors in male rats, while tertiary-butyl alcohol (TBA), an ETBE metabolite, caused kidney tumors in male rats following exposure via drinking water. To understand the contribution of ETBE and TBA kinetics under varying exposure scenarios to these tumor responses, a physiologically based pharmacokinetic model was developed based on a previously published model for methyl tertiary-butyl ether, a structurally similar chemical, and verified against the literature and study report data. The model included ETBE and TBA binding to the male rat-specific protein α2u-globulin, which plays a role in the ETBE and TBA kidney response observed in male rats. Metabolism of ETBE and TBA was described as a single, saturable pathway in the liver. The model predicted similar kidney AUC0-∞ for TBA for various exposure scenarios from ETBE and TBA cancer bioassays, supporting a male-rat-specific mode of action for TBA-induced kidney tumors. The model also predicted nonlinear kinetics at ETBE inhalation exposure concentrations above ~2000 ppm, based on blood AUC0-∞ for ETBE and TBA. The shift from linear to nonlinear kinetics at exposure concentrations below the concentration associated with liver tumors in rats (5000 ppm) suggests the mode of action for liver tumors operates under nonlinear kinetics following chronic exposure and is not relevant for assessing human risk. Copyright © 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd.

  4. Pharmacokinetic, pharmacodynamic and biodistribution following oral administration of nanocarriers containing peptide and protein drugs.

    Science.gov (United States)

    Griffin, Brendan T; Guo, Jianfeng; Presas, Elena; Donovan, Maria D; Alonso, María J; O'Driscoll, Caitriona M

    2016-11-15

    The influence of nanoparticle (NP) formulations on the pharmacokinetic, pharmacodynamic and biodistribution profiles of peptide- and protein-like drugs following oral administration is critically reviewed. The possible mechanisms of absorption enhancement and the effects of the physicochemical properties of the NP are examined. The potential advantages and challenges of physiologically-based pharmacokinetic (PBPK) modelling to help predict efficacy in man are discussed. The importance of developing and expanding the regulatory framework to help translate the technology into the clinic and accelerate the availability of oral nanoparticulate formulations is emphasized. In conclusion, opportunities for future work to improve the state of the art of oral nanomedicines are identified. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. 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.

  6. 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.

  7. Pharmacokinetics and effects on serum cholinesterase activities of organophosphorus pesticides acephate and chlorpyrifos in chimeric mice transplanted with human hepatocytes.

    Science.gov (United States)

    Suemizu, Hiroshi; Sota, Shigeto; Kuronuma, Miyuki; Shimizu, Makiko; Yamazaki, Hiroshi

    2014-11-01

    Organophosphorus pesticides acephate and chlorpyrifos in foods have potential to impact human health. The aim of the current study was to investigate the pharmacokinetics of acephate and chlorpyrifos orally administered at lowest-observed-adverse-effect-level doses in chimeric mice transplanted with human hepatocytes. Absorbed acephate and its metabolite methamidophos were detected in serum from wild type mice and chimeric mice orally administered 150mg/kg. Approximately 70% inhibition of cholinesterase was evident in plasma of chimeric mice with humanized liver (which have higher serum cholinesterase activities than wild type mice) 1day after oral administrations of acephate. Adjusted animal biomonitoring equivalents from chimeric mice studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Estimated plasma concentrations of acephate and chlorpyrifos in humans were consistent with reported concentrations. Acephate cleared similarly in humans and chimeric mice but accidental/incidental overdose levels of chlorpyrifos cleared (dependent on liver metabolism) more slowly from plasma in humans than it did in mice. The data presented here illustrate how chimeric mice transplanted with human hepatocytes in combination with a simple PBPK model can assist evaluations of toxicological potential of organophosphorus pesticides.

  8. The pharmacokinetic/pharmacodynamic pipeline: translating anticancer drug pharmacology to the clinic.

    Science.gov (United States)

    Zhou, Qingyu; Gallo, James M

    2011-03-01

    Progress in an understanding of the genetic basis of cancer coupled to molecular pharmacology of potential new anticancer drugs calls for new approaches that are able to address key issues in the drug development process, including pharmacokinetic (PK) and pharmacodynamic (PD) relationships. The incorporation of predictive preclinical PK/PD models into rationally designed early-stage clinical trials offers a promising way to relieve a significant bottleneck in the drug discovery pipeline. The aim of the current review is to discuss some considerations for how quantitative PK and PD analyses for anticancer drugs may be conducted and integrated into a global translational effort, and the importance of examining drug disposition and dynamics in target tissues to support the development of preclinical PK/PD models that can be subsequently extrapolated to predict pharmacologic characteristics in patients. In this article, we describe three different physiologically based (PB) PK modeling approaches, i.e., the whole-body PBPK model, the hybrid PBPK model, and the two-pore model for macromolecules, as well as their applications. General conclusions are that greater effort should be made to generate more clinical data that could validate scaled preclinical PB-PK/PD tumor-based models and, thus, stimulate a framework for preclinical to clinical translation. Finally, given the innovative techniques to measure tissue drug concentrations and associated biomarkers of drug responses, development of predictive PK/PD models will become a standard approach for drug discovery and development.

  9. Using pharmacokinetic modelling to improve prescribing practices of intravenous aminophylline in childhood asthma exacerbations.

    Science.gov (United States)

    Cooney, Lewis; McBride, Antonia; Lilley, Andrew; Sinha, Ian; Johnson, Trevor N; Hawcutt, Daniel B

    2017-04-01

    To evaluate physiologically based pharmacokinetic modelling (PBPK) software in paediatric asthma patients using intravenous aminophylline. Prospective clinical audit of children receiving iv aminophylline (July 2014 to June 2016), and in-silico modelling using Simcyp software. Thirty-eight admissions (25 children) were included. Children with aminophylline levels ≥10 mg/l had equivalent clinical outcomes compared to those model. PBPK modelling of a 5 mg/kg iv loading dose (≤18yr) shows a mean Cmax of 8.99 mg/L (5th-95th centiles 5.5-13.7 mg/L), with 70.3% of subjects  20 mg/L. For an aminophylline infusion (0-12 y) of 1.0  mg/kg/h, the mean steady state infusion concentration was 16.4 mg/L, (5th-95th centiles 5.3-32 mg/L), with 26.8% having a serum concentration >20 mg/L. For 12-18yr receiving 0.5  mg/kg/h infusion, the mean steady state infusion concentration was 9.37 mg/L (5th-95th centiles 3.4-18 mg/L), with 59.8% having a serum concentration modelling correlates well with clinical data. Current aminophylline iv loading dosage recommendations achieve levels 20 mg/l). Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Development and application of a human PBPK model for bromodichloromethane to investigate the impacts of multi-route exposure.

    Science.gov (United States)

    Kenyon, Elaina M; Eklund, Christopher; Leavens, Teresa; Pegram, Rex A

    2016-09-01

    As a result of its presence in water as a volatile disinfection byproduct, bromodichloromethane (BDCM), which is mutagenic, poses a potential health risk from exposure via oral, dermal and inhalation routes. We developed a refined human physiologically based pharmacokinetic (PBPK) model for BDCM (including new chemical-specific human parameters) to evaluate the impact of BDCM exposure during showering and bathing on important measures of internal dose compared with oral exposure. The refined model adequately predicted data from the published literature for oral, dermal and bathing/showering exposures. A liter equivalency approach (L-eq) was used to estimate BDCM concentration in a liter of water consumed by the oral route that would be required to produce the same internal dose of BDCM resulting from a 20-min bath or a 10-min shower in water containing 10 µg l(-1) BDCM. The oral liter equivalent concentrations for the bathing scenario were 605, 803 and 5 µg l(-1) BDCM for maximum venous blood concentration (Cmax), the area under the curve (AUCv) and the amount metabolized in the liver per hour (MBDCM), respectively. For a 10-min showering exposure, the oral L-eq concentrations were 282, 312 and 2.1 µg l(-1) for Cmax, AUC and MBDCM, respectively. These results demonstrate large contributions of dermal and inhalation exposure routes to the internal dose of parent chemical reaching the systemic circulation, which could be transformed to mutagenic metabolites in extrahepatic target tissues. Thus, consideration of the contribution of multiple routes of exposure when evaluating risks from water-borne BDCM is needed, and this refined human model will facilitate improved assessment of internal doses from real-world exposures. Published 2015. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

  11. Comparing translational population-PBPK modelling of brain microdialysis with bottom-up prediction of brain-to-plasma distribution in rat and human.

    Science.gov (United States)

    Ball, Kathryn; Bouzom, François; Scherrmann, Jean-Michel; Walther, Bernard; Declèves, Xavier

    2014-11-01

    The prediction of brain extracellular fluid (ECF) concentrations in human is a potentially valuable asset during drug development as it can provide the pharmacokinetic input for pharmacokinetic-pharmacodynamic models. This study aimed to compare two translational modelling approaches that can be applied at the preclinical stage of development in order to simulate human brain ECF concentrations. A population-PBPK model of the central nervous system was developed based on brain microdialysis data, and the model parameters were translated to their corresponding human values to simulate ECF and brain tissue concentration profiles. In parallel, the PBPK modelling software Simcyp was used to simulate human brain tissue concentrations, via the bottom-up prediction of brain tissue distribution using two different sets of mechanistic tissue composition-based equations. The population-PBPK and bottom-up approaches gave similar predictions of total brain concentrations in both rat and human, while only the population-PBPK model was capable of accurately simulating the rat ECF concentrations. The choice of PBPK model must therefore depend on the purpose of the modelling exercise, the in vitro and in vivo data available and knowledge of the mechanisms governing the membrane permeability and distribution of the drug.

  12. A systems pharmacokinetic and pharmacodynamic approach to identify opportunities and pitfalls in energy stress-mediated chemoprevention: the use of metformin and other biguanides.

    Science.gov (United States)

    Thompson, Matthew D; Thompson, Henry J

    2012-12-01

    Metformin, a widely used anti-hyperglycemic drug in the biguanide class, is currently under investigation for the prevention of cancer. Surprisingly however, considering the time and cost of clinical chemoprevention trials and the current scrutiny of cancer chemoprevention, limited attention has been given to integrating available data, identifying the subpopulations most likely to benefit, or to quantitatively understanding the potential pitfalls of biguanide chemoprevention. Herein, a physiologically-based pharmacokinetic (PBPK) and pharmacodynamic framework is proposed for integrating information on physicochemical, cell-based, animal, and human studies of various biguanides to identify gaps in knowledge and to build a systems model that may facilitate the planning of randomized cancer chemoprevention trials of metformin.

  13. 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.

  14. Modelling the exposure to chemicals for risk assessment: a comprehensive library of multimedia and PBPK models for integration, prediction, uncertainty and sensitivity analysis - the MERLIN-Expo tool.

    Science.gov (United States)

    Ciffroy, P; Alfonso, B; Altenpohl, A; Banjac, Z; Bierkens, J; Brochot, C; Critto, A; De Wilde, T; Fait, G; Fierens, T; Garratt, J; Giubilato, E; Grange, E; Johansson, E; Radomyski, A; Reschwann, K; Suciu, N; Tanaka, T; Tediosi, A; Van Holderbeke, M; Verdonck, F

    2016-10-15

    MERLIN-Expo is a library of models that was developed in the frame of the FP7 EU project 4FUN in order to provide an integrated assessment tool for state-of-the-art exposure assessment for environment, biota and humans, allowing the detection of scientific uncertainties at each step of the exposure process. This paper describes the main features of the MERLIN-Expo tool. The main challenges in exposure modelling that MERLIN-Expo has tackled are: (i) the integration of multimedia (MM) models simulating the fate of chemicals in environmental media, and of physiologically based pharmacokinetic (PBPK) models simulating the fate of chemicals in human body. MERLIN-Expo thus allows the determination of internal effective chemical concentrations; (ii) the incorporation of a set of functionalities for uncertainty/sensitivity analysis, from screening to variance-based approaches. The availability of such tools for uncertainty and sensitivity analysis aimed to facilitate the incorporation of such issues in future decision making; (iii) the integration of human and wildlife biota targets with common fate modelling in the environment. MERLIN-Expo is composed of a library of fate models dedicated to non biological receptor media (surface waters, soils, outdoor air), biological media of concern for humans (several cultivated crops, mammals, milk, fish), as well as wildlife biota (primary producers in rivers, invertebrates, fish) and humans. These models can be linked together to create flexible scenarios relevant for both human and wildlife biota exposure. Standardized documentation for each model and training material were prepared to support an accurate use of the tool by end-users. One of the objectives of the 4FUN project was also to increase the confidence in the applicability of the MERLIN-Expo tool through targeted realistic case studies. In particular, we aimed at demonstrating the feasibility of building complex realistic exposure scenarios and the accuracy of the

  15. Predicting dopamine D2 receptor occupancy in humans using a physiology-based approach

    NARCIS (Netherlands)

    Johnson, Martin; Kozielska, Magdalena; Pilla Reddy, Venkatesh; Vermeulen, An; Barton, Hugh A.; Grimwood, Sarah; de Greef, Rik; Groothuis, Genoveva; Danhof, Meindert; Proost, Johannes

    2011-01-01

    Objectives: A hybrid physiology-based pharmacokinetic and pharmacodynamic model (PBPKPD) was used to predict the time course of dopamine receptor occupancy (D2RO) in human striatum following the administration of antipsychotic (AP) drugs, using in vitro and in silico information. Methods: A hybrid P

  16. Multiscale Modeling of Antibody-Drug Conjugates: Connecting Tissue and Cellular Distribution to Whole Animal Pharmacokinetics and Potential Implications for Efficacy.

    Science.gov (United States)

    Cilliers, Cornelius; Guo, Hans; Liao, Jianshan; Christodolu, Nikolas; Thurber, Greg M

    2016-09-01

    Antibody-drug conjugates exhibit complex pharmacokinetics due to their combination of macromolecular and small molecule properties. These issues range from systemic concerns, such as deconjugation of the small molecule drug during the long antibody circulation time or rapid clearance from nonspecific interactions, to local tumor tissue heterogeneity, cell bystander effects, and endosomal escape. Mathematical models can be used to study the impact of these processes on overall distribution in an efficient manner, and several types of models have been used to analyze varying aspects of antibody distribution including physiologically based pharmacokinetic (PBPK) models and tissue-level simulations. However, these processes are quantitative in nature and cannot be handled qualitatively in isolation. For example, free antibody from deconjugation of the small molecule will impact the distribution of conjugated antibodies within the tumor. To incorporate these effects into a unified framework, we have coupled the systemic and organ-level distribution of a PBPK model with the tissue-level detail of a distributed parameter tumor model. We used this mathematical model to analyze new experimental results on the distribution of the clinical antibody-drug conjugate Kadcyla in HER2-positive mouse xenografts. This model is able to capture the impact of the drug-antibody ratio (DAR) on tumor penetration, the net result of drug deconjugation, and the effect of using unconjugated antibody to drive ADC penetration deeper into the tumor tissue. This modeling approach will provide quantitative and mechanistic support to experimental studies trying to parse the impact of multiple mechanisms of action for these complex drugs.

  17. Parameterization of small intestinal water volume using PBPK modeling.

    Science.gov (United States)

    Maharaj, Anil; Fotaki, Nikoletta; Edginton, Andrea

    2015-01-25

    To facilitate accurate predictions of oral drug disposition, mechanistic absorption models require optimal parameterization. Furthermore, parameters should maintain a biological basis to establish confidence in model predictions. This study will serve to calculate an optimal parameter value for small intestinal water volume (SIWV) using a model-based approach. To evaluate physiologic fidelity, derived volume estimates will be compared to experimentally-based SIWV determinations. A compartmental absorption and transit (CAT) model, created in Matlab-Simulink®, was integrated with a whole-body PBPK model, developed in PK-SIM 5.2®, to provide predictions of systemic drug disposition. SIWV within the CAT model was varied between 52.5mL and 420mL. Simulations incorporating specific SIWV values were compared to pharmacokinetic data from compounds exhibiting solubility induced non-proportional changes in absorption using absolute average fold-error. Correspondingly, data pertaining to oral administration of acyclovir and chlorothiazide were utilized to derive estimates of SIWV. At 400mg, a SIWV of 116mL provided the best estimates of acyclovir plasma concentrations. A similar SIWV was found to best depict the urinary excretion pattern of chlorothiazide at a dose of 100mg. In comparison, experimentally-based estimates of SIWV within adults denote a central tendency between 86 and 167mL. The derived SIWV (116mL) represents the optimal parameter value within the context of the developed CAT model. This result demonstrates the biological basis of the widely utilized CAT model as in vivo SIWV determinations correspond with model-based estimates.

  18. APPLICATION OF A MULTIROUTE HUMAN PBPK MODEL FOR BROMODICHLOROMETHANE (BDCM)

    Science.gov (United States)

    Due to its presence in water as a volatile disinfection byproduct, BDCM poses a risk for exposure via multiple routes. Mechanistic data suggest target tissue metabolism could be important for some types of BDCM-induced toxicity. Utilizing our refined PBPK model for BDCM, the impa...

  19. Physiological modeling reveals novel pharmacokinetic behavior for inhaled octamethylcyclotetrasiloxane in rats.

    Science.gov (United States)

    Andersen, M E; Sarangapani, R; Reitz, R H; Gallavan, R H; Dobrev, I D; Plotzke, K P

    2001-04-01

    Octamethylcyclotetrasiloxane (D4) is an ingredient in selected consumer and precision cleaning products. Workplace inhalation exposures may occur in some D4 production operations. In this study, we analyzed tissue, plasma, and excreta time-course data following D4 inhalation in Fischer 344 rats (K. Plotzke et al., 2000, Drug Metab. Dispos. 28, 192-204) to assess the degree to which the disposition of D4 is similar to or different from that of volatile hydrocarbons that lack silicone substitution. We first applied a basic physiologically based pharmacokinetic (PBPK) model (J. C. Ramsey and M. E. Andersen, 1984, Toxicol. Appl. Pharmacol. 73, 159-175) to characterize the biological determinants of D4 kinetics. Parameter estimation techniques indicated an unusual set of characteristics, i.e., a low blood:air (P(b:a) congruent with 0.9) and a high fat:blood partition coefficient (P(f:b) congruent with 550). These parameters were then determined experimentally by equilibrating tissue or liquid samples with saturated atmospheres of D4. Consistent with the estimates from the time-course data, blood:air partition coefficients were small, ranging from 1.9 to 6.9 in six samples. Perirenal fat:air partition coefficients were large, from 1400 to 2500. The average P(f:b) was determined to be 485. This combination of partitioning characteristics leads to rapid exhalation of free D4 at the cessation of the inhalation exposure followed by a much slower redistribution of D4 from fat and tissue storage compartments. The basic PK model failed to describe D4 tissue kinetics in the postexposure period and had to be expanded by adding deep-tissue compartments in liver and lung, a mobile chylomicron-like lipid transport pool in blood, and a second fat compartment. Model parameters for the refined model were optimized using single-exposure data in male and female rats exposed at three concentrations: 7, 70, and 700 ppm. With inclusion of induction of D4 metabolism at 700 ppm (3-fold in

  20. Lumping in pharmacokinetics.

    Science.gov (United States)

    Brochot, Céline; Tóth, János; Bois, Frédéric Y

    2005-12-01

    Pharmacokinetic (PK) models simplify biological complexity by dividing the body into interconnected compartments. The time course of the chemical's amount (or concentration) in each compartment is then expressed as a system of ordinary differential equations. The complexity of the resulting system of equations can rapidly increase if a precise description of the organism is needed. However, difficulties arise when the PK model contains more variables and parameters than comfortable for mathematical and computational treatment. To overcome such difficulties, mathematical lumping methods are new and powerful tools. Such methods aim at reducing a differential system by aggregating several variables into one. Typically, the lumped model is still a differential equation system, whose variables are interpretable in terms of variables of the original system. In practice, the reduced model is usually required to satisfy some constraints. For example, it may be necessary to keep state variables of interest for prediction unlumped. To accommodate such constraints, constrained lumping methods have are also available. After presenting the theory, we study, here, through practical examples, the potential of such methods in toxico/pharmacokinetics. As a tutorial, we first simplify a 2-compartment pharmacokinetic model by symbolic lumping. We then explore the reduction of a 6-compartment physiologically based pharmacokinetic model for 1,3-butadiene with numerical constrained lumping. The lumping methods presented here can be easily automated, and are applicable to first-order ordinary differential equation systems.

  1. Acute Exposure to Perchlorethylene alters Rat Visual Evoked Potentials in Relation to Brain Concentration

    Science.gov (United States)

    These experiments sought to establish a dose-effect relationship between the concentration of perchloroethylene (PCE) in brain tissue and concurrent changes in visual function. A physiologically-based pharmacokinetic (PBPK) model was implemented to predict concentrations of PCE ...

  2. Acute Exposure to Perchlorethylene alters Rat Visual Evoked Potentials in Relation to Brain Concentration

    Science.gov (United States)

    These experiments sought to establish a dose-effect relationship between the concentration of perchloroethylene (PCE) in brain tissue and concurrent changes in visual function. A physiologically-based pharmacokinetic (PBPK) model was implemented to predict concentrations of PCE ...

  3. 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...

  4. 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...

  5. The impact of variation in scaling factors on the estimation of internal dose metrics: a case study using bromodichloromethane (BDCM)

    Science.gov (United States)

    Many physiologically based pharmacokinetic (PBPK) models include values for metabolic rate parameters extrapolated from in vitro metabolism studies using scaling factors such as mg of microsomal protein per gram of liver (MPPGL) and liver mass (FVL). Variation in scaling factor ...

  6. Statistical Inferences from Formaldehyde Dna-Protein Cross-Link Data

    Science.gov (United States)

    Physiologically-based pharmacokinetic (PBPK) modeling has reached considerable sophistication in its application in the pharmacological and environmental health areas. Yet, mature methodologies for making statistical inferences have not been routinely incorporated in these applic...

  7. 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.

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

    Science.gov (United States)

    Smith, Jordan Ned; Campbell, James A; Busby-Hjerpe, Andrea L; Lee, Sookwang; Poet, Torka S; Barr, Dana B; Timchalk, Charles

    2009-06-30

    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 micromol/l), TCPy/L-TCPy blood AUC (94.9 micromol/lh), 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

  9. Evolving PBPK applications in regulatory risk assessment: current situation and future goals

    Science.gov (United States)

    The presentation includes current applications of PBPK modeling in regulatory risk assessment and discussions on conflicts between assuring consistency with experimental data in current situation and the desire for animal-free model development.

  10. Comparative Kinetics and Distribution to Target Tissues of Organophosphates Using Physiologically - Based Pharmacokinetic Modeling

    Science.gov (United States)

    2008-03-01

    diagnosis . It is now being reported that over 300,000 American troops have been exposed to sub-lethal doses of the gas. Some of the chronic long term...chronic fatigue, muscle weakness and fibromyalgia (Kennedy, 2007). Acute verses chronic The near term effects of high exposure to chemical warfare

  11. Quantitative Evaluation of Dichloroacetic Acid Kinetics in Human -- A Physiologically-Based Pharmacokinetic Modeling Investigation

    Science.gov (United States)

    2008-01-01

    use include mild liver dysfunction, transient central neuropathy , peripheral neuropathy and hypocalcemia. The clinical effects are generally...Naviaux, R.K., McGowan, K.A., Levine, F., Nyhan, W.L., Loupis-Geller, A., Haas, R.H., 2004. Chronic treatment of mitochondrial disease patients with...Momoi, M.Y., 2004. Dichloroacetate treatment for mitochondrial cytopathy: long-term effects in MELAS. Brain Devel. 26, 453-458. Schultz, I.R

  12. A Physiologically Based Pharmacokinetic Model for the Oxime TMB-4: Simulation of Rodent and Human Data

    Science.gov (United States)

    2013-01-13

    values) (Voicu et al. 2010). Medically, oximes are administered to counteract organophosphate (OP) poisoning . OPs form serine-conjugated phosphonates...AH, Warnet JM (2011) Does modulation of organic cation transporters improve pralidoxime activity in an animal model of organophosphate poisoning ...model structure for the organophosphate diisopropylfluorophosphate, the model includes key sites of acetylcholinesterase inhibition (brain and diaphragm

  13. Physiologically based kinetic modeling of the bioactivation of myristicin

    NARCIS (Netherlands)

    Al-Malahmeh, Amer J.; Al-Ajlouni, Abdelmajeed; Wesseling, Sebastiaan; Soffers, Ans E.M.F.; Al-Subeihi, A.; Kiwamoto, Reiko; Vervoort, Jacques; Rietjens, Ivonne M.C.M.

    2016-01-01

    The present study describes physiologically based kinetic (PBK) models for the alkenylbenzene myristicin that were developed by extension of the PBK models for the structurally related alkenylbenzene safrole in rat and human. The newly developed myristicin models revealed that the formation of th

  14. Human insulin dynamics in women: a physiologically based model.

    Science.gov (United States)

    Weiss, Michael; Tura, Andrea; Kautzky-Willer, Alexandra; Pacini, Giovanni; D'Argenio, David Z

    2016-02-01

    Currently available models of insulin dynamics are mostly based on the classical compartmental structure and, thus, their physiological utility is limited. In this work, we describe the development of a physiologically based model and its application to data from 154 patients who underwent an insulin-modified intravenous glucose tolerance test (IM-IVGTT). To determine the time profile of endogenous insulin delivery without using C-peptide data and to evaluate the transcapillary transport of insulin, the hepatosplanchnic, renal, and peripheral beds were incorporated into the circulatory model as separate subsystems. Physiologically reasonable population mean estimates were obtained for all estimated model parameters, including plasma volume, interstitial volume of the peripheral circulation (mainly skeletal muscle), uptake clearance into the interstitial space, hepatic and renal clearance, as well as total insulin delivery into plasma. The results indicate that, at a population level, the proposed physiologically based model provides a useful description of insulin disposition, which allows for the assessment of muscle insulin uptake.

  15. Kinetics of drug action in disease states: towards physiology-based pharmacodynamic (PBPD) models.

    Science.gov (United States)

    Danhof, Meindert

    2015-10-01

    Gerhard Levy started his investigations on the "Kinetics of Drug Action in Disease States" in the fall of 1980. The objective of his research was to study inter-individual variation in pharmacodynamics. To this end, theoretical concepts and experimental approaches were introduced, which enabled assessment of the changes in pharmacodynamics per se, while excluding or accounting for the cofounding effects of concomitant changes in pharmacokinetics. These concepts were applied in several studies. The results, which were published in 45 papers in the years 1984-1994, showed considerable variation in pharmacodynamics. These initial studies on kinetics of drug action in disease states triggered further experimental research on the relations between pharmacokinetics and pharmacodynamics. Together with the concepts in Levy's earlier publications "Kinetics of Pharmacologic Effects" (Clin Pharmacol Ther 7(3): 362-372, 1966) and "Kinetics of pharmacologic effects in man: the anticoagulant action of warfarin" (Clin Pharmacol Ther 10(1): 22-35, 1969), they form a significant impulse to the development of physiology-based pharmacodynamic (PBPD) modeling as novel discipline in the pharmaceutical sciences. This paper reviews Levy's research on the "Kinetics of Drug Action in Disease States". Next it addresses the significance of his research for the evolution of PBPD modeling as a scientific discipline. PBPD models contain specific expressions to characterize in a strictly quantitative manner processes on the causal path between exposure (in terms of concentration at the target site) and the drug effect (in terms of the change in biological function). Pertinent processes on the causal path are: (1) target site distribution, (2) target binding and activation and (3) transduction and homeostatic feedback.

  16. A Generic Integrated Physiologically based Whole-body Model of the Glucose-Insulin-Glucagon Regulatory System

    Science.gov (United States)

    Schaller, S; Willmann, S; Lippert, J; Schaupp, L; Pieber, T R; Schuppert, A; Eissing, T

    2013-01-01

    Models of glucose metabolism are a valuable tool for fundamental and applied medical research in diabetes. Use cases range from pharmaceutical target selection to automatic blood glucose control. Standard compartmental models represent little biological detail, which hampers the integration of multiscale data and confines predictive capabilities. We developed a detailed, generic physiologically based whole-body model of the glucose-insulin-glucagon regulatory system, reflecting detailed physiological properties of healthy populations and type 1 diabetes individuals expressed in the respective parameterizations. The model features a detailed representation of absorption models for oral glucose, subcutaneous insulin and glucagon, and an insulin receptor model relating pharmacokinetic properties to pharmacodynamic effects. Model development and validation is based on literature data. The quality of predictions is high and captures relevant observed inter- and intra-individual variability. In the generic form, the model can be applied to the development and validation of novel diabetes treatment strategies. PMID:23945606

  17. 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…

  18. Quinolone pharmacokinetics.

    Science.gov (United States)

    Robson, R A

    1992-12-01

    Fluoroquinolones have broad antibacterial spectra and are active against most Gram-negative and many Gram-positive species. They exhibit excellent oral bioavailability, extensive tissue penetration, low protein binding, and a long elimination half-life. This review compares and contrasts the pharmakonetics of some quinolone antibiotics - especially pefloxacin, ciprofloxacin, enoxacin, norfloxacin, ofloxacin, fleroxacin and lomefloxacin - in terms of their adsorption, distribution, metabolism, elimination, and interactions with other drugs and with food. In addition, the pharmacokinetics of these agents in the elderly and in patients with renal or hepatic impairment is discussed. The fluoroquinolones are established as a major class of antibiotics in the treatment of infections but pharmacokinetics factors should be considered when deciding on the most appropriate of these agents to use in individual patients.

  19. Physiologically Based Absorption Modeling to Impact Biopharmaceutics and Formulation Strategies in Drug Development-Industry Case Studies.

    Science.gov (United States)

    Kesisoglou, Filippos; Chung, John; van Asperen, Judith; Heimbach, Tycho

    2016-09-01

    In recent years, there has been a significant increase in use of physiologically based pharmacokinetic models in drug development and regulatory applications. Although most of the published examples have focused on aspects such as first-in-human (FIH) dose predictions or drug-drug interactions, several publications have highlighted the application of these models in the biopharmaceutics field and their use to inform formulation development. In this report, we present 5 case studies of use of such models in this biopharmaceutics/formulation space across different pharmaceutical companies. The case studies cover different aspects of biopharmaceutics or formulation questions including (1) prediction of absorption prior to FIH studies; (2) optimization of formulation and dissolution method post-FIH data; (3) early exploration of a modified-release formulation; (4) addressing bridging questions for late-stage formulation changes; and (5) prediction of pharmacokinetics in the fed state for a Biopharmaceutics Classification System class I drug with fasted state data. The discussion of the case studies focuses on how such models can facilitate decisions and biopharmaceutic understanding of drug candidates and the opportunities for increased use and acceptance of such models in drug development and regulatory interactions.

  20. Development of a Physiologically Based Computational Kidney Model to Describe the Renal Excretion of Hydrophilic Agents in Rats

    Science.gov (United States)

    Niederalt, Christoph; Wendl, Thomas; Kuepfer, Lars; Claassen, Karina; Loosen, Roland; Willmann, Stefan; Lippert, Joerg; Schultze-Mosgau, Marcus; Winkler, Julia; Burghaus, Rolf; Bräutigam, Matthias; Pietsch, Hubertus; Lengsfeld, Philipp

    2013-01-01

    A physiologically based kidney model was developed to analyze the renal excretion and kidney exposure of hydrophilic agents, in particular contrast media, in rats. In order to study the influence of osmolality and viscosity changes, the model mechanistically represents urine concentration by water reabsorption in different segments of kidney tubules and viscosity dependent tubular fluid flow. The model was established using experimental data on the physiological steady state without administration of any contrast media or drugs. These data included the sodium and urea concentration gradient along the cortico-medullary axis, water reabsorption, urine flow, and sodium as well as urea urine concentrations for a normal hydration state. The model was evaluated by predicting the effects of mannitol and contrast media administration and comparing to experimental data on cortico-medullary concentration gradients, urine flow, urine viscosity, hydrostatic tubular pressures and single nephron glomerular filtration rate. Finally the model was used to analyze and compare typical examples of ionic and non-ionic monomeric as well as non-ionic dimeric contrast media with respect to their osmolality and viscosity. With the computational kidney model, urine flow depended mainly on osmolality, while osmolality and viscosity were important determinants for tubular hydrostatic pressure and kidney exposure. The low diuretic effect of dimeric contrast media in combination with their high intrinsic viscosity resulted in a high viscosity within the tubular fluid. In comparison to monomeric contrast media, this led to a higher increase in tubular pressure, to a reduction in glomerular filtration rate and tubular flow and to an increase in kidney exposure. The presented kidney model can be implemented into whole body physiologically based pharmacokinetic models and extended in order to simulate the renal excretion of lipophilic drugs which may also undergo active secretion and reabsorption

  1. Drug Distribution to Human Tissues: Prediction and Examination of the Basic Assumption in In Vivo Pharmacokinetics-Pharmacodynamics (PK/PD) Research.

    Science.gov (United States)

    Poulin, Patrick

    2015-06-01

    mathematical correction to the basic assumption of similar free drug concentration in plasma and tissues can be derived from the tissue composition-based model. Note that this assumption will be further challenged in a dynamic in vivo system in a companion manuscript. Overall, this study was a first attempt to predict the in vivo Kp values for specific human tissues by considering separately the effect of fup and fut , with the aim of facilitating the use of physiologically-based PK (PBPK) model in PK/PD studies. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  2. Application of Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling in Cumulative Risk Assessment for N-Methyl Carbamate Insecticides

    Science.gov (United States)

    Human exposure to xenobiotics may occur through multiple pathways and routes of entry punctuated by exposure intervals throughout a work or leisure day. Exposure to a single environmental chemical along multiple pathways and routes (aggregate exposure) may have an influence on an...

  3. A physiologically based in silico kinetic model predicting plasma cholesterol concentrations in humans

    NARCIS (Netherlands)

    Pas, van de N.C.A.; Woutersen, R.A.; Ommen, van B.; Rietjens, I.M.C.M.; Graaf, de A.A.

    2012-01-01

    Increased plasma cholesterol concentration is associated with increased risk of cardiovascular disease. This study describes the development, validation, and analysis of a physiologically based kinetic (PBK) model for the prediction of plasma cholesterol concentrations in humans. This model was dire

  4. A physiologically based in silico kinetic model predicting plasma cholesterol concentrations in humans

    NARCIS (Netherlands)

    Pas, N.C.A. van de; Woutersen, R.A.; Ommen, B. van; Rietjens, I.M.C.M.; Graaf, A.A. de

    2012-01-01

    Increased plasma cholesterol concentration is associated with increased risk of cardiovascular disease. This study describes the development, validation, and analysis of a physiologically based kinetic (PBK) model for the prediction of plasma cholesterol concentrations in humans. This model was

  5. Influence of dosing schedule on organ exposure to cyclosporin in pediatric hematopoietic stem cell transplantation: analysis with a PBPK model.

    Science.gov (United States)

    Gérard, Cécile; Bleyzac, Nathalie; Girard, Pascal; Freyer, Gilles; Bertrand, Yves; Tod, Michel

    2010-12-01

    Cyclosporin is administered by intermittent infusions (II) or continuous infusions (CI) to prevent acute graft-versus-host disease (aGVHD). Because cyclosporin disposition is nonlinear, organ exposure may be higher after II than after CI, but saturation of receptors must be accounted for. The aim of the study was to compare both types of administration using a mechanistic model. A physiologically based pharmacokinetic model was developed to estimate cyclosporin exposure and receptor occupancies (RO) in aGVHD target organs and kidneys and to compare these estimations in pediatric patients that received cyclosporin either by II or CI. The relevant biological parameters were based on a clinical study in 2 groups of pediatric patients that received cyclosporin either by II (n = 31) or CI (n = 30). Simulations showed that the exposure to cyclosporin in the interstitial fluid of aGVHD target organs was greater at day 1 after II than after CI. In kidneys, the opposite order was observed. AUC(RO) in all organs was greater after CI than after II. The therapeutic index (the ratio of AUC(RO) in blood to AUC(RO) in kidneys) was greater with CI than with II. CI may be slightly more favorable than II for aGVHD prevention.

  6. 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.

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

    Science.gov (United States)

    McNally, Kevin; Cotton, Richard; Cocker, John; Jones, Kate; Bartels, Mike; Rick, David; Price, Paul; Loizou, George

    2012-01-01

    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.

  8. MOLECULAR MODELS OF PARATHYROID METABOLISM BY CARBOXYLESTERASES: DIFFERENTIAL EFFECTS DUE TO STEREOCHEMISTRY.

    Science.gov (United States)

    PARATHYROIDS ARE A CHEMICAL CLASS OF WIDELY USED INSECTICIDES, & AT LEAST 16 CHEMICALS IN THIS CLASS ARE REGISTERED FOR USE IN THE US. IN ORDER TO EXTRAPOLATE THE KNOWLEDGE FROM RODENTS TO HUMANS, PHYSIOLOGICALLY-BASED PHARMACOKINETIC (pbpk) MODELS ARE CURRENTLY BEING DEVELOPED.

  9. 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.

  10. Links between cyclosporin exposure in tissues and graft-versus-host disease in pediatric bone marrow transplantation: analysis by a PBPK model.

    Science.gov (United States)

    Gérard, Cécile; Bleyzac, Nathalie; Girard, Pascal; Freyer, Gilles; Bertrand, Yves; Tod, Michel

    2011-03-01

    In hematopoietic stem cell transplantation (HSCT), cyclosporin is used to prevent graft-versus-host disease (GVHD). However, cyclosporin distribution in tissues is not linear, resulting in uncertainty regarding optimal dosing and monitoring. The objective of this study was to link the probability and severity of acute GVHD to cyclosporin exposure in blood, GVHD target organs, and lymphoid organs. A physiologically based pharmacokinetic model of cyclosporin disposition and logistic regression models were used. Sixty-one pediatric patients undergoing HSCT were studied. Cyclosporin was administered by intermittent (n = 31) or continuous infusion (n = 30). At steady state (1 day before acute GVHD), exposures in all organs were related with the probability and severity of acute GVHD. Average cyclosporin concentration or, equivalently, its area under the curve (AUC) was the pharmacokinetic index best correlated with the anti-GVHD effect. Cyclosporin AUC in interstitial fluid of lymphoid organs was a superior index than that in blood, but marginally. Hence, AUC in blood maybe used as an index of cyclosporin efficacy. Using our model, target AUCs in blood could be defined for malignant and non-malignant diseases, as well as the equivalent target values for C(2) and C(0) concentrations.

  11. 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.

  12. Paediatric pharmacokinetics: key considerations

    Science.gov (United States)

    Batchelor, Hannah Katharine; Marriott, John Francis

    2015-01-01

    A number of anatomical and physiological factors determine the pharmacokinetic profile of a drug. Differences in physiology in paediatric populations compared with adults can influence the concentration of drug within the plasma or tissue. Healthcare professionals need to be aware of anatomical and physiological changes that affect pharmacokinetic profiles of drugs to understand consequences of dose adjustments in infants and children. Pharmacokinetic clinical trials in children are complicated owing to the limitations on blood sample volumes and perception of pain in children resulting from blood sampling. There are alternative sampling techniques that can minimize the invasive nature of such trials. Population based models can also limit the sampling required from each individual by increasing the overall sample size to generate robust pharmacokinetic data. This review details key considerations in the design and development of paediatric pharmacokinetic clinical trials. PMID:25855821

  13. Physiologically Based Biokinetic (PBBK) Modeling of Safrole Bioactivation and Detoxification in Humans as Compared With Rats

    NARCIS (Netherlands)

    Martati, E.; Boersma, M.G.; Spenkelink, A.; Khadka, D.B.; Bladeren, van P.J.; Rietjens, I.; Punt, A.

    2012-01-01

    A physiologically based biokinetic (PBBK) model for the alkenylbenzene safrole in humans was developed based on in vitro- and in silico-derived kinetic parameters. With the model obtained, the time- and dose-dependent formation of the proximate and ultimate carcinogenic metabolites, 1'-hydroxysafrol

  14. Physiologically based biokinetic (PBBK) model for safrole bioactivation and detoxification in rats

    NARCIS (Netherlands)

    Martati, E.; Boersma, M.G.; Spenkelink, A.; Khadka, D.B.; Punt, A.; Vervoort, J.J.M.; Bladeren, van P.J.; Rietjens, I.

    2011-01-01

    A physiologically based biokinetic (PBBK) model for alkenylbenzene safrole in rats was developed using in vitro metabolic parameters determined using relevant tissue fractions. The performance of the model was evaluated by comparison of the predicted levels of 1,2-dihydroxy-4-allylbenzene and 1'-hyd

  15. Predicting individual responses to pravastatin using a physiologically based kinetic model for plasma cholesterol concentrations

    NARCIS (Netherlands)

    Pas, N.C.A. van de; Rullmann, J.A.C.; Woutersen, R.A.; Ommen, B. van; Rietjens, I.M.C.M.; Graaf, A.A. de

    2014-01-01

    We used a previously developed physiologically based kinetic (PBK) model to analyze the effect of individual variations in metabolism and transport of cholesterol on pravastatin response. The PBK model is based on kinetic expressions for 21 reactions that interconnect eight different body

  16. PBPK modeling of the cis- and trans-permethrin isomers and their major urinary metabolites in rats.

    Science.gov (United States)

    Willemin, Marie-Emilie; Desmots, Sophie; Le Grand, Rozenn; Lestremau, François; Zeman, Florence A; Leclerc, Eric; Moesch, Christian; Brochot, Céline

    2016-03-01

    Permethrin, a pyrethroid insecticide, is suspected to induce neuronal and hormonal disturbances in humans. The widespread exposure of the populations has been confirmed by the detection of the urinary metabolites of permethrin in biomonitoring studies. Permethrin is a chiral molecule presenting two forms, the cis and the trans isomers. Because in vitro studies indicated a metabolic interaction between the trans and cis isomers of permethrin, we adapted and calibrated a PBPK model for trans- and cis-permethrin separately in rats. The model also describes the toxicokinetics of three urinary metabolites, cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis- and trans-DCCA), 3-phenoxybenzoic acid (3-PBA) and 4'OH-phenoxybenzoic acid (4'-OH-PBA). In vivo experiments performed in Sprague-Dawley rats were used to calibrate the PBPK model in a Bayesian framework. The model captured well the toxicokinetics of permethrin isomers and their metabolites including the rapid absorption, the accumulation in fat, the extensive metabolism of the parent compounds, and the rapid elimination of metabolites in urine. Average hepatic clearances in rats were estimated to be 2.4 and 5.7 L/h/kg for cis- and trans-permethrin, respectively. High concentrations of the metabolite 4'-OH-PBA were measured in urine compared to cis- and trans-DCCA and 3-PBA. The confidence in the extended PBPK model was then confirmed by good predictions of published experimental data obtained using the isomers mixture. The extended PBPK model could be extrapolated to humans to predict the internal dose of exposure to permethrin from biomonitoring data in urine.

  17. 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...

  18. 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 Midazolam gut wall clearance (CLint,G) was slightly lower in patients after 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.

  19. Lisdexamfetamine: A pharmacokinetic review.

    Science.gov (United States)

    Comiran, Eloisa; Kessler, Félix Henrique; Fröehlich, Pedro Eduardo; Limberger, Renata Pereira

    2016-06-30

    Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used to treat Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED) symptoms. The in vivo pharmacodynamics of LDX is the same as that of its active product d-AMPH, although there are a few qualitative and quantitative differences due to pharmacokinetics. Due to the specific pharmacokinetics of the long-acting stimulants, this article revises the pharmacokinetic studies on LDX, the newest amphetamine pro-drug. The Medline/Pubmed, Science Direct and Biblioteca Virtual em Saúde (Lilacs and Ibecs) (2007-2016) databases were searched for articles and their list of references. As for basic pharmacokinetics studies, since LDX is a newly developed medication, there are few results concerning biotransformation, distribution and the use of different biological matrices for analysis. This is the first robust review on this topic, gathering data from all clinical pharmacokinetics studies available in the literature. The particular pharmacokinetics of LDX plays a major role in studying this pro-drug, since this knowledge was essential to understand some reports on clinical effects in literature, e.g. the small likelihood of reducing the effect by interactions, the effect of long duration use and the still questionable reduction of the potential for abuse. In general the already well-known pharmacokinetic properties of amphetamine make LDX relatively predictable, simplifying the use of LDX in clinical practice. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Towards a physiologically based diagnosis of anorexia nervosa and bulimia nervosa.

    Science.gov (United States)

    Hatch, Kent A; Spangler, Diane L; Backus, Elizabeth M; Balagna, Jonathan T; Burns, Keven S; Guzman, Brooke S; Hubbard, Matthew J; Lindblad, Stephanie L; Roeder, Beverly L; Ryther, Natalie E; Seawright, Max A; Tyau, Jaymie N; Williams, Dustin

    2007-11-01

    Diagnosis of anorexia nervosa (AN) and bulimia nervosa (BN), while including such physiological data as weight and the reproductive status of the individual, are primarily based on questionnaires and interviews that rely on self-report of both body-related concerns and eating-related behaviors. While some key components of eating disorders are psychological and thus introspective in nature, reliance on self-report for the assessment of eating-related behaviors and nutritional status lacks the objectivity that a physiologically based measure could provide. The development of a more physiologically informed diagnosis for AN and BN would provide a more objective means of diagnosing these disorders, provide a sound physiological basis for diagnosing subclinical disorders and could also aid in monitoring the effectiveness of treatments for these disorders. Empirically supported, physiologically based methods for diagnosing AN and BN are reviewed herein as well as promising physiological measures that may potentially be used in the diagnosis of AN and BN.

  1. A physiologically-based recirculatory meta-model for nasal fentanyl in man

    DEFF Research Database (Denmark)

    Upton, RN; Foster, DJR; Christrup, Lona Louring;

    2012-01-01

    Pharmacokinetic (PK) and pharmacodynamic (PD) data were available from a study of a nasal delivery system for the opioid analgesic fentanyl, together with data on the kinetics of fentanyl in arterial blood in man, and in the lung and brain of sheep. Our aim was to reconcile these data using...

  2. 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.

  3. A Physiologically-Based Flow Network Model for Hepatic Drug Elimination I: Regular Lattice Lobule Model

    CERN Document Server

    Rezania, Vahid; Coombe, Dennis; Tuszynski, Jack A

    2011-01-01

    We develop a physiologically-based lattice model for the transport and metabolism of drugs in the functional unit of the liver, called the lobule. In contrast to earlier studies, we have emphasized the dominant role of convection in well-vascularized tissue with a given structure. Estimates of convective, diffusive and reaction contributions are given. We have compared drug concentration levels observed exiting the lobule with their predicted detailed distribution inside the lobule, assuming that most often the former is accessible information while the latter is not.

  4. Clinical pharmacokinetics of melatonin

    DEFF Research Database (Denmark)

    Harpsøe, Nathja Groth; Andersen, Lars Peter Holst; Gögenur, Ismail

    2015-01-01

    was performed in PubMed and Embase databases. The pharmacokinetic variables included maximal plasma/serum concentration (Cmax), time to maximal plasma/serum concentration (Tmax), elimination half-life (T1/2), area-under-the-curve plasma/serum concentrations (AUC), clearance (Cl), volume of distribution (VD......) and 1602 L (4 mg, oral). Bioavailability of oral melatonin ranged from 9 to 33%. Pharmacokinetics was affected by age, caffeine, smoking, oral contraceptives, feeding status, and fluvoxamine. Critically ill patients displayed accelerated absorption and compromised elimination. CONCLUSIONS: Despite...

  5. Antifungal pharmacokinetics and pharmacodynamics.

    Science.gov (United States)

    Lepak, Alexander J; Andes, David R

    2014-11-10

    Successful treatment of infectious diseases requires choice of the most suitable antimicrobial agent, comprising consideration of drug pharmacokinetics (PK), including penetration into infection site, pathogen susceptibility, optimal route of drug administration, drug dose, frequency of administration, duration of therapy, and drug toxicity. Antimicrobial pharmacokinetic/pharmacodynamic (PK/PD) studies consider these variables and have been useful in drug development, optimizing dosing regimens, determining susceptibility breakpoints, and limiting toxicity of antifungal therapy. Here the concepts of antifungal PK/PD studies are reviewed, with emphasis on methodology and application. The initial sections of this review focus on principles and methodology. Then the pharmacodynamics of each major antifungal drug class (polyenes, flucytosine, azoles, and echinocandins) is discussed. Finally, the review discusses novel areas of pharmacodynamic investigation in the study and application of combination therapy.

  6. Pharmacokinetics of fexofenadine

    DEFF Research Database (Denmark)

    Lappin, Graham; Shishikura, Yoko; Jochemsen, Roeline;

    2010-01-01

    ). Fexofenadine was administered to 6 healthy male volunteers in a three way cross-over design. A microdose (100microg) of (14)C-drug was administered orally (period 1) and intravenously by 30min infusion (period 2). In period 3 an intravenous tracer dose (100microg) of (14)C-drug was administered simultaneously......A human pharmacokinetic study was performed to assess the ability of a microdose to predict the pharmacokinetics of a therapeutic dose of fexofenadine and to determine its absolute oral bioavailability. Fexofenadine was chosen to represent an unmetabolized transporter substrate (P-gP and OATP...... with an oral unlabelled therapeutic dose (120mg). Plasma was collected from all 3 periods and analysed for both total (14)C content and parent drug by accelerator mass spectrometry (AMS). For period 3, plasma samples were also analysed using HPLC-fluorescence to determine total drug concentration. Urine...

  7. Pharmacokinetics of levodopa.

    Science.gov (United States)

    Contin, Manuela; Martinelli, Paolo

    2010-11-01

    This paper reviews the clinically relevant determinants of levodopa peripheral pharmacokinetics and main observed changes in the levodopa concentration-effect relationship with Parkinson's disease (PD) progression. Available clinically practical strategies to optimise levodopa pharmacokinetics and pharmacodynamics are briefly discussed. Levodopa shows particular pharmacokinetics including an extensive presystemic metabolism, overcome by the combined use of extracerebral inhibitors of the enzyme L: -amino acid decarboxylase and rapid absorption in the proximal small bowel by a saturable facilitated transport system shared with other large neutral amino acids. Drug transport from plasma to the brain is mediated by the same carriers operating in the intestinal mucosa. The main strategies to assure reproducibility of both intestinal absorption and delivery to the brain, and the clinical effect include standardization of levodopa dosing with respect to meal times and a controlled dietary protein intake. Levodopa plasma half-life is very short, resulting in marked plasma drug concentration fluctuations which are matched, as the disease progresses, to swings in the therapeutic response ("wearing-off" phenomena). "Wearing-off" phenomena can also be associated, at the more advanced disease stages, with a "negative", both parkinsonism-exacerbating and dyskinetic effect of levodopa at low, subtherapeutic plasma concentrations. Dyskinesias may also be related to high-levodopa, excessive plasma concentrations. Recognition of the different levodopa toxic response patterns can be difficult on a clinical basis alone and simultaneous monitoring of the levodopa concentration-effect relationship may prove useful to disclose the underlying mechanism and in planning the correct management. Clinically practical strategies to optimise levodopa pharmacokinetics, and possibly its therapeutic response, include liquid drug solutions, controlled release formulations and the use of inhibitors

  8. Pharmacokinetics of rilmenidine

    Energy Technology Data Exchange (ETDEWEB)

    Genissel, P.; Bromet, N. (Biopharmacie Servier, Orleans (France))

    1989-09-18

    Rilmenidine is a novel antihypertensive agent related to alpha 2-adrenoceptor agonist, used in the treatment of mild or moderate hypertension at the oral dose of 1 mg once a day or 1 mg twice a day. 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 close to one and a time to peak plasma concentration of two hours. Rilmenidine was not subjected to presystemic metabolism. Distribution was independent of the free fraction since rilmenidine was weakly bound to plasma proteins (less than 10 percent). The volume of distribution was approximately 5 liters/kg (315 liters). Elimination was rapid, with a total body plasma clearance of approximately 450 ml/minute and an elimination half-life of approximately eight hours. Renal excretion was the major elimination process (two thirds of the total clearance); the parent drug in urine accounted for about 65 percent of the dose administered. Metabolism was very poor; few metabolites were found in urine and no metabolites were detected in plasma. Linear pharmacokinetics was demonstrated for rilmenidine from 0.5 to 2 mg; at 3 mg, a slight deviation from linearity was observed. In repeated administration, the linearity with dose of the pharmacokinetics of rilmenidine was confirmed.

  9. Lipid rafts-mediated endocytosis and physiology-based cell membrane traffic models of doxorubicin liposomes.

    Science.gov (United States)

    Li, Yinghuan; Gao, Lei; Tan, Xi; Li, Feiyang; Zhao, Ming; Peng, Shiqi

    2016-08-01

    The clathrin-mediated endocytosis is likely a major mechanism of liposomes' internalization. A kinetic approach was used to assess the internalization mechanism of doxorubicin (Dox) loaded cationic liposomes and to establish physiology-based cell membrane traffic mathematic models. Lipid rafts-mediated endocytosis, including dynamin-dependent or -independent endocytosis of noncaveolar structure, was a dominant process. The mathematic models divided Dox loaded liposomes binding lipid rafts (B) into saturable binding (SB) and nonsaturable binding (NSB) followed by energy-driven endocytosis. The intracellular trafficking demonstrated early endosome-late endosome-lysosome or early/late endosome-cytoplasm-nucleus pathways. The three properties of liposome structures, i.e., cationic lipid, fusogenic lipid, and pegylation, were investigated to compare their contributions to cell membrane and intracellular traffic. The results revealed great contribution of cationic lipid DOTAP and fusogenic lipid DOPE to cell membrane binding and internalization. The valid Dox in the nuclei of HepG2 and A375 cells treated with cationic liposomes containing 40mol% of DOPE were 1.2-fold and 1.5-fold higher than that in the nuclei of HepG2 and A375 cells treated with liposomes containing 20mol% of DOPE, respectively, suggesting the dependence of cell type. This tendency was proportional to the increase of cell-associated total liposomal Dox. The mathematic models would be useful to predict intracellular trafficking of liposomal Dox.

  10. Developing a physiologically based approach for modeling plutonium decorporation therapy with DTPA.

    Science.gov (United States)

    Kastl, Manuel; Giussani, Augusto; Blanchardon, Eric; Breustedt, Bastian; Fritsch, Paul; Hoeschen, Christoph; Lopez, Maria Antonia

    2014-11-01

    To develop a physiologically based compartmental approach for modeling plutonium decorporation therapy with the chelating agent Diethylenetriaminepentaacetic acid (Ca-DTPA/Zn-DTPA). Model calculations were performed using the software package SAAM II (©The Epsilon Group, Charlottesville, Virginia, USA). The Luciani/Polig compartmental model with age-dependent description of the bone recycling processes was used for the biokinetics of plutonium. The Luciani/Polig model was slightly modified in order to account for the speciation of plutonium in blood and for the different affinities for DTPA of the present chemical species. The introduction of two separate blood compartments, describing low-molecular-weight complexes of plutonium (Pu-LW) and transferrin-bound plutonium (Pu-Tf), respectively, and one additional compartment describing plutonium in the interstitial fluids was performed successfully. The next step of the work is the modeling of the chelation process, coupling the physiologically modified structure with the biokinetic model for DTPA. RESULTS of animal studies performed under controlled conditions will enable to better understand the principles of the involved mechanisms.

  11. Review of acute chemical incidents as a first step in evaluating the usefulness of physiologically based pharmacokinetic models in such incidents

    NARCIS (Netherlands)

    Hunault, C. C.; Boerleider, R. Z.; Hof, B. G H; Kliest, J. J G; Meijer, M.; Nijhuis, N. J.; De Vries, I.; Meulenbelt, J.|info:eu-repo/dai/nl/079479227

    2014-01-01

    Context. Acute chemical incidents can have substantial public health consequences in terms of morbidity and mortality. Objective. We aimed to characterize acute chemical incidents and near-misses in the Netherlands and compare the results with previous studies. This review is a first step in

  12. 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)

    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...

  13. Estimating Margin of Exposure to Thyroid Peroxidase Inhibitors Using High-throughput In Vitro Data, High-throughput Exposure Modeling, and Physiologically-Based Pharmacokinetic/Pharmacodynamic Modeling

    Science.gov (United States)

    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...

  14. 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, Andrea L.; Kousba, Ahmed A.; Timchalk, Chuck

    2004-12-01

    Chlorpyrifos (CPF) and diazinon (DZN) are inhibitors of acetylcholinesterase due to the effects of their active oxon metabolites. The inhibition of acetylcholinesterase results in a buildup of acetylcholine within the nerve synapses leading to a variety of neurotoxic effects (Mileson et al., 1998). These effects are most clearly seen following acute high dose exposures but they can also be observed in lower dose chronic cases as well. Chlorpyrifos is the active ingredient in commonly used organophosphorous (OP) insecticides like DURSBAN and LORSBAN (Timchalk et. al, 2002). Chlorpyrifos and diazinon are used to eliminate pests in agricultural applications like cotton and fruit crops. Every year globally there are approximately 3 million cases of organophosphate poisoning reported resulting in 200,000 deaths (Haywood et al., 2000). The public is exposed to these chemicals on a regular basis at chronic low levels from food and water contamination, dermal contact and inhalation. The United States National Health and Nutrition Examination Survey indicated that of approximately 3,600 persons from all 64 NHANES III locations, 70% tested positive for TCP in urine, suggesting exposure to chlorpyrifos (NHANES III, 1994). The chemical structures of chlorpyrifos, diazinon, and their major metabolites trichlorpyridinol (TCP), and isopropyl-methyl-hydroxypyrimidine (IMHP) are shown in Figure 1. The parent compounds, CPF and DZN, are metabolized to their potent inhibiting oxon forms via a desulfuration reaction initiated by cytochrome P450 (CYP)(Poet et al., 2003; Amitai et al., 1998). Competing with the formation of oxon is the detoxification metabolism of CPF to TCP and DZN to IMHP via a dearylation reaction utilizing the same enzymes. A-esterase (PON1) and other B-esterases also contribute to the production of TCP and IMHP through the metabolism of CPF-oxon and DZN-oxon, respectively (Poet et al., 2003; Ma et al., 1994). The ratio between the toxification/detoxification reactions determines the degree of enzyme inhibition and can be used to evaluate metabolism processes (Timchalk et al., 2002).

  15. Review of acute chemical incidents as a first step in evaluating the usefulness of physiologically based pharmacokinetic models in such incidents

    NARCIS (Netherlands)

    Hunault, C. C.; Boerleider, R. Z.; Hof, B. G H; Kliest, J. J G; Meijer, M.; Nijhuis, N. J.; De Vries, I.; Meulenbelt, J.

    2014-01-01

    Context. Acute chemical incidents can have substantial public health consequences in terms of morbidity and mortality. Objective. We aimed to characterize acute chemical incidents and near-misses in the Netherlands and compare the results with previous studies. This review is a first step in evaluat

  16. Pharmacokinetic evaluation of pemetrexed

    DEFF Research Database (Denmark)

    Sørensen, Jens Benn

    2011-01-01

    of the 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......INTRODUCTION: Pemetrexed is a multi-targeted antifolate cytotoxic agent that has demonstrated activity in a number of very common cancer types including NSCLC in both first- and second-line settings and in the treatment of malignant mesothelioma. AREAS COVERED: This article focuses on all...

  17. Pharmacokinetics of Melatonin

    DEFF Research Database (Denmark)

    Andersen, Lars Peter Holst; Gögenur, Ismail; Rosenberg, Jacob

    2016-01-01

    Despite widespread clinical application of melatonin, several unanswered questions remain regarding the pharmacokinetics of this drug. This lack of knowledge may contribute to the inconsistency of results in previous clinical studies. Currently, a t max value of 30-45 min and a t ½elimination of 45...... min are well established. Several questions relate to what constitutes a clinically effective plasma concentration, the choice of ideal administration route, and the optimal method of analysis. Furthermore, investigations of melatonin metabolites in humans are urgently needed in order to characterize...

  18. Physiologically based kinetic modeling of bioactivation and detoxification of the alkenylbenzene methyleugenol in human as compared with rat

    NARCIS (Netherlands)

    Al-Subeihi, A.A.; Spenkelink, A.; Punt, A.; Boersma, M.G.; Bladeren, van P.J.; Rietjens, I.

    2012-01-01

    This study defines a physiologically based kinetic (PBK) model for methyleugenol (ME) in human based on in vitro and in silico derived parameters. With the model obtained, bioactivation and detoxification of methyleugenol (ME) at different doses levels could be investigated. The outcomes of the curr

  19. Physiologically based kinetic models for the alkenylbenzene elemicin in rat and human and possible implications for risk assessment.

    NARCIS (Netherlands)

    Berg, van den S.J.; Punt, A.; Soffers, A.E.M.F.; Vervoort, J.J.M.; Ngeleja, S.; Spenkelink, B.; Rietjens, I.M.C.M.

    2012-01-01

    The present study describes physiologically based kinetic (PBK) models for the alkenylbenzene elemicin (3,4,5-trimethoxyallylbenzene) in rat and human, based on the PBK models previously developed for the structurally related alkenylbenzenes estragole, methyleugenol, and safrole. Using the newly dev

  20. Physiologically based kinetic modeling of hesperidin metabolism and its use to predict in vivo effective doses in humans

    NARCIS (Netherlands)

    Boonpawa, Rungnapa; Spenkelink, Bert; Punt, Ans; Rietjens, Ivonne

    2017-01-01

    Scope: To develop a physiologically based kinetic (PBK) model that describes the absorption, distribution, metabolism, and excretion of hesperidin in humans, enabling the translation of in vitro concentration-response curves to in vivo dose-response curves. Methods and results: The PBK model for

  1. Computational Systems Chemical Biology

    OpenAIRE

    Oprea, Tudor I.; Elebeoba E. May; 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).

  2. [Pharmacokinetics of carbapenems].

    Science.gov (United States)

    Suchánková, H; Rychlíčková, J; Urbánek, K

    2012-06-01

    Carbapenems, beta-lactam antibiotics, are ideal candidates for the treatment of serious nosocomial infections including sepsis for their exceptionally broad antibacterial spectrum and high efficiency. They are administered parenterally by intravenous infusion. Carbapenems penetrate well and rapidly into many different tissue compartments and the interstitial fluid. They are metabolized by renal dihydropeptidase-1. Therefore, imipenem must be co-administered with an inhibitor of dihydropeptidase-1. Other carbapenems registered in the Czech Republic (meropenem, ertapenem and doripenem) are more stable to this enzyme. Carbapenems are mainly eliminated via the kidneys and dose adjustment in patients with renal impairment is necessary. The elimination half-life of most carbapenems is around 1 hour with the exception of ertapenem, with 3.8-hour half-life, which allows its once-daily use. Carbapenems are a group of antibiotics with time-dependent effect. Their typical pharmaceutical property is a limited stability in solution after dilution. Administration in the prolonged infusion appears to be a convenient strategy to achieve higher efficiency. Pharmacokinetic parameters of carbapenems may vary individually, especially in critically ill patients and those treated by renal replacement therapy. Therefore, individualization of dosing regimens based on knowledge of pharmacokinetic parameters of individual patients may be useful.

  3. Physiologically-based toxicokinetic modeling of zearalenone and its metabolites: application to the Jersey girl study.

    Directory of Open Access Journals (Sweden)

    Dwaipayan Mukherjee

    Full Text Available Zearalenone (ZEA, a fungal mycotoxin, and its metabolite zeranol (ZAL are known estrogen agonists in mammals, and are found as contaminants in food. Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada. This article presents the development and application of a Physiologically-Based Toxicokinetic (PBTK model for ZEA and ZAL and their primary metabolites, zearalenol, zearalanone, and their conjugated glucuronides, for rats and for human subjects. The PBTK modeling study explicitly simulates critical metabolic pathways in the gastrointestinal and hepatic systems. Metabolic events such as dehydrogenation and glucuronidation of the chemicals, which have direct effects on the accumulation and elimination of the toxic compounds, have been quantified. The PBTK model considers urinary and fecal excretion and biliary recirculation and compares the predicted biomarkers of blood, urinary and fecal concentrations with published in vivo measurements in rats and human subjects. Additionally, the toxicokinetic model has been coupled with a novel probabilistic dietary exposure model and applied to the Jersey Girl Study (JGS, which involved measurement of mycoestrogens as urinary biomarkers, in a cohort of young girls in New Jersey, USA. A probabilistic exposure characterization for the study population has been conducted and the predicted urinary concentrations have been compared to measurements considering inter-individual physiological and dietary variability. The in vivo measurements from the JGS fall within the high and low predicted distributions of biomarker values corresponding to dietary exposure estimates calculated by the probabilistic modeling system. The work described here is the first of its kind to present a comprehensive framework developing estimates of potential exposures to mycotoxins and linking them with biologically relevant doses and biomarker

  4. Physiologically-based toxicokinetic models help identifying the key factors affecting contaminant uptake during flood events

    Energy Technology Data Exchange (ETDEWEB)

    Brinkmann, Markus; Eichbaum, Kathrin [Department of Ecosystem Analysis, Institute for Environmental Research,ABBt – Aachen Biology and Biotechnology, RWTH Aachen University, Worringerweg 1, 52074 Aachen (Germany); Kammann, Ulrike [Thünen-Institute of Fisheries Ecology, Palmaille 9, 22767 Hamburg (Germany); Hudjetz, Sebastian [Department of Ecosystem Analysis, Institute for Environmental Research,ABBt – Aachen Biology and Biotechnology, RWTH Aachen University, Worringerweg 1, 52074 Aachen (Germany); Institute of Hydraulic Engineering and Water Resources Management, RWTH Aachen University, Mies-van-der-Rohe-Straße 1, 52056 Aachen (Germany); Cofalla, Catrina [Institute of Hydraulic Engineering and Water Resources Management, RWTH Aachen University, Mies-van-der-Rohe-Straße 1, 52056 Aachen (Germany); Buchinger, Sebastian; Reifferscheid, Georg [Federal Institute of Hydrology (BFG), Department G3: Biochemistry, Ecotoxicology, Am Mainzer Tor 1, 56068 Koblenz (Germany); Schüttrumpf, Holger [Institute of Hydraulic Engineering and Water Resources Management, RWTH Aachen University, Mies-van-der-Rohe-Straße 1, 52056 Aachen (Germany); Preuss, Thomas [Department of Environmental Biology and Chemodynamics, Institute for Environmental Research,ABBt- Aachen Biology and Biotechnology, RWTH Aachen University, Worringerweg 1, 52074 Aachen (Germany); and others

    2014-07-01

    Highlights: • A PBTK model for trout was coupled with a sediment equilibrium partitioning model. • The influence of physical exercise on pollutant uptake was studies using the model. • Physical exercise during flood events can increase the level of biliary metabolites. • Cardiac output and effective respiratory volume were identified as relevant factors. • These confounding factors need to be considered also for bioconcentration studies. - Abstract: As a consequence of global climate change, we will be likely facing an increasing frequency and intensity of flood events. Thus, the ecotoxicological relevance of sediment re-suspension is of growing concern. It is vital to understand contaminant uptake from suspended sediments and relate it to effects in aquatic biota. Here we report on a computational study that utilizes a physiologically based toxicokinetic model to predict uptake, metabolism and excretion of sediment-borne pyrene in rainbow trout (Oncorhynchus mykiss). To this end, data from two experimental studies were compared with the model predictions: (a) batch re-suspension experiments with constant concentration of suspended particulate matter at two different temperatures (12 and 24 °C), and (b) simulated flood events in an annular flume. The model predicted both the final concentrations and the kinetics of 1-hydroxypyrene secretion into the gall bladder of exposed rainbow trout well. We were able to show that exhaustive exercise during exposure in simulated flood events can lead to increased levels of biliary metabolites and identified cardiac output and effective respiratory volume as the two most important factors for contaminant uptake. The results of our study clearly demonstrate the relevance and the necessity to investigate uptake of contaminants from suspended sediments under realistic exposure scenarios.

  5. Physiologically based biokinetic (PBBK) model for safrole bioactivation and detoxification in rats.

    Science.gov (United States)

    Martati, E; Boersma, M G; Spenkelink, A; Khadka, D B; Punt, A; Vervoort, J; van Bladeren, P J; Rietjens, I M C M

    2011-06-20

    A physiologically based biokinetic (PBBK) model for alkenylbenzene safrole in rats was developed using in vitro metabolic parameters determined using relevant tissue fractions. The performance of the model was evaluated by comparison of the predicted levels of 1,2-dihydroxy-4-allylbenzene and 1'-hydroxysafrole glucuronide to levels of these metabolites reported in the literature to be excreted in the urine of rats exposed to safrole and by comparison of the predicted amount of total urinary safrole metabolites to the reported levels of safrole metabolites in the urine of safrole exposed rats. These comparisons revealed that the predictions adequately match observed experimental values. Next, the model was used to predict the relative extent of bioactivation and detoxification of safrole at different oral doses. At low as well as high doses, P450 mediated oxidation of safrole mainly occurs in the liver in which 1,2-dihydroxy-4-allylbenzene was predicted to be the major P450 metabolite of safrole. A dose dependent shift in P450 mediated oxidation leading to a relative increase in bioactivation at high doses was not observed. Comparison of the results obtained for safrole with the results previously obtained with PBBK models for the related alkenylbenzenes estragole and methyleugenol revealed that the overall differences in bioactivation of the three alkenylbenzenes to their ultimate carcinogenic 1'-sulfooxy metabolites are limited. This is in line with the generally less than 4-fold difference in their level of DNA binding in in vitro and in vivo studies and their almost similar BMDL(10) values (lower confidence limit of the benchmark dose that gives 10% increase in tumor incidence over background level) obtained in in vivo carcinogenicity studies. It is concluded that in spite of differences in the rates of specific metabolic conversions, overall the levels of bioactivation of the three alkenylbenzenes are comparable which is in line with their comparable

  6. Physiologically based biokinetic (PBBK) modeling of safrole bioactivation and detoxification in humans as compared with rats.

    Science.gov (United States)

    Martati, Erryana; Boersma, Marelle G; Spenkelink, Albertus; Khadka, Dambar B; van Bladeren, Peter J; Rietjens, Ivonne M C M; Punt, Ans

    2012-08-01

    A physiologically based biokinetic (PBBK) model for the alkenylbenzene safrole in humans was developed based on in vitro- and in silico-derived kinetic parameters. With the model obtained, the time- and dose-dependent formation of the proximate and ultimate carcinogenic metabolites, 1-hydroxysafrole and 1-sulfooxysafrole in human liver were estimated and compared with previously predicted levels of these metabolites in rat liver. In addition, Monte Carlo simulations were performed to predict interindividual variation in the formation of these metabolites in the overall population. For the evaluation of the model performance, a comparison was made between the predicted total amount of urinary metabolites of safrole and the reported total levels of metabolites in the urine of humans exposed to safrole, which adequately matched. The model results revealed no dose-dependent shifts in safrole metabolism and no relative increase in bioactivation at dose levels up to 100mg/kg body weight/day. Species differences were mainly observed in the detoxification pathways of 1-hydroxysafrole, with the formation of 1-oxosafrole being a main detoxification pathway of 1-hydroxysafrole in humans but a minor pathway in rats, and glucuronidation of 1-hydroxysafrole being less important in humans than in rats. The formation of 1-sulfooxysafrole was predicted to vary 4- to 17-fold in the population (fold difference between the 95th and median, and 95th and 5th percentile, respectively), with the median being three to five times higher in human than in rat liver. Comparison of the PBBK results for safrole with those previously obtained for the related alkenylbenzenes estragole and methyleugenol revealed that differences in 1-sulfooxy metabolite formation are limited, being only twofold to fivefold.

  7. A physiologically based toxicokinetic model for methylmercury in female American kestrels

    Science.gov (United States)

    Nichols, J.W.; Bennett, R.S.; Rossmann, R.; French, J.B.; Sappington, K.G.

    2010-01-01

    A physiologically based toxicokinetic (PBTK) model was developed to describe the uptake, distribution, and elimination of methylmercury (CH 3Hg) in female American kestrels. The model consists of six tissue compartments corresponding to the brain, liver, kidney, gut, red blood cells, and remaining carcass. Additional compartments describe the elimination of CH3Hg to eggs and growing feathers. Dietary uptake of CH 3Hg was modeled as a diffusion-limited process, and the distribution of CH3Hg among compartments was assumed to be mediated by the flow of blood plasma. To the extent possible, model parameters were developed using information from American kestrels. Additional parameters were based on measured values for closely related species and allometric relationships for birds. The model was calibrated using data from dietary dosing studies with American kestrels. Good agreement between model simulations and measured CH3Hg concentrations in blood and tissues during the loading phase of these studies was obtained by fitting model parameters that control dietary uptake of CH 3Hg and possible hepatic demethylation. Modeled results tended to underestimate the observed effect of egg production on circulating levels of CH3Hg. In general, however, simulations were consistent with observed patterns of CH3Hg uptake and elimination in birds, including the dominant role of feather molt. This model could be used to extrapolate CH 3Hg kinetics from American kestrels to other bird species by appropriate reassignment of parameter values. Alternatively, when combined with a bioenergetics-based description, the model could be used to simulate CH 3Hg kinetics in a long-term environmental exposure. ?? 2010 SETAC.

  8. Physiologically-Based Toxicokinetic Modeling of Zearalenone and Its Metabolites: Application to the Jersey Girl Study

    Science.gov (United States)

    Mukherjee, Dwaipayan; Royce, Steven G.; Alexander, Jocelyn A.; Buckley, Brian; Isukapalli, Sastry S.; Bandera, Elisa V.; Zarbl, Helmut; Georgopoulos, Panos G.

    2014-01-01

    Zearalenone (ZEA), a fungal mycotoxin, and its metabolite zeranol (ZAL) are known estrogen agonists in mammals, and are found as contaminants in food. Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada. This article presents the development and application of a Physiologically-Based Toxicokinetic (PBTK) model for ZEA and ZAL and their primary metabolites, zearalenol, zearalanone, and their conjugated glucuronides, for rats and for human subjects. The PBTK modeling study explicitly simulates critical metabolic pathways in the gastrointestinal and hepatic systems. Metabolic events such as dehydrogenation and glucuronidation of the chemicals, which have direct effects on the accumulation and elimination of the toxic compounds, have been quantified. The PBTK model considers urinary and fecal excretion and biliary recirculation and compares the predicted biomarkers of blood, urinary and fecal concentrations with published in vivo measurements in rats and human subjects. Additionally, the toxicokinetic model has been coupled with a novel probabilistic dietary exposure model and applied to the Jersey Girl Study (JGS), which involved measurement of mycoestrogens as urinary biomarkers, in a cohort of young girls in New Jersey, USA. A probabilistic exposure characterization for the study population has been conducted and the predicted urinary concentrations have been compared to measurements considering inter-individual physiological and dietary variability. The in vivo measurements from the JGS fall within the high and low predicted distributions of biomarker values corresponding to dietary exposure estimates calculated by the probabilistic modeling system. The work described here is the first of its kind to present a comprehensive framework developing estimates of potential exposures to mycotoxins and linking them with biologically relevant doses and biomarker measurements

  9. Adaptation to shift work: physiologically based modeling of the effects of lighting and shifts' start time.

    Science.gov (United States)

    Postnova, Svetlana; Robinson, Peter A; Postnov, Dmitry D

    2013-01-01

    Shift work has become an integral part of our life with almost 20% of the population being involved in different shift schedules in developed countries. However, the atypical work times, especially the night shifts, are associated with reduced quality and quantity of sleep that leads to increase of sleepiness often culminating in accidents. It has been demonstrated that shift workers' sleepiness can be improved by a proper scheduling of light exposure and optimizing shifts timing. Here, an integrated physiologically-based model of sleep-wake cycles is used to predict adaptation to shift work in different light conditions and for different shift start times for a schedule of four consecutive days of work. The integrated model combines a model of the ascending arousal system in the brain that controls the sleep-wake switch and a human circadian pacemaker model. To validate the application of the integrated model and demonstrate its utility, its dynamics are adjusted to achieve a fit to published experimental results showing adaptation of night shift workers (n = 8) in conditions of either bright or regular lighting. Further, the model is used to predict the shift workers' adaptation to the same shift schedule, but for conditions not considered in the experiment. The model demonstrates that the intensity of shift light can be reduced fourfold from that used in the experiment and still produce good adaptation to night work. The model predicts that sleepiness of the workers during night shifts on a protocol with either bright or regular lighting can be significantly improved by starting the shift earlier in the night, e.g.; at 21:00 instead of 00:00. Finally, the study predicts that people of the same chronotype, i.e. with identical sleep times in normal conditions, can have drastically different responses to shift work depending on their intrinsic circadian and homeostatic parameters.

  10. A physiologically based, multi-scale model of skeletal muscle structure and function

    Directory of Open Access Journals (Sweden)

    Oliver eRöhrle

    2012-09-01

    Full Text Available Models of skeletal muscle can be classified as phenomenological or biophysical. Phenomenological models predict the muscle's response to a specified input based on experimental measurements. Prominent phenomenological models are the Hill-type muscle models, which have been incorporated into rigid-body modelling frameworks, and three-dimensional continuum-mechanical models. Biophysically based models attempt to predict the muscle's response as emerging from the underlying physiology of the system. In this contribution, the conventional biophysically based modelling methodology is extended to include several structural and functional characteristics of skeletal muscle. The result is a physiologically based, multi-scale skeletal muscle finite element model that is capable of representing detailed, geometrical descriptions of skeletal muscle fibres and their grouping. Together with a well-established model of motor unit recruitment, the electro-physiological behaviour of single muscle fibres within motor units is computed and linked to a continuum-mechanical constitutive law. The bridging between the cellular level and the organ level has been achieved via a multi-scale constitutive law and homogenisation. The effect of homogenisation has been investigated by varying the number of embedded skeletal muscle fibres and/or motor units and computing the resulting exerted muscle forces while applying the same excitatory input. All simulations were conducted using an anatomically realistic finite element model of the Tibialis Anterior muscle. Given the fact that the underlying electro-physiological cellular muscle model is capable of modelling metabolic fatigue effects such as potassium accumulation in the T-tubular space and inorganic phosphate build-up, the proposed framework provides a novel simulation-based way to investigate muscle behaviour ranging from motor unit recruitment to force generation and fatigue.

  11. A generalized physiologically-based toxicokinetic modeling system for chemical mixtures containing metals

    Directory of Open Access Journals (Sweden)

    Isukapalli Sastry S

    2010-06-01

    Full Text Available Abstract Background Humans are routinely and concurrently exposed to multiple toxic chemicals, including various metals and organics, often at levels that can cause adverse and potentially synergistic effects. However, toxicokinetic modeling studies of exposures to these chemicals are typically performed on a single chemical basis. Furthermore, the attributes of available models for individual chemicals are commonly estimated specifically for the compound studied. As a result, the available models usually have parameters and even structures that are not consistent or compatible across the range of chemicals of concern. This fact precludes the systematic consideration of synergistic effects, and may also lead to inconsistencies in calculations of co-occurring exposures and corresponding risks. There is a need, therefore, for a consistent modeling framework that would allow the systematic study of cumulative risks from complex mixtures of contaminants. Methods A Generalized Toxicokinetic Modeling system for Mixtures (GTMM was developed and evaluated with case studies. The GTMM is physiologically-based and uses a consistent, chemical-independent physiological description for integrating widely varying toxicokinetic models. It is modular and can be directly "mapped" to individual toxicokinetic models, while maintaining physiological consistency across different chemicals. Interaction effects of complex mixtures can be directly incorporated into the GTMM. Conclusions The application of GTMM to different individual metals and metal compounds showed that it explains available observational data as well as replicates the results from models that have been optimized for individual chemicals. The GTMM also made it feasible to model toxicokinetics of complex, interacting mixtures of multiple metals and nonmetals in humans, based on available literature information. The GTMM provides a central component in the development of a "source

  12. Adaptation to shift work: physiologically based modeling of the effects of lighting and shifts' start time.

    Directory of Open Access Journals (Sweden)

    Svetlana Postnova

    Full Text Available Shift work has become an integral part of our life with almost 20% of the population being involved in different shift schedules in developed countries. However, the atypical work times, especially the night shifts, are associated with reduced quality and quantity of sleep that leads to increase of sleepiness often culminating in accidents. It has been demonstrated that shift workers' sleepiness can be improved by a proper scheduling of light exposure and optimizing shifts timing. Here, an integrated physiologically-based model of sleep-wake cycles is used to predict adaptation to shift work in different light conditions and for different shift start times for a schedule of four consecutive days of work. The integrated model combines a model of the ascending arousal system in the brain that controls the sleep-wake switch and a human circadian pacemaker model. To validate the application of the integrated model and demonstrate its utility, its dynamics are adjusted to achieve a fit to published experimental results showing adaptation of night shift workers (n = 8 in conditions of either bright or regular lighting. Further, the model is used to predict the shift workers' adaptation to the same shift schedule, but for conditions not considered in the experiment. The model demonstrates that the intensity of shift light can be reduced fourfold from that used in the experiment and still produce good adaptation to night work. The model predicts that sleepiness of the workers during night shifts on a protocol with either bright or regular lighting can be significantly improved by starting the shift earlier in the night, e.g.; at 21:00 instead of 00:00. Finally, the study predicts that people of the same chronotype, i.e. with identical sleep times in normal conditions, can have drastically different responses to shift work depending on their intrinsic circadian and homeostatic parameters.

  13. Insulin aspart pharmacokinetics

    DEFF Research Database (Denmark)

    Rasmussen, Christian Hove; Roge, Rikke Meldgaard; Ma, Zhulin

    2014-01-01

    Background: Insulin aspart (IAsp) is used by many diabetics as a meal-time insulin to control postprandial glucose levels. As is the case with many other insulin types, the pharmacokinetics (PK), and consequently the pharmacodynamics (PD), is associated with clinical variability, both between...... to investigate and quantify the properties of the subcutaneous depot. Data from Brange et al. (1990) are used to determine the effects of insulin chemistry in subcutis on the absorption rate. Intravenous (i.v.) bolus and infusion PK data for human insulin are used to understand and quantify the systemic...... distribution and elimination (Porksen et al., 1997; Sjostrand et al., 2002). PK and PD profiles for type 1 diabetics from Chen et al. (2005) are analyzed to demonstrate the effects of IAsp antibodies in terms of bound and unbound insulin. PK profiles from Thorisdottir et al. (2009) and Ma et al. (2012b...

  14. 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.

  15. Pharmacokinetics of Cannabinoids

    Directory of Open Access Journals (Sweden)

    Iain J McGilveray

    2005-01-01

    Full Text Available Delta-9-tetrahydrocannabinol (Δ-9-THC is the main psychoactive ingredient of cannabis (marijuana. The present review focuses on the pharmacokinetics of THC, but also includes known information for cannabinol and cannabidiol, as well as the synthetic marketed cannabinoids, dronabinol (synthetic THC and nabilone. The variability of THC in plant material (0.3% to 30% leads to variability in tissue THC levels from smoking, which is, in itself, a highly individual process. THC bioavailability averages 30%. With a 3.55% THC cigarette, a peak plasma level of 152±86.3 ng/mL occured approximately 10 min after inhalation. Oral THC, on the other hand, is only 4% to 12% bioavailable and absorption is highly variable. THC is eliminated from plasma in a multiphasic manner, with low amounts detectable for over one week after dosing. A major active 11-hydroxy metabolite is formed after both inhalation and oral dosing (20% and 100% of parent, respectively. THC is widely distributed, particularly to fatty tissues, but less than 1% of an administered dose reaches the brain, while the spleen and body fat are long-term storage sites. The elimination of THC and its many metabolites (from all routes occurs via the feces and urine. Metabolites persist in the urine and feces for severalweeks. Nabilone is well absorbed and the pharmacokinetics, although variable, appear to be linear from oral doses of 1 mg to 4 mg (these doses show a plasma elimination half-life of approximately 2 h. As with THC, there is a high first-pass effect, and the feces to urine ratio of excretion is similar to other cannabinoids. Pharmacokineticpharmacodynamic modelling with plasma THC versus cardiac and psychotropic effects show that after equilibrium is reached, the intensity of effect is proportional to the plasma THC profile. Clinical trials have found that nabilone produces less tachycardia and less euphoria than THC for a similar antiemetic response.

  16. Pharmacokinetic interactions with thiazolidinediones.

    Science.gov (United States)

    Scheen, André J

    2007-01-01

    Type 2 diabetes mellitus is a complex disease combining defects in insulin secretion and insulin action. New compounds called thiazolidinediones or glitazones have been developed for reducing insulin resistance. After the withdrawal of troglitazone because of liver toxicity, two compounds are currently used in clinical practice, rosiglitazone and pioglitazone. These compounds are generally used in combination with other pharmacological agents. Because they are metabolised via cytochrome P450 (CYP), glitazones are exposed to numerous pharmacokinetic interactions. CYP2C8 and CYP3A4 are the main isoenzymes catalysing biotransformation of pioglitazone (as with troglitazone), whereas rosiglitazone is metabolised by CYP2C9 and CYP2C8. For both rosiglitazone and pioglitazone, the most relevant interactions have been described in healthy volunteers with rifampicin (rifampin), which results in a significant decrease of area under the plasma concentration-time curve [AUC] (54-65% for rosiglitazone, p<0.001; 54% for pioglitazone, p<0.001), and with gemfibrozil, which results in a significant increase of AUC (130% for rosiglitazone, p<0.001; 220-240% for pioglitazone, p<0.001). The relevance of such drug-drug interactions in patients with type 2 diabetes remains to be evaluated. However, in the absence of clinical data, it is prudent to reduce the dosage of each glitazone by half in patients treated with gemfibrozil. Conversely, rosiglitazone and pioglitazone do not seem to significantly affect the pharmacokinetics of other compounds. Although some food components have also been shown to potentially interfere with drugs metabolised with the CYP system, no published study deals specifically with these possible CYP-mediated food-drug interactions with glitazones.

  17. 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

  18. Pharmacokinetics of clomipramine during pregnancy

    NARCIS (Netherlands)

    Ter Horst, P G J; Proost, J H; Smit, J P; Vries, M T; de Jong-van den Berg, Lolkje; Wilffert, B

    2015-01-01

    Clomipramine is one of the drugs for depression during pregnancy; however, pharmacokinetic data of clomipramine and its active metabolite desmethylclomipramine in this vulnerable period are lacking. In this study, we describe clomipramine and desmethylclomipramine concentrations including their rati

  19. Biomarkers of environmental benzene exposure

    Energy Technology Data Exchange (ETDEWEB)

    Weisel, C.; Yu, R.; Roy, A.; Georgopoulos, P. [Environmental and Occupational Health Sciences Institute, Piscataway, NJ (United States)

    1996-12-01

    Environmental exposures to benzene result in increases in body burden that are reflected in various biomarkers of exposure, including benzene in exhaled breath, benzene in blood and urinary trans-trans-muconic acid and S-phenylmercapturic acid. A review of the literature indicates that these biomarkers can be used to distinguish populations with different levels of exposure (such as smokers from nonsmokers and occupationally exposed from environmentally exposed populations) and to determine differences in metabolism. Biomarkers in humans have shown that the percentage of benzene metabolized by the ring-opening pathway is greater at environmental exposures than that at higher occupational exposures, a trend similar to that found in animal studies. This suggests that the dose-response curve is nonlinear; that potential different metabolic mechanisms exist at high and low doses; and that the validity of a linear extrapolation of adverse effects measured at high doses to a population exposed to lower, environmental levels of benzene is uncertain. Time-series measurements of the biomarker, exhaled breath, were used to evaluate a physiologically based pharmacokinetic (PBPK) model. Biases were identified between the PBPK model predictions and experimental data that were adequately described using an empirical compartmental model. It is suggested that a mapping of the PBPK model to a compartmental model can be done to optimize the parameters in the PBPK model to provide a future framework for developing a population physiologically based pharmacokinetic model. 44 refs., 3 figs., 1 tab.

  20. Clinical pharmacokinetics of phenobarbital in neonates

    NARCIS (Netherlands)

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

    2000-01-01

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

  1. [Elements of pharmacodynamics and pharmacokinetics].

    Science.gov (United States)

    Piette, F; Soubrie, C

    1990-05-21

    A knowledge of pharmacokinetic data is particularly important with drugs that have a narrow margin of safety. Exhaustive pre-marketing pharmacokinetic investigations and pharmacokinetic studies in populations are the two principal means of acquiring such knowledge. Although popular, the concept of half-life which decreases with age for many drugs is insufficient to calculate dosage in elderly people. Measurements of creatinine clearance provide an almost mathematical approach to the dosage of drugs that are excreted exclusively by the kidneys. In contrast, changes in hepatic metabolism with age and pathology are difficult to evaluate, and their consequences are often vaguely perceived. Our knowledge of relationships between age and pharmacodynamics is still in infancy. Owing to the wide consumption of medicine by elderly people, drug interactions are frequent at all stages, including absorption, metabolization, transport and site of action.

  2. Pharmacokinetic profile of fesoterodine.

    Science.gov (United States)

    Malhotra, B; Guan, Z; Wood, N; Gandelman, K

    2008-11-01

    Fesoterodine is a new antimuscarinic agent for the treatment of overactive bladder. Following oral administration, fesoterodine is rapidly and extensively hydrolyzed by nonspecific esterases to its active moiety: 5-hydroxymethyl tolterodine (5-HMT). The cytochrome P450 (CYP) enzymes are not involved in the formation of 5-HMT; however, CYP2D6 and CYP3A4 provide 2 alternative pathways for further metabolism and inactivation of 5-HMT. Single oral doses of 4 mg, 8 mg or 12 mg of fesoterodine sustained-release tablets in the fasted state and 8 mg in a fed state. This single-center, open-label, randomized, crossover study investigated the effects of fesoterodine in healthy volunteers comprised of CYP2D6 extensive metabolizers (EMs; n = 16) and CYP2D6 poor metabolizers (PMs; n = 8) after either an overnight fast or a high-fat and high-calorie breakfast. Adverse events, vital signs, ECG recordings and laboratory tests were monitored for safety assessment. For the principal active moiety, 5-HMT, the maximum plasma concentration (Cmax), area under the concentration-time curve from time zero to time of last measurable concentration (AUC0-t) and amount excreted in urine (Ae) increased proportionally with dose in both EM and PM subjects. The mean Cmax and AUC0-t in PMs were approximately twice those observed in EMs. CYP2D6 status had no effect on time to reach Cmax (5 h), renal clearance (approximately 250 ml/min), or half-life (approximately 8 h). Fesoterodine was well tolerated at all doses. While the incidence of dry mouth increased from 8 - 12 mg, all occurrences were mild-to-moderate. Fesoterodine demonstrated a pharmacokinetic (PK) profile that was favorable for once-daily dosing. The systemic exposure to 5-HMT increased proportionally with dose and was about 2-fold higher in PMs compared with EMs. There was no clinically relevant effect of food on the PK of fesoterodine. Fesoterodine was well tolerated at all dose levels studied.

  3. Bayesian Analysis of a Lipid-Based Physiologically Based Toxicokinetic Model for a Mixture of PCBs in Rats

    Directory of Open Access Journals (Sweden)

    Alan F. Sasso

    2012-01-01

    Full Text Available A lipid-based physiologically based toxicokinetic (PBTK model has been developed for a mixture of six polychlorinated biphenyls (PCBs in rats. The aim of this study was to apply population Bayesian analysis to a lipid PBTK model, while incorporating an internal exposure-response model linking enzyme induction and metabolic rate. Lipid-based physiologically based toxicokinetic models are a subset of PBTK models that can simulate concentrations of highly lipophilic compounds in tissue lipids, without the need for partition coefficients. A hierarchical treatment of population metabolic parameters and a CYP450 induction model were incorporated into the lipid-based PBTK framework, and Markov-Chain Monte Carlo was applied to in vivo data. A mass balance of CYP1A and CYP2B in the liver was necessary to model PCB metabolism at high doses. The linked PBTK/induction model remained on a lipid basis and was capable of modeling PCB concentrations in multiple tissues for all dose levels and dose profiles.

  4. 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

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

    NARCIS (Netherlands)

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

    2017-01-01

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

  6. 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.

  7. [Dalbavancin: pharmacokinetic and pharmacodynamic parameters].

    Science.gov (United States)

    Azanza, José Ramón; Sádaba, Belén; Reis, Joana

    2017-01-01

    Dalbavancin is a new lipoglycopeptide antibiotic whose structure influences its pharmacokinetic profile. It is not absorbed after oral administration and is therefore administered intravenously. It is distributed through intracellular fluid, reaching adequate concentrations in the skin, bone, blister fluid and synovial fluid. Plasma protein binding is very high. Concentrations in brain tissue and cerebrospinal fluid (CSF) are inadequate. Excretion is through non-microsomal metabolism with inactive metabolites and through the kidneys by glomerular filtration. Dalbavancin is eliminated slowly, as shown by its clearance value and its terminal elimination half-life, which exceeds 300 hours. This means that adequate concentrations of the drug remain in plasma and tissues for a prolonged period and explains the dosing regimen: a first dose of 1g followed 7 days later by a 500mg dose. The pharmacokinetics are linear and show little intra- and interindividual variability. There are no pharmacokinetic interactions. Dose adjustment is not required for patients with mild or moderate renal insufficiency (creatinine clearance ≥ 30 to 79ml/min). Dosage adjustment is not required in patients regularly receiving elective haemodialysis (3 times/week) and the drug can be administered without consideration of haemodialysis times. In patients with chronic renal insufficiency, whose creatinine clearance is < 30ml/min and who are not regularly receiving elective haemodialysis, the recommended dose should be reduced to 750mg per week, followed 1 week later by 375mg. Dosage adjustment does not seem necessary in patients with liver failure or in older patients. There is no information on the most appropriate dosage in children. The pharmacokinetic/pharmacodynamics parameter that best describes the effectiveness of dalbavancin is the ratio between the area under the curve and the minimum inhibitory concentration.

  8. PHARMACOKINETIC AND PHARMACODYNAMIC INTERACTION FOR A BINARY MIXTURE OF CHLORPYRIFOS AND DIAZINON IN THE RAT

    Energy Technology Data Exchange (ETDEWEB)

    Timchalk, Chuck; Poet, Torka S.; Hinman, Melissa N.; Busby, Andrea L.; Kousba, Ahmed A.

    2005-05-15

    Chlorpyrifos (CPF) and diazinon (DZN) are two commonly used organophosphorus (OP) insecticides and potential exists for concurrent exposures. The primary neurotoxic effects from OP pesticide exposures result from the inhibition of acetylcholinesterase (AChE) by their oxon metabolites. The pharmacokinetic and pharmacodynamic impact of acute binary exposures to CPF and DZN in rats were evaluated in this study. Rats were orally administered CPF, DZN or a CPF/DZN mixture (0, 15, 30 or 60 mg/kg) and blood (plasma and RBC), and brain were collected at 0, 3, 6, 12 and 24 h post-dosing, urine was also collected at 24 h. Chlorpyrifos, DZN and their respective metabolites 3,5,6-trichloro-2-pyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP) were quantified in blood and/or urine and cholinesterase (ChE) inhibition was measured in brain, RBCs and plasma. Co-exposure to CPF/DZN at 15/15 mg/kg, did not appreciably alter the pharmacokinetics of CPF, DZN or their metabolites in blood; whereas, a 60/60 mg/kg dose resulted in a transient increase in Cmax, AUC, and decreased clearance of both compounds, likely due to competition between CPF and DZN for CYP450 metabolism. At lower doses, most likely to be encountered in occupational or environmental exposures, the pharmacokinetics were linear. A dose-dependent inhibition of ChE was noted in tissues for both the single and co-exposures. The overall potency for ChE inhibition was greater for CPF than DZN and the binary mixture response appeared to be strongly influenced by CPF. A comparison of the ChE binary response at the low dose (15 mg/kg), where there were no apparent pharmacokinetic interactions, suggested that the overall ChE response was additive. These are the first reported experiments we are aware of that characterize both the pharmacokinetic and pharmacodynamic interactions between CPF and DZN in the rat, and will be used to further develop a binary physiologically based pharmacokinetic and pharmacodynamic

  9. Clinical pharmacokinetic profile of modafinil.

    Science.gov (United States)

    Robertson, Philmore; Hellriegel, Edward T

    2003-01-01

    Modafinil is a unique wake-promoting agent for oral administration. Its pharmacological properties are distinct from those of other CNS agents, and it selectively targets neuronal pathways in the sleep/wake centres of the brain. After single or multiple oral doses, modafinil is readily absorbed, reaching maximum plasma concentrations at 2-4 hours after administration and pharmacokinetic steady state within 2-4 days. Its pharmacokinetics are dose-independent between 200 and 600 mg/day. The elimination half-life is approximately 12-15 hours, which is largely reflective of the pharmacokinetics of the longer-lived l-enantiomer. Modafinil is primarily eliminated via metabolism, mainly in the liver, with subsequent excretion in the urine. Less than 10% of the dose is excreted as unchanged drug. Metabolism is largely via amide hydrolysis, with lesser contributions from cytochrome P450 (CYP)-mediated oxidative pathways. In patients who are renally or hepatically compromised, the elimination processes can be slowed, and in a similar manner (although to a lesser extent), elimination in the elderly may be reduced due to normal effects of aging. Because modafinil is administered concomitantly with other medications, the potential for metabolic drug-drug interactions has been examined both in vitro and in vivo. In vitro, modafinil was observed to produce a reversible inhibition of CYP2C19 in human liver microsomes. It also caused a small, but concentration-dependent, induction of CYP1A2, CYP2B6 and CYP3A4 activities and suppression of CYP2C9 activity in primary cultures of human hepatocytes. Clinical studies have been conducted to examine the potential for interactions with methylphenidate, dexamfetamine, warfarin, ethinylestradiol and triazolam. The only substantive interactions observed were with ethinylestradiol and triazolam, apparently through induction of CYP3A4, primarily in the gastrointestinal system. Overall, the results of the interaction studies suggest that

  10. Development of a decision tree to classify the most accurate tissue-specific tissue to plasma partition coefficient algorithm for a given compound.

    Science.gov (United States)

    Yun, Yejin Esther; Cotton, Cecilia A; Edginton, Andrea N

    2014-02-01

    Physiologically based pharmacokinetic (PBPK) modeling is a tool used in drug discovery and human health risk assessment. PBPK models are mathematical representations of the anatomy, physiology and biochemistry of an organism and are used to predict a drug's pharmacokinetics in various situations. Tissue to plasma partition coefficients (Kp), key PBPK model parameters, define the steady-state concentration differential between tissue and plasma and are used to predict the volume of distribution. The experimental determination of these parameters once limited the development of PBPK models; however, in silico prediction methods were introduced to overcome this issue. The developed algorithms vary in input parameters and prediction accuracy, and none are considered standard, warranting further research. In this study, a novel decision-tree-based Kp prediction method was developed using six previously published algorithms. The aim of the developed classifier was to identify the most accurate tissue-specific Kp prediction algorithm for a new drug. A dataset consisting of 122 drugs was used to train the classifier and identify the most accurate Kp prediction algorithm for a certain physicochemical space. Three versions of tissue-specific classifiers were developed and were dependent on the necessary inputs. The use of the classifier resulted in a better prediction accuracy than that of any single Kp prediction algorithm for all tissues, the current mode of use in PBPK model building. Because built-in estimation equations for those input parameters are not necessarily available, this Kp prediction tool will provide Kp prediction when only limited input parameters are available. The presented innovative method will improve tissue distribution prediction accuracy, thus enhancing the confidence in PBPK modeling outputs.

  11. Population pharmacokinetics of abacavir in pregnant women.

    Science.gov (United States)

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

    2014-10-01

    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.

  12. 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...

  13. 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…

  14. Simulation of Human Plasma Concentrations of Thalidomide and Primary 5-Hydroxylated Metabolites Explored with Pharmacokinetic Data in Humanized TK-NOG Mice.

    Science.gov (United States)

    Nishiyama, Sayako; Suemizu, Hiroshi; Shibata, Norio; Guengerich, F Peter; Yamazaki, Hiroshi

    2015-11-16

    Plasma concentrations of thalidomide and primary 5-hydroxylated metabolites including 5,6-dihydroxythalidomide and glutathione (GSH) conjugate(s) were investigated in chimeric mice with highly "humanized" liver cells harboring cytochrome P450 3A5*1. Following oral administration of thalidomide (100 mg/kg), plasma concentrations of GSH conjugate(s) of 5-hydroxythalidomide were higher in humanized mice than in controls. Simulation of human plasma concentrations of thalidomide were achieved with a simplified physiologically based pharmacokinetic model in accordance with reported thalidomide concentrations. The results indicate that the pharmacokinetics in humans of GSH conjugate and/or catechol primary 5-hydroxylated thalidomide contributing in vivo activation can be estimated for the first time.

  15. Physiologically based kinetic models for the alkenylbenzene elemicin in rat and human and possible implications for risk assessment.

    Science.gov (United States)

    van den Berg, Suzanne J P L; Punt, Ans; Soffers, Ans E M F; Vervoort, Jacques; Ngeleja, Stephen; Spenkelink, Bert; Rietjens, Ivonne M C M

    2012-11-19

    The present study describes physiologically based kinetic (PBK) models for the alkenylbenzene elemicin (3,4,5-trimethoxyallylbenzene) in rat and human, based on the PBK models previously developed for the structurally related alkenylbenzenes estragole, methyleugenol, and safrole. Using the newly developed models, the level of metabolic activation of elemicin in rat and human was predicted to obtain insight in species differences in the bioactivation of elemicin and read across to the other methoxy allylbenzenes, estragole and methyleugenol. Results reveal that the differences between rat and human in the formation of the proximate carcinogenic metabolite 1'-hydroxyelemicin and the ultimate carcinogenic metabolite 1'-sulfoxyelemicin are limited (rat and human liver. The insights thus obtained were used to perform a risk assessment for elemicin using the margin of exposure (MOE) approach and read across to the other methoxy allylbenzene derivatives for which in vivo animal tumor data are available. This reveals that elemicin poses a lower priority for risk management as compared to its structurally related analogues estragole and methyleugenol. Altogether, the results obtained indicate that PBK modeling provides an important insight in the occurrence of species differences in the metabolic activation of elemicin. Moreover, they provide an example of how PBK modeling can facilitate a read across in risk assessment from compounds for which in vivo toxicity studies are available to a compound for which only limited toxicity data have been described, thus contributing to the development of alternatives for animal testing.

  16. A simple, physiologically-based model of sea turtle remigration intervals and nesting population dynamics: Effects of temperature.

    Science.gov (United States)

    Neeman, Noga; Spotila, James R; O'Connor, Michael P

    2015-09-07

    Variation in the yearly number of sea turtles nesting at rookeries can interfere with population estimates and obscure real population dynamics. Previous theoretical models suggested that this variation in nesting numbers may be driven by changes in resources at the foraging grounds. We developed a physiologically-based model that uses temperatures at foraging sites to predict foraging conditions, resource accumulation, remigration probabilities, and, ultimately, nesting numbers for a stable population of sea turtles. We used this model to explore several scenarios of temperature variation at the foraging grounds, including one-year perturbations and cyclical temperature oscillations. We found that thermally driven resource variation can indeed synchronize nesting in groups of turtles, creating cohorts, but that these cohorts tend to break down over 5-10 years unless regenerated by environmental conditions. Cohorts were broken down faster at lower temperatures. One-year perturbations of low temperature had a synchronizing effect on nesting the following year, while high temperature perturbations tended to delay nesting in a less synchronized way. Cyclical temperatures lead to cyclical responses both in nesting numbers and remigration intervals, with the amplitude and lag of the response depending on the duration of the cycle. Overall, model behavior is consistent with observations at nesting beaches. Future work should focus on refining the model to fit particular nesting populations and testing further whether or not it may be used to predict observed nesting numbers and remigration intervals.

  17. Study on inter-ethnic human differences in bioactivation and detoxification of estragole using physiologically based kinetic modeling.

    Science.gov (United States)

    Ning, Jia; Louisse, Jochem; Spenkelink, Bert; Wesseling, Sebastiaan; Rietjens, Ivonne M C M

    2017-03-29

    Considering the rapid developments in food safety in the past decade in China, it is of importance to obtain insight into what extent safety and risk assessments of chemicals performed for the Caucasian population apply to the Chinese population. The aim of the present study was to determine physiologically based kinetic (PBK) modeling-based predictions for differences between Chinese and Caucasians in terms of metabolic bioactivation and detoxification of the food-borne genotoxic carcinogen estragole. The PBK models were defined based on kinetic constants for hepatic metabolism derived from in vitro incubations using liver fractions of the two ethnic groups, and used to evaluate the inter-ethnic differences in metabolic activation and detoxification of estragole. The models predicted that at realistic dietary intake levels, only 0.02% of the dose was converted to the ultimate carcinogenic metabolite 1'-sulfooxyestragole in Chinese subjects, whereas this amounted to 0.09% of the dose in Caucasian subjects. Detoxification of 1'-hydroxyestragole, mainly via conversion to 1'-oxoestragole, was similar within the two ethnic groups. The 4.5-fold variation in formation of the ultimate carcinogenic metabolite of estragole accompanied by similar rates of detoxification may indicate a lower risk of estragole for the Chinese population at similar levels of exposure. The study provides a proof of principle for how PBK modeling can identify differences in ethnic sensitivity and provide a more refined risk assessment for a specific ethnic group for a compound of concern.

  18. In vitro physiologically based extraction test (PBET) and bioaccessibility of arsenic and lead from various mine waste materials.

    Science.gov (United States)

    Bruce, Scott; Noller, Barry; Matanitobua, Vitukawalu; Ng, Jack

    2007-10-01

    In vivo models show that the bioavailability of soil contaminants varies between site and type of matrix. Studies demonstrated that assuming 100% bioavailability of arsenic (As) and lead (Pb) from soils and mine waste materials overestimates the risk associated with human exposure. In in vitro systems, the simulated bioavailability of a contaminant is referred to as the "bioaccessibility" and is used as an alternative quantitative indicator for in vivo derived bioavailability estimates. The general concept of the in vitro extraction test is to predict the bioavailability of inorganic substances from solid matrices by simulating the gastrointestinal tract (GIT) environment. The aims of this study were to: (1) investigate the bioaccessibility of As and Pb from various mine wastes, including tailings, heap leach, and waste rock, using a physiologically based extraction test (PBET); (2) validate the bioaccessibility values from PBET with in vivo bioavailability values measured using animal models; and (3) correlate PBET results with the bioavailability values measured from alternative in vivo models (rats and cattle, from Bruce, 2004). Significant correlation was observed between bioaccessibility values from PBET, and bioavailability values generated for both rats and cattle, demonstrating the potential to utilize PBET as a relatively inexpensive alternative to in vivo models for bioavailability assessment.

  19. Pharmacokinetic monitoring of antiepileptic drugs.

    Science.gov (United States)

    Aldaz, A; Ferriols, R; Aumente, D; Calvo, M V; Farre, M R; García, B; Marqués, R; Mas, P; Porta, B; Outeda, M; Soy, D

    2011-01-01

    Monitoring plasma levels of antiepileptic drugs for the treatment and prophylaxis of epilepsy is one of the strategies enabling clinical results to improve by reducing adverse affects and increasing effectiveness. The objective of this article is to review the basic aspects in the monitoring of antiepileptic drugs using a consensus document prepared and endorsed by the pharmacokinetics and pharmacogenetics working group (PK.gen) of the Sociedad Española de Farmacia Hospitalaria (Spanish Society of Hospital Pharmacists). Copyright © 2010 SEFH. Published by Elsevier Espana. All rights reserved.

  20. Effect of multiple intravenous doses of lanicemine (AZD6765) on the pharmacokinetics of midazolam in healthy subjects.

    Science.gov (United States)

    Bui, Khanh H; Zhou, Diansong; Agbo, Felix; Guo, Jian

    2015-09-01

    The objectives of the present study were to evaluate safety and tolerability as well as the effects of multiple doses of lanicemine on the pharmacokinetics of a CYP3A substrate, midazolam. A total of 46 healthy volunteers were enrolled in the open-label, fixed-sequence, nonrandomized study. All volunteers received an oral dose of 5 mg of midazolam alone or after 6 days of 150 mg daily intravenous infusion of lanicemine. Lanicemine reached a plasma Cmax of 1.51 μg/mL after 150 mg daily dosing to steady state. The geometric mean CL, Vss, and t1/2 of lanicemine were 8.1 L/h, 122.0 L, and 10.4 hours, respectively. The geometric least-squares mean ratios and 90% confidence intervals for midazolam AUC0- ∞ , and Cmax were within the 80% to 125% limits when lanicemine plus midazolam treatment was compared with midazolam alone, demonstrating that daily dosing with 150 mg of lanicemine for 6 days had no effect on CYP3A activity. Comprehensive physiologically based pharmacokinetic modeling using in vitro and in silico findings also indicated lanicemine would have little impact on the pharmacokinetics of CYP3A substrate, such as midazolam. In addition, lanicemine and midazolam administered alone or in combination were generally safe and well tolerated.

  1. Comparison of cerebral pharmacokinetics of buprenorphine and norbuprenorphine in an in vivo sheep model.

    Science.gov (United States)

    Jensen, M L; Foster, D; Upton, R; Grant, C; Martinez, A; Somogyi, A

    2007-04-01

    The pharmacokinetics and time course of blood-brain equilibration of buprenorphine (BUP) and norbuprenorphine (norBUP) in sheep were characterized. Sheep were administered 0.04 mg kg(-1) BUP or 0.6 mg kg(-1) norBUP as 4-min i.v. infusions. The cerebral kinetics were inferred from arterio-sagittal sinus concentration gradients and changes in cerebral blood flow. These data were fitted to physiologically based pharmacokinetic models. BUP cerebral kinetics were best described by a membrane-limited model with a large equilibration delay (half-life of 20 min) between brain and blood due to intermediate permeability (47 ml min(-1)) and a large cerebral distribution volume (595 ml). Significant limitation in permeability (6 ml min(-1)) characterized the cerebral kinetics of norBUP with a cerebral distribution volume (157 ml) giving a blood-brain equilibration half-life (21 min) similar to that for BUP. The logD of BUP and norBUP were 3.93 +/- 0.08 and 1.18 +/- 0.04 (mean +/- SD), respectively. Both compounds revealed slow cerebral equilibration with variations in degree of permeability and distribution volume reflecting the difference in lipophilicity. It is possible that norBUP contributes to the central effects seen after chronic BUP administration as this study demonstrated its entry into the brain.

  2. Emerging areas of research in the assessment of pharmacokinetics in patients with chronic kidney disease.

    Science.gov (United States)

    Tortorici, Michael A; Cutler, David L; Hazra, Anasuya; Nolin, Thomas D; Rowland-Yeo, Karen; Venkatakrishnan, Karthik

    2015-03-01

    Chronic kidney disease (CKD) has been shown to alter the pharmacokinetics of drugs that are eliminated not only via the renal pathway but also by nonrenal clearance and transport. Dosing recommendations in subjects with CKD have historically come from small pharmacokinetic (PK) studies, which have been insulated from the broader clinical development strategy. Opportunities for prospective strategic integration of both preclinical and clinical data on drug clearance mechanisms, model-based approaches, and clinical knowledge of therapeutic index are therefore often missed in designing and analyzing the results of PK studies in subjects with CKD, and eventually providing dosing recommendations. These considerations are valuable in designing informative PK studies in subjects with CKD, as well as for guiding kidney function-related inclusion/exclusion criteria in the broader clinical program and ultimately defining dosing guidelines that optimize benefit-risk balance for these special patient populations based on all available data. This paper offers points to consider for drug developers to increase adoption of a contemporary multidisciplinary approach, which includes key considerations on study design and conduct, methodologies for analysis (population PK and physiologically based PK modeling), and a roadmap to interpret the effect of kidney function on the overall benefit-risk profile of drugs in development.

  3. Mode of action based risk assessment of the botanical food-borne alkenylbenzene apiol from parsley using physiologically based kinetic (PBK) modelling and read-across from safrole

    NARCIS (Netherlands)

    Alajlouni, A.M.; Al-Malahmeh, A.J.; Kiwamoto, Reiko; Wesseling, Sebastiaan; Soffers, A.E.M.F.; Al-Subeihi, A.A.A.; Vervoort, Jacques; Rietjens, I.M.C.M.

    2016-01-01

    The present study developed physiologically-based kinetic (PBK) models for the alkenylbenzene apiol in order to facilitate risk assessment based on read-across from the related alkenylbenzene safrole. Model predictions indicate that in rat liver the formation of the 1'-sulfoxy metabolite is about

  4. Application of physiologically based toxicokinetic modelling to study the impact of the exposure scenario on the toxicokinetics and the behavioural effects of toluene in rats

    NARCIS (Netherlands)

    Asperen, J. van; Rijcken, W.R.P.; Lammers, J.H.C.M.

    2003-01-01

    The toxicity of inhalatory exposure to organic solvents may not only be related to the total external dose, but also to the pattern of exposure. In this study physiologically based toxicokinetic (PBTK) modelling has been used to study the impact of the exposure scenario on the toxicokinetics and the

  5. Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin.

    Science.gov (United States)

    Olivares-Morales, Andrés; Ghosh, Avijit; Aarons, Leon; Rostami-Hodjegan, Amin

    2016-11-01

    A new minimal Segmented Transit and Absorption model (mSAT) model has been recently proposed and combined with intrinsic intestinal effective permeability (P eff,int ) to predict the regional gastrointestinal (GI) absorption (f abs ) of several drugs. Herein, this model was extended and applied for the prediction of oral bioavailability and pharmacokinetics of oxybutynin and its enantiomers to provide a mechanistic explanation of the higher relative bioavailability observed for oxybutynin's modified-release OROS® formulation compared to its immediate-release (IR) counterpart. The expansion of the model involved the incorporation of mechanistic equations for the prediction of release, transit, dissolution, permeation and first-pass metabolism. The predicted pharmacokinetics of oxybutynin enantiomers after oral administration for both the IR and OROS® formulations were in close agreement with the observed data. The predicted absolute bioavailability for the IR formulation was within 5% of the observed value, and the model adequately predicted the higher relative bioavailability observed for the OROS® formulation vs. the IR counterpart. From the model predictions, it can be noticed that the higher bioavailability observed for the OROS® formulation was mainly attributable to differences in the intestinal availability (F G ) rather than due to a higher colonic f abs , thus confirming previous hypotheses. The predicted f abs was almost 70% lower for the OROS® formulation compared to the IR formulation, whereas the F G was almost eightfold higher than in the IR formulation. These results provide further support to the hypothesis of an increased F G as the main factor responsible for the higher bioavailability of oxybutynin's OROS® formulation vs. the IR.

  6. Pharmacokinetic enhancers in HIV therapeutics.

    Science.gov (United States)

    Larson, Kajal B; Wang, Kun; Delille, Cecile; Otofokun, Igho; Acosta, Edward P

    2014-10-01

    Maximal and durable viral load suppression is one of the most important goals of HIV therapy and is directly related to adequate drug exposure. Protease inhibitors (PIs), an important component of the antiretroviral armada, were historically associated with poor oral bioavailability and high pill burden. However, because the PIs are metabolized by cytochrome P450 (CYP) 3A enzymes, intentional inhibition of these enzymes leads to higher drug exposure, lower pill burden, and therefore simplified dosing schedules with this class of drug. This is the basis of pharmacokinetic enhancement. In HIV therapy, two pharmacokinetic enhancers or boosting agents are used: ritonavir and cobicistat. Both agents inhibit CYP3A4, with cobicistat being a more specific CYP inhibitor than ritonavir. Unlike ritonavir, cobicistat does not have antiretroviral activity. Cobicistat has been evaluated in clinical trials and was recently approved in the USA as a fixed-dose combination with the integrase inhibitor, elvitegravir and two nucleos(t)ide analogs. Additional studies are examining cobicistat in fixed-dose combinations with various PIs. In this review, we summarize current knowledge of these agents and clinically relevant drug regimens and ongoing trials. Studies with elvitegravir and the novel PI TMC319011 are also discussed.

  7. Pharmacokinetics interactions of monoclonal antibodies.

    Science.gov (United States)

    Ferri, Nicola; Bellosta, Stefano; Baldessin, Ludovico; Boccia, Donatella; Racagni, Giorgi; Corsini, Alberto

    2016-09-01

    The clearance of therapeutic monoclonal antibodies (mAbs) typically does not involve cytochrome P450 (CYP450)-mediated metabolism or interaction with cell membrane transporters, therefore the pharmacokinetics interactions of mAbs and small molecule drugs are limited. However, a drug may affect the clearance of mAbs through the modulation of immune response (e.g., methotrexate reduces the clearance of infliximab, adalimumab, and golimumab, possibly due to methotrexate's inhibitory effect on the formation of antibodies against the mAbs). In addition, mAbs that are cytokine modulators may modify the metabolism of drugs through their effects on P450 enzymes expression. For example, cytokine modulators such as tocilizumab (anti-IL-6 receptor antibody) may reverse the "inhibitory" effect of IL-6 on CYP substrates, resulting in a "normalization" of CYP activities. Finally, a drug may alter the clearance of mAbs by either increasing or reducing the levels of expression of targets of mAbs on the cell surface. For instance, statins and fibrates induce PCSK9 expression and therefore increase cellular uptake and clearance of alirocumab and evolocumab, anti-PCSK9 antibodies. In the present review, we will provide an overview on the pharmacokinetics properties of mAbs as related to the most relevant examples of mAbs-small molecule drug interaction.

  8. 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.

  9. [Interspecies allometric scaling in pharmacokinetics of drugs].

    Science.gov (United States)

    Sylvia, M

    1998-11-01

    Allometric scaling is an empirical examination of the relationships between the pharmacokinetic parameters and size (usually body weight, ratio of organ- and body weight, breathing number, etc.). Interspecies pharmacokinetics tend to approximate, the organism, as the sum of organs and tissues according to material balance. The allometric equations for the pharmacokinetic parameters were applied to scale the data with respect to pharmacokinetic time and remove the chronological time dependency. When the data of at least three species are available, the pharmacokinetic parameters can be fit according to body weight in log-log regression. Allometric scaling is not applicable in all cases, only when the selected species has similar physiological behaviour, such as protein-binding, metabolism, etc. Valuable information for the evaluation of the effect and the biopharmaceutical characteristics may emerge from more creative data analysis based on all result collected during the preclinical evaluation of a new drug. Author examined the applicability of the interspecies scaling method in the case of a new drug depogen, using drotaverin as reference. The pharmacokinetic data were collected from mouse, rat and dog and during the evaluation human data were applied too. The usual pharmacokinetic parameters were determined (MRT, MAT, beta, etc.), the results of allometric analysis were collected and the standard deviation of measured and calculated values were given.

  10. 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.

  11. A physiologically based toxicokinetic (PBTK) model for moderately hydrophobic organic chemicals in the European eel (Anguilla anguilla)

    Energy Technology Data Exchange (ETDEWEB)

    Brinkmann, Markus [Department of Ecosystem Analysis, Institute for Environmental Research, ABBt — Aachen Biology and Biotechnology, RWTH Aachen University, Aachen (Germany); Freese, Marko; Pohlmann, Jan-Dag; Kammann, Ulrike [Thünen Institute of Fisheries Ecology, Hamburg (Germany); Preuss, Thomas G. [Environmental Biology and Chemodynamics, Institute for Environmental Research, ABBt — Aachen Biology and Biotechnology, RWTH Aachen University, Aachen (Germany); Buchinger, Sebastian; Reifferscheid, Georg [Federal Institute of Hydrology (BFG), Department G3: Biochemistry, Ecotoxicology, Koblenz (Germany); Beiermeister, Anne; Hanel, Reinhold [Thünen Institute of Fisheries Ecology, Hamburg (Germany); Hollert, Henner, E-mail: Henner.hollert@bio5.rwth-aachen.de [Department of Ecosystem Analysis, Institute for Environmental Research, ABBt — Aachen Biology and Biotechnology, RWTH Aachen University, Aachen (Germany); State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing (China); College of Resources and Environmental Science, Chongqing University, Chongqing (China); Key Laboratory of Yangtze Water Environment, Ministry of Education, Tongji University, Shanghai 200092 (China)

    2015-12-01

    The European eel (Anguilla anguilla) is a facultatively catadromous fish species with a complex life cycle. Its current population status is alarming: recruitment has decreased drastically since the 1980s and its stock is still considered to be outside safe biological limits. Although there is no consensus on the reasons for this situation, it is currently thought to have resulted from a combination of different stressors, including anthropogenic contaminants. To deepen our understanding of the processes leading to the accumulation of lipophilic organic contaminants in yellow eels (i.e. the feeding, continental growth stage), we developed a physiologically based toxicokinetic model using our own data and values from the literature. Such models can predict the uptake and distribution of water-borne organic chemicals in the whole fish and in different tissues at any time during exposure. The predictive power of the model was tested against experimental data for six chemicals with n-octanol-water partitioning coefficient (log K{sub ow}) values ranging from 2.13–4.29. Model performance was excellent, with a root mean squared error of 0.28 log units. This model has the potential to help identify suitable habitats for restocking under eel management plans. - Highlights: • A PBTK model was developed for European eel (Anguilla anguilla). • Own experimental data and data from the literature were used for parameterization. • The predictive power of the model was excellent, with RMSE of 0.28 log units. • The developed model can be amended with sub-models for dietary and dermal exposure.

  12. A physiologically based in silico model for trans-2-hexenal detoxification and DNA adduct formation in rat.

    Science.gov (United States)

    Kiwamoto, Reiko; Rietjens, Ivonne M C M; Punt, Ans

    2012-12-17

    trans-2-Hexenal (2-hexenal) is an α,β-unsaturated aldehyde that occurs naturally in a wide range of fruits, vegetables, and spices. 2-Hexenal as well as other α,β-unsaturated aldehydes that are natural food constituents or flavoring agents may raise a concern for genotoxicity due to the ability of the α,β-unsaturated aldehyde moiety to react with DNA. Controversy remains, however, on whether α,β-unsaturated aldehydes result in significant DNA adduct formation in vivo at realistic dietary exposure. In this study, a rat physiologically based in silico model was developed for 2-hexenal as a model compound to examine the time- and dose-dependent detoxification and DNA adduct formation of this selected α,β-unsaturated aldehyde. The model was developed based on in vitro and literature-derived parameters, and its adequacy was evaluated by comparing predicted DNA adduct formation in the liver of rats exposed to 2-hexenal with reported in vivo data. The model revealed that at an exposure level of 0.04 mg/kg body weight, a value reflecting estimated daily human dietary intake, 2-hexenal is rapidly detoxified predominantly by conjugation with glutathione (GSH) by glutathione S-transferases. At higher dose levels, depletion of GSH results in a shift to 2-hexenal oxidation and reduction as the major pathways for detoxification. The level of DNA adduct formation at current levels of human dietary intake was predicted to be more than 3 orders of magnitude lower than endogenous DNA adduct levels. These results support that rapid detoxification of 2-hexenal reduces the risk arising from 2-hexenal exposure and that at current dietary exposure levels, DNA adduct formation is negligible.

  13. In vivo validation of DNA adduct formation by estragole in rats predicted by physiologically based biodynamic modelling.

    Science.gov (United States)

    Paini, Alicia; Punt, Ans; Scholz, Gabriele; Gremaud, Eric; Spenkelink, Bert; Alink, Gerrit; Schilter, Benoît; van Bladeren, Peter J; Rietjens, Ivonne M C M

    2012-11-01

    Estragole is a naturally occurring food-borne genotoxic compound found in a variety of food sources, including spices and herbs. This results in human exposure to estragole via the regular diet. The objective of this study was to quantify the dose-dependent estragole-DNA adduct formation in rat liver and the urinary excretion of 1'-hydroxyestragole glucuronide in order to validate our recently developed physiologically based biodynamic (PBBD) model. Groups of male outbred Sprague Dawley rats (n = 10, per group) were administered estragole once by oral gavage at dose levels of 0 (vehicle control), 5, 30, 75, 150, and 300mg estragole/kg bw and sacrificed after 48h. Liver, kidney and lungs were analysed for DNA adducts by LC-MS/MS. Results obtained revealed a dose-dependent increase in DNA adduct formation in the liver. In lungs and kidneys DNA adducts were detected at lower levels than in the liver confirming the occurrence of DNA adducts preferably in the target organ, the liver. The results obtained showed that the PBBD model predictions for both urinary excretion of 1'-hydroxyestragole glucuronide and the guanosine adduct formation in the liver were comparable within less than an order of magnitude to the values actually observed in vivo. The PBBD model was refined using liver zonation to investigate whether its predictive potential could be further improved. The results obtained provide the first data set available on estragole-DNA adduct formation in rats and confirm their occurrence in metabolically active tissues, i.e. liver, lung and kidney, while the significantly higher levels found in liver are in accordance with the liver as the target organ for carcinogenicity. This opens the way towards future modelling of dose-dependent estragole liver DNA adduct formation in human.

  14. The ecological and physiological bases of variation in the phenology of gonad growth in an urban and desert songbird.

    Science.gov (United States)

    Davies, Scott; Lane, Samuel; Meddle, Simone L; Tsutsui, Kazuyoshi; Deviche, Pierre

    2016-05-01

    Birds often adjust to urban areas by advancing the timing (phenology) of vernal gonad growth. However, the ecological and physiological bases of this adjustment are unclear. We tested whether the habitat-related disparity in gonad growth phenology of male Abert's towhees, Melozone aberti, is due to greater food availability in urban areas of Phoenix, Arizona USA or, alternatively, a habitat-related difference in the phenology of key food types. To better understand the physiological mechanism underlying variation in gonad growth phenology, we compared the activity of the reproductive system at all levels of hypothalamo-pituitary-gonadal (HPG) axis. We found no habitat-associated difference in food availability (ground arthropod biomass), but, in contrast to the seasonal growth of leaves on desert trees, the leaf foliage of urban trees was already developed at the beginning of our study. Multiple estimates of energetic status did not significantly differ between the non-urban and urban towhees during three years that differed in the habitat-related disparity in gonad growth and winter precipitation levels. Thus, our results provide no support for the hypothesis that greater food abundance in urban areas of Phoenix drives the habitat-related disparity in gonad growth phenology in Abert's towhees. By contrast, they suggest that differences in the predictability and magnitude of change in food availability between urban and desert areas of Phoenix contribute to the observed habitat-related disparity in gonad growth. Endocrine responsiveness of the gonads may contribute to this phenomenon as desert - but not urban - towhees had a marked plasma testosterone response to GnRH challenge.

  15. Speciation and cysteine-simplified physiological-based extraction technique (SBET) bioaccesibility of heavy metals in biosolids.

    Science.gov (United States)

    Tongesayi, Tsanangurayi; Dasilva, Patricia; Dilger, Katharine; Hollingsworth, Tristan; Mooney, Melissa

    2011-01-01

    Cysteine residues on proteins have a high affinity for metals yet formulations used to determine bioaccessibility do not contain cysteine or thiol-containing molecules. As a result, we used a cysteine-simplified physiological-based extraction technique (SBET) and, the conventional glycine-SBET to determine bioaccesibility of selected heavy metals in biosolids and compared the data. We also determined speciation of the selected metals in the biosolids to assess further the health risk posed the use of biosolids as a soil amendment in agricultural soils. Samples, including a certified reference standard were analyzed using x-ray fluorescence and flame atomic absorption. Bioaccessibility was higher in cysteine-SBET than glycine-SBET, and regression data show that the two methods give different sets of results. We proposed a bioaccessibility model that involves cysteine and the hydrogen ion complementing each other to dissolve metals. The model also includes a three mode-bioavailability mechanism: absorption of free metal ions; ligand-mediated transport of metal ions from solution; and ligand-mediated transport of metal ions directly from the biosolids into the cell. Low pH in the gut increases bioaccessibility but reduces bioavailability due to protonation of receptor ligands. With the exception of Fe, bioaccessibility was directly correlated to the sequential extraction availability which followed the order: Mn(90.3 %)>Zn(50.3 %)>Cd(26.5 %)>Cu(24.9 %)>Fe(0.367 %). We calculated bioavailability from bioaccessibility using literature estimates of percent bioavailabilities. The order of abundance of the analyzed metals in the biosolids was as follows: Fe>Mn>Zn>Cu>Pb>Cd.

  16. Low heritability in pharmacokinetics of talinolol

    DEFF Research Database (Denmark)

    Matthaei, Johannes; Tzvetkov, Mladen V; Gal, Valerie;

    2016-01-01

    BACKGROUND: Efflux transporters like MDR1 and MRP2 may modulate the pharmacokinetics of about 50 % of all drugs. It is currently unknown how much of the variation in the activities of important drug membrane transporters like MDR1 or MRP2 is determined by genetic or by environmental factors....... In this study we assessed the heritability of the pharmacokinetics of talinolol as a putative probe drug for MDR1 and possibly other membrane transporters. METHODS: Talinolol pharmacokinetics were investigated in a repeated dose study in 42 monozygotic and 13 same-sex dizygotic twin pairs. The oral clearance...

  17. The Use of Spreadsheets for Pharmacokinetic Simulations

    Directory of Open Access Journals (Sweden)

    Joseph Chamberlain

    2003-01-01

    Full Text Available The use of simple spreadsheets is described to create simulations of complex pharmacokinetic phenomena. The basics of spreadsheets are first described and are developed to demonstrate classical pharmacokinetics without the use of differential or integral calculus. Using standard spreadsheet commands, the technique is shown to be applicable to the full range of advanced pharmacokinetic simulations. Demonstrations of the effect of a variety of physiological eventualities are included to show the versatility of the technique. The technique is very simple to use and is always in the complete control of the modeller.

  18. Fluconazole Pharmacokinetics in Burn Patients

    Science.gov (United States)

    Boucher, Bradley A.; King, Stephen R.; Wandschneider, Heidi L.; Hickerson, William L.; Hanes, Scott D.; Herring, Vanessa L.; Canada, Todd W.; Hess, Mary M.

    1998-01-01

    The pharmacokinetics of fluconazole in nine adult patients with severe (30 to 95% total body surface area) burns were studied. There was no significant difference in half-life (t1/2), clearance (CL), or volume of distribution (V) over time in five patients on days 3 and 8 of the study (P > 0.05). Combined parameter estimates (means ± standard deviations) for all nine patients for the two study periods were as follows: t1/2, 24.4 ± 5.8 h; CL, 0.36 ± 0.09 ml/min/kg; and V, 0.72 ± 0.12 liters/kg. These estimates of t1/2 and CL in burn patients were approximately 13% shorter and 30% more rapid, respectively, than the most extreme estimates reported for other populations. PMID:9559811

  19. 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

  20. Pharmacokinetics of Tyrosol Metabolites in Rats

    OpenAIRE

    Da-Hye Lee; Yang-Ji Kim; Min Jung Kim; Jiyun Ahn; Tae-Youl Ha; Sang Hee Lee; Young Jin Jang; Chang Hwa Jung

    2016-01-01

    Tyrosol is considered a potential antioxidant; however, little is known regarding the pharmacokinetics of its metabolites. To study the pharmacokinetics of tyrosol-derived metabolites after oral administration of a single dose of tyrosol, we attempted to identify tyrosol metabolites in rat plasma by using ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Two tyrosol metabolites (M1 and M2) were detected in the plasma. M1 was identified as...

  1. The Toxicological Geochemistry of Dusts, Soils, and Other Earth Materials: Insights From In Vitro Physiologically-based Geochemical Leach Tests

    Science.gov (United States)

    Plumlee, G. S.; Ziegler, T. L.; Lamothe, P.; Meeker, G. P.; Sutley, S.

    2003-12-01

    Exposure to mineral dusts, soils, and other earth materials results in chemical reactions between the materials and different body fluids that include, depending upon the exposure route, lung fluids, gastrointestinal fluids, and perspiration. In vitro physiologically-based geochemical leach tests provide useful insights into these chemical reactions and their potential toxicological implications. We have conducted such leach tests on a variety of earth materials, including asbestos, volcanic ash, dusts from dry lake beds, mine wastes, wastes left from the roasting of mercury ores, mineral processing wastes, coal dusts and coal fly ash, various soils, and complex dusts generated by the World Trade Center collapse. Size-fractionated samples of earth materials that have been well-characterized mineralogically and chemically are reacted at body temperature (37 C) for periods from 2 hours up to multiple days with various proportions of simulated lung, gastric, intestinal, and/or plasma-based fluids. Results indicate that different earth materials may have quite different solubility and dissolution behavior in vivo, depending upon a) the mineralogic makeup of the material, and b) the exposure route. For example, biodurable minerals such as asbestos and volcanic ash particles, whose health effects result because they dissolve very slowly in vivo, bleed off low levels of trace metals into the simulated lung fluids; these include metals such as Fe and Cr that are suspected by health scientists of contributing to the generation of reactive oxygen species and resulting DNA damage in vivo. In contrast, dry lake bed dusts and concrete-rich dusts are highly alkaline and bioreactive, and cause substantial pH increases and other chemical changes in the simulated body fluids. Many of the earth materials tested contain a variety of metals that can be quite soluble (bioaccessible), depending upon the material and the simulated body fluid composition. For example, due to their acidic

  2. Advances in epilepsy treatment: lacosamide pharmacokinetic profile.

    Science.gov (United States)

    Cawello, Willi; Stockis, Armel; Andreas, Jens-Otto; Dimova, Svetlana

    2014-11-01

    Lacosamide (LCM) is a functionalized amino acid specifically developed for use as an antiepileptic drug (AED) and is currently indicated as adjunctive treatment for partial-onset seizures in adults with focal epilepsy (maximum approved dose 400 mg/day). Characterization of the pharmacokinetic profile is an important aspect in the development of LCM. Studies in healthy subjects and in patients with focal epilepsy have established that LCM has several favorable pharmacokinetic characteristics, including rapid absorption and high oral bioavailability not affected by food, linear and dose-proportional pharmacokinetics, low inter- and intraindividual variability, low plasma protein binding, renal elimination, and a low potential for clinically relevant pharmacokinetic drug-drug interactions both with AEDs and other common medications. Studies have demonstrated bioequivalence among the three LCM formulations (oral tablets, oral solution, and solution for intravenous (IV) infusion), allowing direct conversion to or from oral and IV administration without titration. Thus, the favorable and predictable pharmacokinetic profile and bioequivalence of LCM formulations, coupled with the low potential for clinically relevant pharmacokinetic drug-drug interactions, make LCM an easy-to-use adjunctive treatment for the management of patients with focal epilepsy. © 2014 New York Academy of Sciences.

  3. Pharmacokinetics and pharmacokinetic-dynamic modelling of rocuronium in infants and children

    NARCIS (Netherlands)

    Wierda, J.MKH; Meretoja, O.A; Taivainen, T; Proost, Hans

    1997-01-01

    We have determined the pharmacokinetics and pharmacokinetic-pharmacodynamic relationship of rocuronium in infants and children. We studied infants (n = 5, 0.1-0.8 yr) and children (n = 5, 2.3-8 yr), ASA II, in the ICU while undergoing artificial ventilation under i.v. anaesthesia with an arterial ca

  4. Preliminary Mathematical Model for Jet Fuel Exacerbated Noise-Induced Hearing Loss

    Science.gov (United States)

    2013-01-01

    hearing loss . Noise alone induces hearing loss due to loss of hair cells in the cochlea, associated with oxidative stress. Jet fuel toxicity in association with noise may be at least partially explained by increased free radical production and oxidative stress at the cellular level, resulting in hair cell dysfunction and loss. This project combines a physiologically-based pharmacokinetic (PBPK) model to describe jet fuel component concentrations in the cochlea with pharmacodynamic (PD) models of free radical formation in the cochlea by both noise and

  5. Pharmacokinetic modelling of microencapsulated metronidazole

    Institute of Scientific and Technical Information of China (English)

    Mahmood AHMAD; Khalid PERVAIZ; Ghulam MURTAZA; Munaza RAMZAN

    2009-01-01

    The aim of present study is to develop a pharmacokinetic model for microencapsulated metronidazole to predict drug absorption pattern in healthy human and validate this model internally. Metronidazole was microencapsulated into ethylcellulose shells followed by the conversion of these microcapsules into tablets.tablets (T1: fast release, T2: moderate release, T3: slow release and reference) were administered to twenty four healthy human volunteers and serial blood samples were collected for 12 hours followed by their analysis using RP-HPLC. Drug release data were analyzed by various model dependent and independent approaches. Drug absorbed (%) was determined by Wagner-Nelson method from plasma concentration profile. Internal predictability was checked from Cmax and AUC. Optimum dissolution profile was observed in double distilled water and 50coefficient, R2 = 0.900 9, 0.942 6, 0.901 5 and 0.932 for T1, T2, T3 and reference, respectively). Internal predictability was found less than 10%. Good correlation coefficients and low prediction errors elaborate the validity of this mathematical in-vitro in-vivo correlation model as a predictive tool for the determination of pharmaenkinetics from dissolution data.

  6. Pharmacokinetics of marbofloxacin in horses.

    Science.gov (United States)

    Bousquet-Melou, A; Bernard, S; Schneider, M; Toutain, P L

    2002-07-01

    Marbofloxacin is a fluoroquinolone antibiotic expected to be effective in the treatment of infections involving gram-negative and some gram-positive bacteria in horses. In order to design a rational dosage regimen for the substance in horses, the pharmacokinetic properties of marbofloxacin were investigated in 6 horses after i.v., subcutaneous and oral administration of a single dose of 2 mg/kg bwt and the minimal inhibitory concentrations (MIC) assessed for bacteria isolated from equine infectious pathologies. The clearance of marbofloxacin was mean +/- s.d. 0.25 +/- 0.05 l/kg/h and the terminal half-life 756 +/- 1.99 h. The marbofloxacin absolute bioavailabilities after subcutaneous and oral administration were 98 +/- 11% and 62 +/- 8%, respectively. The MIC required to inhibit 90% of isolates (MIC90) was 0.027 microg/ml for enterobacteriaceae and 0.21 microg/ml for Staphylococcus aureus. The values of surrogate markers of antimicrobial efficacy (AUIC, Cmax/MIC ratio, time above MIC90) were calculated and the marbofloxacin concentration profiles simulated for repeated administrations. These data were used to determine rational dosage regimens for target bacteria. Considering the breakpoint values of efficacy indices for fluoroquinolones, a marbofloxacin dosage regimen of 2 mg/kg bwt/24 h by i.v., subcutaneous or oral routes was more appropriate for enterobacteriaceae than for S. aureus.

  7. chronicles of medical history first reports of clinical pharmacokinetics ...

    African Journals Online (AJOL)

    purpose of pharmacokinetics is to study the time course of drug and ... The German Friedrich Hartmut Dost (1910 – 1985) introduced the word. Pharmacokinetics. ..... University College Hospital, Ibadan for material on his father, Professor A.O. ...

  8. Morphine pharmacokinetics during venoarterial extracorporeal membrane oxygenation in neonates

    NARCIS (Netherlands)

    Peters, JWB; Anderson, BJ; Simons, SHP; Uges, DRA; Tibboel, D

    2005-01-01

    Objective: To study morphine pharmacokinetics in neonates undergoing venoarterial ECMO and to quantify differences between these neonates and neonates subjected to noncardiac major surgery. Design and Settings: Observational study in a level III referral center. Patients and methods: Pharmacokinetic

  9. 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

  10. Mode-of-Action Uncertainty for Dual-Mode Carcinogens:Lower Bounds for Naphthalene-Induced Nasal Tumors in Rats Implied byPBPK and 2-Stage Stochastic Cancer Risk Models

    Energy Technology Data Exchange (ETDEWEB)

    Bogen, K T

    2007-01-30

    As reflected in the 2005 USEPA Guidelines for Cancer Risk Assessment, 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-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient to parameterize a biologically based model that reliably 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-dose risk as a function of administered or internal dose. Even when a ''nonlinear'' toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was illustrated for the rodent carcinogen naphthalene. Bioassay data, supplemental toxicokinetic data, and related physiologically based pharmacokinetic and 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen. Plausibility bounds on rat-tumor-type specific DMOA-related uncertainty were obtained using a 2-stage model adapted to reflect the empirical link between genotoxic and cytotoxic effects of the most potent identified genotoxic naphthalene metabolites, 1,2- and 1,4-naphthoquinone. Resulting

  11. 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.

  12. Fenbendazole pharmacokinetics, metabolism, and potentiation in horses.

    Science.gov (United States)

    McKellar, Q A; Gokbulut, C; Muzandu, K; Benchaoui, H

    2002-11-01

    The present study was designed to describe the pharmacokinetics and fecal excretion of fenbendazole (FBZ) and fenbendazole sulphoxide (FBZSO) and their metabolites in horses, to investigate the effects which concurrent feeding has on the absorption and pharmacokinetics of FBZ, and to determine the effect of coadministration of the metabolic inhibitor piperonyl-butoxide on the in vivo pharmacokinetics and in vitro liver microsomal metabolism of sulfide and sulfoxide benzimidazoles. The effect of piperonyl-butoxide on the enantiomeric genesis of the sulfoxide moiety was also investigated. Following administration of FBZSO and FBZ, the fenbendazole sulphone metabolite predominated in plasma, and the C(max) and area under the plasma curve (AUC) values for each moiety were larger (P 4:1 to 1:1. It is concluded that in horses efficacy of FBZSO and FBZ could be improved by administration to unfed animals and coadministration with piperonyl-butoxide.

  13. Pharmacokinetics of oral ranitidine in Mexicans.

    Science.gov (United States)

    Castañeda-Hernández, G; Flores-Murrieta, F J; Granados-Soto, V; Herrera-Abarca, A; Pérez-Urizar, J; Herrera, J E; Hong, E

    1996-01-01

    The pharmacokinetics of oral ranitidine were studied in 24 Mexican male healthy volunteers. Subjects received a tablet containing 150 mg of ranitidine (Azantac, Glaxo de México, Mexico City) after an overnight fast and blood samples were drawn at several times for a period of 24 h. Ranitidine concentration in plasma was measured by high performance liquid chromatography and pharmacokinetic parameters were determined by non-compartmental analysis. Ranitidine plasma concentration increased with time, reaching a maximum of (mean +/- SEM) 484 +/- 34 ng/ml in 2.7 +/- 0.2 h. Plasma levels then decayed with a terminal half-life of 4.8 +/- 0.3 h. The area under the plasma concentration against time curve was 2440 +/- 126 ngh/ml. Oral ranitidine pharmacokinetic parameters in Mexicans appeared to be similar to those previously reported for Caucasians.

  14. SPECIFICS OF DRUG PHARMACOKINETICS IN PREGNANCY

    Directory of Open Access Journals (Sweden)

    A.V. Ostrovskaya

    2010-01-01

    Full Text Available Applying clinical pharmacology guidelines to the mother-fetus system makes it possible to better understand the specifics of pharmacokinetics during pregnancy. The article illustrates the factors that drive these specific features related to both changes in the boy of a future mother and the presence of an extra fetal-placental blood circulation, especially the placenta and developing fetus. These factors influence the results of drug-based treatment during the entire gestational period. Thanks to a rapid development of molecular technologies in the last decade, modern medicine has good prospects of answering questions about individual specifics of pharmacokinetics and metabolism of drugs, increased teratogenic risk driven by specifics of genotypes of the mother and fetus. Key words: pharmacokinetics, drugs, pregnancy, placenta, mother-fetus system. (Pediatric Pharmacology. – 2010; 7(5:44-47

  15. 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....... Metoprolol and torsemide were intravenously administered to 44 monozygotic and 14 dizygotic twin pairs. Metoprolol AUC varied 4.7-fold and torsemide AUC 3.5-fold. A very high fraction of AUC variations, 91% of metoprolol and 86% of torsemide, were found to be due to additive genetic effects. However, known...... of the heritable variability in the pharmacokinetics of metoprolol and torsemide remains to be elucidated. This article is protected by copyright. All rights reserved....

  16. Dermal and underlying tissue pharmacokinetics of salicylic acid after topical application.

    Science.gov (United States)

    Singh, P; Roberts, M S

    1993-08-01

    The time course of salicylic acid at a dermal application site and in local underlying tissues below the site in rats was examined using a physiologically based pharmacokinetic model assuming first-order diffusional mass transfer between the dermis and underlying tissues. The concentrations of salicylic acid in tissues below the applied site were measured and compared with plasma concentrations and concentrations in similar tissues on the contralateral side. The direct penetration of salicylic acid was dominant only to a depth of 3-4 mm below the applied site for the first approximately 2 hr after application. The time course of salicylic acid in individual rats was modeled using known tissue blood flows and tissue-tissue clearances by (i) numerical integration and nonlinear regression of a series of differential equations representing events in individual tissues, and (ii) numerical integration and nonlinear regression of a single differential equation representation of the concentration-time course in an individual tissue with a polynomial representation of salicylate concentrations in other input tissues and an exponential representation of the input from the solution. Tissue-tissue clearances were deduced by both nonlinear regression and mass balance analysis (only for underlying dermis) using area-under-the-curves from salicylic acid tissue penetration data in anesthetized rats. The relative importance of direct penetration and blood supply in determining the concentrations of salicylic acid in deeper tissues was assessed by simulations in which either no direct penetration occurred or there was zero input from blood. Simulations confirm that direct penetration is only evident in the superficial tissues for approximately 2 hr. An attempt was also made to examine the dermal pharmacokinetics of salicylic acid using statistical moments.

  17. Mechanistic Modeling to Predict Midazolam Metabolite Exposure from In Vitro Data.

    Science.gov (United States)

    Nguyen, Hoa Q; Kimoto, Emi; Callegari, Ernesto; Obach, R Scott

    2016-05-01

    Methods to predict the pharmacokinetics of drugs in humans from in vitro data have been established, but corresponding methods to predict exposure to circulating metabolites are unproven. The objective of this study was to use in vitro methods combined with static and dynamic physiologically based pharmacokinetic (PBPK) models to predict metabolite exposures, using midazolam and its major metabolites as a test system. Intrinsic clearances (CLint) of formation of individual metabolites were determined using human liver microsomes. Metabolic CLintof hydroxymidazolam metabolites via oxidation and glucuronidation were also determined. Passive diffusion intrinsic clearances of hydroxymidazolam metabolites were determined using sandwich cultured human hepatocytes and the combination of this term along with the metabolic CLint, and liver blood flow was used to estimate the fraction of the metabolite that can enter the systemic circulation after formation in the liver. The metabolite/parent drug area under the plasma concentration-time curve ratio (AUCm/AUCp) was predicted using a static model relating the fraction of midazolam clearance to each metabolite, the clearance rates of midazolam and hydroxymidazolam metabolites, and the availability of the metabolites. Additionally, the human disposition of midazolam metabolites was simulated using a SimCYP PBPK model. Both approaches yielded AUCm/AUCpratios that were in agreement with the in vivo ratios. This study shows that in vivo midazolam metabolite exposure can be predicted from in vitro data and PBPK modeling. This study emphasized the importance of metabolite systemic availability from its tissue of formation, which remains a challenge to quantitative prediction.

  18. Ethnic and genetic factors in methadone pharmacokinetics: a population pharmacokinetic study.

    Science.gov (United States)

    Bart, Gavin; Lenz, Scott; Straka, Robert J; Brundage, Richard C

    2014-12-01

    Treatment of opiate use disorders with methadone is complicated by wide interindividual variability in pharmacokinetics. To identify potentially contributing covariates in methadone pharmacokinetics, we used population pharmacokinetic modeling to estimate clearance (CL/F) and volume of distribution (V/F) for each methadone enantiomer in an ethnically diverse methadone maintained population. Plasma levels of the opiate-active R-methadone and opiate-inactive S-methadone were measured in 206 methadone maintained subjects approximately two and twenty-three hours after a daily oral dose of rac-methadone. A linear one-compartment population pharmacokinetic model with first-order conditional estimation with interaction (FOCE-I) was used to evaluate methadone CL/F and V/F. The influence of covariates on parameter estimates was evaluated using stepwise covariate modeling. Covariates included ethnicity, gender, weight, BMI, age, methadone dose, and 21 single nucleotide polymorphisms in genes implicated in methadone pharmacokinetics. In the final model, for each enantiomer, Hmong ethnicity reduced CL/F by approximately 30% and the rs2032582 (ABCB1 2677G>T/A) GG genotype was associated with a 20% reduction in CL/F. The presence of the rs3745274 minor allele (CYP2B6 515G>T) reduced CL/F by up to 20% for S-methadone only. A smaller effect of age was noted on CL/F for R-methadone. This is the first report showing the influence of the rs2032582 and rs3745274 variants on methadone pharmacokinetics rather than simply dose requirements or plasma levels. Population pharmacokinetics is a valuable method for identifying the influences on methadone pharmacokinetic variability. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    renal and hepatic clearances, elimination half-life, and mass transfer coefficients, to establish drug biodistribution dynamics in all organs and tissues. This multi-scale model satisfies first principles and conservation of mass, species and momentum.Prediction of organ drug bioaccumulation...... as a function of cardiac output, physiology, pathology or administration route may be possible with the proposed PBPK framework. Successful application of our model-based drug development method may lead to more efficient preclinical trials, accelerated knowledge gain from animal experiments, and shortened time-to-market...

  20. 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 dilu...... of joules required to clear the patients in various PUVA centers....

  1. 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 compound...

  2. Pharmacokinetics of paroxetine in patients with cirrhosis

    DEFF Research Database (Denmark)

    Dalhoff, K; Almdal, T P; Bjerrum, K;

    1991-01-01

    In a 14-day multiple-dose study the pharmacokinetics of paroxetine was investigated in 12 patients with alcoholic cirrhosis and in 6 subjects without liver disease. The dose of 20-30 mg paroxetine daily was adjusted to the reduction in liver function, as assessed by the galactose elimination capa...

  3. Pharmacokinetics of caspofungin in ICU patients

    NARCIS (Netherlands)

    Muilwijk, E.W.; Schouten, J.A.; Leeuwen, H.J. van; Zanten, A.R. van; Lange, D.W. de; Colbers, A.; Verweij, P.E.; Burger, D.M.; Pickkers, P.; Bruggemann, R.J.M.

    2014-01-01

    OBJECTIVES: Caspofungin is used for treatment of invasive fungal infections. As the pharmacokinetics (PK) of antimicrobial agents in critically ill patients can be highly variable, we set out to explore caspofungin PK in ICU patients. METHODS: ICU patients receiving caspofungin were eligible. Patien

  4. Heritability of metoprolol and torsemide pharmacokinetics.

    Science.gov (United States)

    Matthaei, J; Brockmöller, J; Tzvetkov, M V; Sehrt, D; Sachse-Seeboth, C; Hjelmborg, J B; Möller, S; Halekoh, U; Hofmann, U; Schwab, M; Kerb, R

    2015-12-01

    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 the variation in pharmacokinetics of these two clinically important drugs in total is due to genetic factors. Metoprolol and torsemide were intravenously administered to 44 monozygotic and 14 dizygotic twin pairs. Metoprolol area under the curve (AUC) varied 4.7-fold and torsemide AUC 3.5-fold. A very high fraction of AUC variations, 91% of metoprolol and 86% of torsemide, were found to be due to additive genetic effects. However, known genetic variants of CYP2D6, -2C9, and OATP1B1 explained only 39%, 2%, and 39% of that variation, respectively. 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 of the heritable variability in the pharmacokinetics of metoprolol and torsemide remains to be elucidated.

  5. Buspirone pharmacokinetics in patients with cirrhosis

    DEFF Research Database (Denmark)

    Dalhoff, K; Poulsen, H E; Garred, P

    1987-01-01

    The pharmacokinetics of a single oral dose of buspirone (20 mg) were determined in 12 patients with cirrhosis and 12 normal subjects. The mean AUC of buspirone was 55 +/- 38 s.d. ng ml-1 h in cirrhotics and 3.5 +/- 2.4 s.d. ng ml-1 h in normals. The time until maximum concentration (tmax) attaine...

  6. 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.

  7. A Review on Pharmacokinetic Modeling and the Effects of Environmental Stressors on Pharmacokinetics for Operational Medicine: Operational Pharmacokinetics

    Science.gov (United States)

    2009-09-01

    was defined as the fraction of drug removed by the organ from the blood and calculated as CL12/(CL12+QT), where CL12, QT are intrinsic distribution...Pharmacol Exp Ther 221: 368-372. [28] Beovic, B., A. Mrhar, et al. (1999). "Influence of fever on the pharmacokinetics of ciprofloxacin ." Int J...Liberzon, I., S. F. Taylor, et al. (2007). "Altered central micro -opioid receptor binding after psychological trauma." Biol Psychiatry 61: 1030

  8. 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.

  9. Pharmacokinetics of norfloxacin in the elderly.

    Science.gov (United States)

    Lepage, J Y; Caillon, J; Malinowsky, J M; Lequerré, S; Cozian, A; Le Normand, Y; Potel, G; Drugeon, H; Baron, D

    1991-01-01

    9 elderly and 9 younger adult patients, with proven post-operative lower urinary tract infection were treated with 400 mg of norfloxacin twice daily for 5 days. Pharmacokinetics of norfloxacin were measured on days 1 and 5. Compared to the younger adult patients, the elderly showed a decreased creatinine clearance and, following the last dose on day 5, an increased maximum plasma concentration of norfloxacin, an increased area under the concentration-time curve and a decreased total body clearance of norfloxacin. These results confirm that in elderly, as in younger adult patients, the pharmacokinetics of norfloxacin can be described by a linear model and accumulation of the drug during repetitive multiple doses is predictable. The differences between the two groups cannot be considered as clinically significant so that no dose change would be required in elderly patients within the range of creatinine clearance studied.

  10. 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.

  11. Pharmacokinetics of Alternative Administration Routes of Melatonin

    DEFF Research Database (Denmark)

    Zetner, D.; Andersen, L. P.H.; Rosenberg, J.

    2016-01-01

    Background: Melatonin is traditionally administered orally but has a poor and variable bioavailability. This study aims to present an overview of studies investigating the pharmacokinetics of alternative administration routes of melatonin. Methods: A systematic literature search was performed...... and included experimental or clinical studies, investigating pharmacokinetics of alternative administration routes of melatonin in vivo. Alternative administration routes were defined as all administration routes except oral and intravenous. Results: 10 studies were included in the review. Intranasal...... administration exhibited a quick absorption rate and high bioavailability. Transdermal administration displayed a variable absorption rate and possible deposition of melatonin in the skin. Oral transmucosal administration of melatonin exhibited a high plasma concentration compared to oral administration...

  12. [Influence of fever on cefotaxime pharmacokinetics].

    Science.gov (United States)

    Demotes-Mainard, F; Albin, H; Ragnaud, J M; Gin, H; Vincon, G; Aubertin, J

    1988-02-01

    The role of fever on cefotaxime disposition was studied in ten hyperthermic patients. Each subject received intravenously 1 g of cefotaxime on two separated occasions, first when the body temperature was more than 39 degrees C then during a basal state (37 degrees C). Blood samples were taken over 12 hours and urine was collected for 24 hours after injection. After dosing cefotaxime and its metabolite by high performance liquid chromatography, the pharmacokinetic parameters were calculated, especially: plasma and renal clearance, volume of distribution at steady state, area under the curve, and elimination half-life. There is no significant difference in cefotaxime and desacetylcefotaxime disposition between these two states. Hyperthermia has no influence on pharmacokinetics of this cephalosporin.

  13. Pharmacokinetics and bioavailability of drotaverine in humans.

    Science.gov (United States)

    Bolaji, O O; Onyeji, C O; Ogundaini, A O; Olugbade, T A; Ogunbona, F A

    1996-01-01

    The pharmacokinetics and bioavailability of drotaverine was studied in 10 healthy volunteers after administration of single 80 mg oral and intravenous doses of the HCl salt of the drug, in a crossover fashion. Plasma and urine samples were analyzed for the unchanged drug by HPLC. The pharmacokinetic parameters, such as elimination half-life, plasma clearance, renal clearance and apparent volume of distribution, were not influenced by the route of drug administration. The drug was mainly eliminated by non-renal routes since renal clearance accounted for only 0.31 +/- 0.13% of the total plasma clearance. The absolute bioavailability was variable and ranged from 24.5-91% with a mean of 58.2 +/- 18.2% (mean +/- SD). It is suggested that the high variation in the bioavailability of drotaverine HCl after oral administration may result in significant interindividual differences in therapeutic response.

  14. Whatever happened to cassette-dosing pharmacokinetics?

    Science.gov (United States)

    Manitpisitkul, Prasarn; White, Ronald E

    2004-08-01

    Cassette dosing is a procedure that is used for rapidly assessing the pharmacokinetics of a series of discovery drug candidates by dosing a mixture of compounds rather than a single compound. Cassette dosing has advantages and disadvantages associated with its use, which leads to controversy about how and if it should be used. To assess the current practices of the pharmaceutical industry regarding cassette dosing, a survey of several pharmaceutical companies was conducted. Analysis of the survey revealed that opinion on this subject is divided within the pharmaceutical industry. In addition, it was determined that approximately only a half of those companies that perform in vivo pharmacokinetic screening use cassette dosing for this purpose.

  15. Physiologic and pharmacokinetic changes in pregnancy

    OpenAIRE

    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 ...

  16. 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...... is present. Further studies are necessary to establish if the liver is a site of degradation of intact NT in man....

  17. Clinical Pharmacokinetics and Pharmacodynamics of Afatinib.

    Science.gov (United States)

    Wind, Sven; Schnell, David; Ebner, Thomas; Freiwald, Matthias; Stopfer, Peter

    2017-03-01

    Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of afatinib are reached approximately 2-5 h after oral administration and thereafter decline, at least bi-exponentially. Food reduces total exposure to afatinib. Over the clinical dose range of 20-50 mg, afatinib exposure increases slightly more than dose proportional. Afatinib metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5 % in urine. Apart from the parent drug afatinib, the major circulation species in human plasma are the covalently bound adducts to plasma protein. The effective elimination half-life is approximately 37 h, consistent with an accumulation of drug exposure by 2.5- to 3.4-fold based on area under the plasma concentration-time curve (AUC) after multiple dosing. The pharmacokinetic profile of afatinib is consistent across a range of patient populations. Age, ethnicity, smoking status and hepatic function had no influence on afatinib pharmacokinetics, while females and patients with low body weight had increased exposure to afatinib. Renal function is correlated with afatinib exposure, but, as for sex and body weight, the effect size for patients with severe renal impairment (approximately 50 % increase in AUC) is only mildly relative to the extent of unexplained interpatient variability in afatinib exposure. Afatinib has a low potential as a victim or perpetrator of drug-drug interactions, especially with cytochrome P450-modulating agents. However, concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the

  18. Studies on Pharmacokinetics of Porcine Somatotropin Liposomes

    Institute of Scientific and Technical Information of China (English)

    XU Chuan-lai; JI Cheng; HAO Kai; LI Xiang-qian; YAO Hui-yuan

    2005-01-01

    This paper focuses on the pharmacokinetics in fattening pigs as well as the change of serum resulting from the use of porcine somatotropin(PST) and its liposomes. A slow-release model was determined to be relevant to following an examination of all dynamic parameters. The results indicate that the slow-release effect of PST liposomes was significant, with an extended release time of over 7 d.

  19. 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...

  20. Clinical Pharmacokinetic and Pharmacodynamic Profile of Cinacalcet

    OpenAIRE

    Boubaker, Karima; Hedri, Hafedh; Kheder, Adel

    2014-01-01

    The purpose of this letter is to explain clinical pharmacokinetic, pharmacodynamic profile and indication of cinacalcet therapy particularly in chronic kidney disease. Chronic kidney disease and progressive renal failure are associated with phosphate retention and impaired formation of active vitamin D, or calcitriol (1α-25-dihydroxyvitamin D), leading to hypocalcemia, increased secretion of parathyroid hormone, and, eventually, hyperplasia of the parathyroid gland. Secondary hyperparathyroid...

  1. 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

  2. The Pharmacokinetics and Pharmacodynamics of Iron Preparations

    OpenAIRE

    Susanna Burckhardt; Peter Geisser

    2011-01-01

    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...

  3. Clinical pharmacokinetics of levodopa in parkinson's disease.

    Science.gov (United States)

    Bianchine, J R; Shaw, G M

    1976-01-01

    Although levodopa has provided a major advance in the treatment of parkinsonism, its maximum benefits have not yet been realised, in part because of its complicated pharmacokinetics. This review summarises that available pharmacokinetic data involving levodopa, especially as it relates to therapeutic response of parkinsonian patients. A large number of factors, including protein intake, gastric emptying time, pyridoxine ingestion, and dopa decarboxylase activity, affect plasma levels of levodopa attained following oral administration of this drug. Other variables influence the rate of brain uptake of levodopa from the blood. Even so, plasma levodopa concentration correlates significantly with dosage size in a large parkinsonian population and also coincides with therapeutic response in many, but not all, patients. Therefore, in certain instances, valuable information may be derived by correlating clinical response with plasma levodopa concentration. Cerebrospinal fluid levels of homovanillic acid, a major metabolite of dopamine, may have some value in predicting clinical response to levodopa. This relationship, however, has not been firmly established. Concentration of homovanillic acid or levodopa in body fluids may also be closely related to certain adverse side-effects, including abnormal involuntary movements, gastric discomfort and psychiatric disturbances. Evidence indicates that a clearer understanding of levodopa pharmacokinetics may improve the clinical management of parkinsonism.

  4. Pharmacokinetics of oral rufinamide in dogs.

    Science.gov (United States)

    Wright, H M; Chen, A V; Martinez, S E; Davies, N M

    2012-12-01

    The objective of this study was to determine the pharmacokinetic properties and short-term adverse effect profile of single-dose oral rufinamide in healthy dogs. Six healthy adult dogs were included in the study. The pharmacokinetics of rufinamide were calculated following administration of a single mean oral dose of 20.0 mg/kg (range 18.6-20.8 mg/kg). Plasma rufinamide concentrations were determined using high-performance liquid chromatography, and pharmacokinetic data were analyzed using commercial software. No adverse effects were observed. The mean terminal half-life was 9.86 ± 4.77 h. The mean maximum plasma concentration was 19.6 ± 5.8 μg/mL, and the mean time to maximum plasma concentration was 9.33 ± 4.68 h. Mean clearance was 1.45 ± 0.70 L/h. The area under the curve (to infinity) was 411 ± 176 μg · h/mL. Results of this study suggest that rufinamide given orally at 20 mg/kg every 12 h in healthy dogs should result in a plasma concentration and half-life sufficient to achieve the therapeutic level extrapolated from humans without short-term adverse effects. Further investigation into the efficacy and long-term safety of rufinamide in the treatment of canine epilepsy is warranted.

  5. Pharmacokinetic interaction study between ranitidine and metoclopramide.

    Science.gov (United States)

    Leucuţa, Adrian; Vlase, Laurian; Farcău, Dorin; Nanulescu, Mircea

    2004-09-01

    The pharmacokinetics of metoclopramide in healthy volunteers was evaluated to determine if previously repeated doses of ranitidine inhibit the metabolism of the gastrointestinal prokinetic drug. Metoclopramide 20 mg (tablets) in combination with ranitidine 150 mg (tablets) were administered to 14 healthy human volunteers in a two treatment study design, separated by 5 days in which the ranitidine alone was administrated in single p.o. doses twice daily. Plasma concentrations of metoclopramide were determined during a 24 hour period following drug administration. Metoclopramide plasma concentrations were determined by a validated RP-HPLC method. Pharmacokinetic parameters were calculated with compartmental and non-compartmental analysis. In the two periods of treatments, the mean peak plasma concentrations Cmax were 44 ng/ml (metoclopramide alone) and 49.2 ng/ml (metoclopramide and ranitidine). The time taken to reach the peak, Tmax, was 1.15 hrs, and 1.21 hrs, respectively. The total areas under the curve (AUC) was 314.3 ng.hr/ml and 354.06 ng.hr/ml, respectively. The half-life (T 1/2) was 5.6 hr and 6.7 hr. A statistically significant difference was observed for both AUC and half-life of metoclopramide when administered alone or after 5 days of treatment with ranitidine. The experimental data proved the pharmacokinetic interaction between ranitidine of metoclopramide, and suggest monitoring adverse effects in patients.

  6. Pharmacokinetics of antibiotics in pregnancy and labour.

    Science.gov (United States)

    Philipson, A

    1979-01-01

    Few of the articles published on antibiotics and pregnancy are concerned with pharmacokinetics. It is particularly difficult to evaluate possible alterations in pharmacokinetic parameters that may be due to pregnancy. Most data available have been obtained in connection with abortion or delivery. Such data may not be representative for pregnancy as such. Marked changes in most organ systems, particularly in renal function, but in composition and amounts of body fluids as well, make it likely that several pharmacokinetic parameters change, possibly gradually as pregnancy progresses. Accumulated data for several beta-lactam antibiotics, and also for aminoglycosides indicate that antibiotics eliminated mainly by renal excretion will produce lower levels in serum or plasma in pregnant women than in other individuals. Also, the half-life of certain antibiotics in serum is shorter during pregnancy. Transplacental passage occurs for all antibiotics according to the physicochemical properties of the drug. Bolus injections to a pregnant woman are more efficient than continuous infusion in producing high levels of antibiotic in fetal serum and amniotic fluid. Fetal tissue levels are higher following multiple doses than after a single dose. Lower serum levels of antibiotics in pregnant women than in other individuals following the same dosage will be unsatisfactory as micr-organisms are less likely to be affected.

  7. Pharmacokinetics of Tyrosol Metabolites in Rats

    Directory of Open Access Journals (Sweden)

    Da-Hye Lee

    2016-01-01

    Full Text Available Tyrosol is considered a potential antioxidant; however, little is known regarding the pharmacokinetics of its metabolites. To study the pharmacokinetics of tyrosol-derived metabolites after oral administration of a single dose of tyrosol, we attempted to identify tyrosol metabolites in rat plasma by using ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS. Two tyrosol metabolites (M1 and M2 were detected in the plasma. M1 was identified as tyrosol-4-sulfate (T4S with an [M − H]− ion at m/z 217. While M2 showed an [M − H]− ion at m/z 151.0, its metabolite was not identified. Pharmacokinetic analysis of T4S and M2 showed rapid uptake after oral administration of tyrosol within 1 h. The metabolites were rapidly distributed in most organs and tissues and eliminated within 4 h. The greatest T4S deposition by tissue weight was observed in the liver, followed by the kidney and spleen, while M2 was most concentrated in the kidney followed by the liver and spleen. These findings indicate that T4S and M2 were distributed mainly in tissues with an abundant blood supply and were rapidly excreted in urine.

  8. Pharmacokinetics of Tyrosol Metabolites in Rats.

    Science.gov (United States)

    Lee, Da-Hye; Kim, Yang-Ji; Kim, Min Jung; Ahn, Jiyun; Ha, Tae-Youl; Lee, Sang Hee; Jang, Young Jin; Jung, Chang Hwa

    2016-01-21

    Tyrosol is considered a potential antioxidant; however, little is known regarding the pharmacokinetics of its metabolites. To study the pharmacokinetics of tyrosol-derived metabolites after oral administration of a single dose of tyrosol, we attempted to identify tyrosol metabolites in rat plasma by using ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Two tyrosol metabolites (M1 and M2) were detected in the plasma. M1 was identified as tyrosol-4-sulfate (T4S) with an [M - H](-) ion at m/z 217. While M2 showed an [M - H](-) ion at m/z 151.0, its metabolite was not identified. Pharmacokinetic analysis of T4S and M2 showed rapid uptake after oral administration of tyrosol within 1 h. The metabolites were rapidly distributed in most organs and tissues and eliminated within 4 h. The greatest T4S deposition by tissue weight was observed in the liver, followed by the kidney and spleen, while M2 was most concentrated in the kidney followed by the liver and spleen. These findings indicate that T4S and M2 were distributed mainly in tissues with an abundant blood supply and were rapidly excreted in urine.

  9. Allometric scaling of marbofloxacin pharmacokinetics: a retrospective analysis.

    Science.gov (United States)

    Yohannes, S; Hossain, Md Akil; Kim, J Y; Lee, S J; Kwak, D M; Suh, J W; Park, S C

    2014-01-01

    The association between physiologically dependent pharmacokinetic parameters (CL(B), T1/2beta, Vd(ss)) of marbofloxacin and body weight was studied in eight animal species based on allometric equation Y = aWb, where 'Y' is the pharmacokinetic parameter, 'W' is body weight, 'a' is allometric coefficient (intercept) and 'b' is the exponent that describes relation between pharmacokinetic parameter and body weight. The body clearance of marbofloxacin has shown significant (P marbofloxacin in animal species that have not been studied yet. However further study considering large sample size and other parameters influencing pharmacokinetics of marbofloxacin is recommended.

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

    NARCIS (Netherlands)

    Stolk, L M L; Degraeuwe, P L J; Nieman, F H M; de Wolf, M C; de Boer, A

    2002-01-01

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

  11. Influence of obesity on propofol pharmacokinetics : derivation of a pharmacokinetic model

    NARCIS (Netherlands)

    Cortinez, L. I.; Anderson, B. J.; Penna, A.; Olivares, L.; Munoz, H. R.; Holford, N. H. G.; Struys, M. M. R. F.; Sepulveda, P.

    2010-01-01

    The objective of this study was to develop a pharmacokinetic (PK) model to characterize the influence of obesity on propofol PK parameters. Nineteen obese ASA II patients undergoing bariatric surgery were studied. Patients received propofol 2 mg kg(-1) bolus dose followed by a 5-20-40-120 min,

  12. Influence of obesity on propofol pharmacokinetics : derivation of a pharmacokinetic model

    NARCIS (Netherlands)

    Cortinez, L. I.; Anderson, B. J.; Penna, A.; Olivares, L.; Munoz, H. R.; Holford, N. H. G.; Struys, M. M. R. F.; Sepulveda, P.

    2010-01-01

    The objective of this study was to develop a pharmacokinetic (PK) model to characterize the influence of obesity on propofol PK parameters. Nineteen obese ASA II patients undergoing bariatric surgery were studied. Patients received propofol 2 mg kg(-1) bolus dose followed by a 5-20-40-120 min, 10-8-

  13. An Allometric Model of Remifentanil Pharmacokinetics and Pharmacodynamics

    NARCIS (Netherlands)

    Eleveld, Douglas J.; Proost, Johannes H.; Vereecke, Hugo; Absalom, Anthony R.; Olofsen, Erik; Vuyk, Jaap; Struys, Michel M. R. F.

    Background: Pharmacokinetic and pharmacodynamic models are used to predict and explore drug infusion schemes and their resulting concentration profiles for clinical application. Our aim was to develop a pharmacokinetic-pharmacodynamic model for remifentanil that is accurate in patients with a wide

  14. 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....

  15. 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....

  16. Maraviroc Pharmacokinetics in HIV-1-Infected Pregnant Women

    NARCIS (Netherlands)

    Colbers, A.; Best, B.; Schalkwijk, S.J.; Wang, J; Stek, A.; Tenorio, C.H.; Hawkins, D.; Taylor, G.; Kreitchmann, R.; Burchett, S.; Haberl, A.; Kabeya, K.; Kasteren, M.E.E. van; Smith, E.; Capparelli, E.; Burger, D.M.; Mirochnick, M.; Ven, A. van der

    2015-01-01

    OBJECTIVE: To describe the pharmacokinetics of maraviroc in human immunodeficiency virus (HIV)-infected women during pregnancy and post partum. METHODS: HIV-infected pregnant women receiving maraviroc as part of clinical care had intensive steady-state 12-hour pharmacokinetic profiles performed

  17. 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.

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

    Science.gov (United States)

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

    2014-08-01

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

  19. Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide.

    Science.gov (United States)

    Chen, Nianhang; Zhou, Simon; Palmisano, Maria

    2017-02-01

    Lenalidomide is a lead therapeutic in multiple myeloma and deletion 5q myelodysplastic syndromes and shows promising activities in other hematologic malignancies. This article presents a comprehensive review of the clinical pharmacokinetics and pharmacodynamics of lenalidomide. Oral lenalidomide is rapidly and highly absorbed (>90 % of dose) under fasting conditions. Food affects oral absorption, reducing area under the concentration-time curve (AUC) by 20 % and maximum concentration (C max) by 50 %. The increase in AUC and C max is dose proportional, and interindividual variability in plasma exposure is low to moderate. Lenalidomide distributes into semen but is undetectable 3 days after stopping treatment. Biotransformation of lenalidomide in humans includes chiral inversion, trivial hydroxylation, and slow non-enzymatic hydrolysis. Approximately 82 % of an oral dose is excreted as lenalidomide in urine within 24 h. Lenalidomide has a short half-life (3-4 h) and does not accumulate in plasma upon repeated dosing. Its pharmacokinetics are consistent across patient populations, regardless of the type of hematologic malignancy. Renal function is the only important factor affecting lenalidomide plasma exposure. Lenalidomide has no QT prolongation risk at approved doses, and higher plasma exposure to lenalidomide is associated with increased risk of neutropenia and thrombocytopenia. Despite being a weak substrate of P-glycoprotein (P-gp) in vitro, lenalidomide does not have clinically significant pharmacokinetic interactions with P-gp substrates/inhibitors in controlled studies. The AUC-matched dose adjustment is recommended for patients with renal impairment at the start of therapy. No dose adjustment for lenalidomide is needed on the basis of age, ethnicity, mild hepatic impairment, or drug-drug interactions.

  20. Pharmacokinetics and pharmacodynamics of intravenous inotropic agents.

    Science.gov (United States)

    Lehtonen, Lasse A; Antila, Saila; Pentikäinen, Pertti J

    2004-01-01

    Positive inotropic drugs have various mechanisms of action. Long-term use of cyclic adenosine monophosphate (cAMP)-dependent drugs has adverse effects on the prognosis of heart failure patients, whereas digoxin has neutral effect on mortality. There are, however, little data on the effects of intravenous inotropic drugs on the outcome of patients. Intravenous inotropic agents are used to treat cardiac emergencies and refractory heart failure. beta-Adrenergic agonists are rapid acting and easy to titrate, with short elimination half-life. However, they increase myocardial oxygen consumption and are thus hazardous during myocardial ischaemia. Furthermore they may promote myocyte apoptosis. Phosphodiesterase (PDE) III inhibiting drugs (amrinone, milrinone and enoximone) increase contractility by reducing the degradation of cAMP. In addition, they reduce both preload and afterload via vasodilation. Short-term use of intravenous milrinone is not associated with increased mortality, and some symptomatic benefit may be obtained when it is used in refractory heart failure. Furthermore, PDE III inhibitors facilitate weaning from the cardiopulmonary bypass machine after cardiac surgery. Levosimendan belongs to a new group of positive inotropic drugs, the calcium sensitisers. It has complex pharmacokinetics and long-lasting haemodynamic effects as a result of its active metabolites. In comparative trials, it has been better tolerated than the most widely used beta-agonist inotropic drug, dobutamine. The pharmacokinetics of the intravenous inotropic drugs might sometimes greatly modify and prolong the response to the therapy, for example because of long-acting active metabolites. These drugs display considerable differences in their pharmacokinetics and pharmacodynamics, and the selection of the most appropriate inotropic drug for each patient should be based on careful consideration of the clinical status of the patient and on the pharmacology of the drug.

  1. Population Pharmacokinetics of Vancomycin in Thai Patients

    Directory of Open Access Journals (Sweden)

    Tunggul Adi Purwonugroho

    2012-01-01

    Full Text Available Population pharmacokinetics of vancomycin in Thai adult patients was determined by non-linear mixed-effects approach using 319 vancomycin serum concentrations from 212 patients. The data were best fitted by a two-compartment model and it was used to examine the effect of patient characteristics on the vancomycin pharmacokinetics. In the final model, there was a linear relationship between vancomycin clearance, CL (L/h, and creatinine clearance calculated by Cockcroft-Gault equation, CLCr (mL/min: CL=0.044×CLCr. Meanwhile, volume of central compartment, 1 (L, was linearly related with the age (years old: 1=0.542× Age. Intercompartment clearance ( and volume of peripheral compartment (2 was 6.95 L/h and 44.2 L, respectively. The interindividual variability for CL, 1, , and 2 was 35.78, 20.93, 39.50, and 57.27%, respectively. Whereas, the intraindividual variability was 4.51 mg/L. Final model then was applied to predict serum vancomycin concentrations on validation group. Predictive performance revealed a bias of −1.43 mg/L (95% CI: −5.82–2.99 and a precision of 12.2 mg/L (95% CI: −1.60–26.16. In conclusion, population pharmacokinetic of vancomycin in Thai adult patients was developed. The model could be used to create vancomycin dosage regimen in the type of patient similar with the present study.

  2. Pharmacokinetics of icodextrin in peritoneal dialysis patients.

    Science.gov (United States)

    Moberly, James B; Mujais, Salim; Gehr, Todd; Hamburger, Richard; Sprague, Stuart; Kucharski, Andrew; Reynolds, Robin; Ogrinc, Francis; Martis, Leo; Wolfson, Marsha

    2002-10-01

    Pharmacokinetics of icodextrin in peritoneal dialysis patients. Icodextrin is a glucose polymer osmotic agent used to provide sustained ultrafiltration during long peritoneal dialysis (PD) dwells. A number of studies have evaluated the steady-state blood concentrations of icodextrin during repeated use; however, to date the pharmacokinetics of icodextrin have not been well studied. The current study was conducted to determine the absorption, plasma kinetics and elimination of icodextrin and metabolites following a single icodextrin exchange. Thirteen PD patients were administered 2.0 L of solution containing 7.5% icodextrin for a 12-hour dwell. Icodextrin (total of all glucose polymers) and specific polymers with degrees of polymerization ranging from two to seven (DP2 to DP7) were measured in blood, urine and dialysate during the dwell and after draining the solution from the peritoneal cavity. A median of 40.1% (60.24 g) of the total administered dose (150 g) was absorbed during the 12-hour dwell. Plasma levels of icodextrin and metabolites rose during the dwell and declined after drain, closely corresponding to the one-compartment pharmacokinetic model assuming zero-order absorption and first-order elimination. Peak plasma concentrations (median C peak = 2.23 g/L) were observed at the end of the dwell (median Tmax = 12.7 h) and were significantly correlated with patients' body weight (R2 = 0.805, P insulin or glucose levels during icodextrin administration, indicating that icodextrin does not result in hyperglycemia or hyperinsulinemia as occurs during dextrose-based dialysis. Serum sodium and chloride declined in parallel with the rise in plasma levels of icodextrin, supporting the hypothesis that these electrolyte changes are the result of the increased plasma osmolality due to the presence of icodextrin metabolites. The pharmacokinetics of icodextrin in blood following intraperitoneal administration conforms to a simple, single-compartment model that can be

  3. Mode of action based risk assessment of the botanical food-borne alkenylbenzene apiol from parsley using physiologically based kinetic (PBK) modelling and read-across from safrole.

    Science.gov (United States)

    Alajlouni, Abdalmajeed M; Al Malahmeh, Amer J; Kiwamoto, Reiko; Wesseling, Sebastiaan; Soffers, Ans E M F; Al-Subeihi, Ala A A; Vervoort, Jacques; Rietjens, Ivonne M C M

    2016-03-01

    The present study developed physiologically-based kinetic (PBK) models for the alkenylbenzene apiol in order to facilitate risk assessment based on read-across from the related alkenylbenzene safrole. Model predictions indicate that in rat liver the formation of the 1'-sulfoxy metabolite is about 3 times lower for apiol than for safrole. These data support that the lower confidence limit of the benchmark dose resulting in a 10% extra cancer incidence (BMDL10) that would be obtained in a rodent carcinogenicity study with apiol may be 3-fold higher for apiol than for safrole. These results enable a preliminary risk assessment for apiol, for which tumor data are not available, using a BMDL10 value of 3 times the BMDL10 for safrole. Based on an estimated BMDL10 for apiol of 5.7-15.3 mg/kg body wt per day and an estimated daily intake of 4 × 10(-5) mg/kg body wt per day, the margin of exposure (MOE) would amount to 140,000-385,000. This indicates a low priority for risk management. The present study shows how PBK modelling can contribute to the development of alternatives for animal testing, facilitating read-across from compounds for which in vivo toxicity studies on tumor formation are available to compounds for which these data are unavailable.

  4. Evaluating functional roles of phase resetting in generation of adaptive human bipedal walking with a physiologically based model of the spinal pattern generator.

    Science.gov (United States)

    Aoi, Shinya; Ogihara, Naomichi; Funato, Tetsuro; Sugimoto, Yasuhiro; Tsuchiya, Kazuo

    2010-05-01

    The central pattern generators (CPGs) in the spinal cord strongly contribute to locomotor behavior. To achieve adaptive locomotion, locomotor rhythm generated by the CPGs is suggested to be functionally modulated by phase resetting based on sensory afferent or perturbations. Although phase resetting has been investigated during fictive locomotion in cats, its functional roles in actual locomotion have not been clarified. Recently, simulation studies have been conducted to examine the roles of phase resetting during human bipedal walking, assuming that locomotion is generated based on prescribed kinematics and feedback control. However, such kinematically based modeling cannot be used to fully elucidate the mechanisms of adaptation. In this article we proposed a more physiologically based mathematical model of the neural system for locomotion and investigated the functional roles of phase resetting. We constructed a locomotor CPG model based on a two-layered hierarchical network model of the rhythm generator (RG) and pattern formation (PF) networks. The RG model produces rhythm information using phase oscillators and regulates it by phase resetting based on foot-contact information. The PF model creates feedforward command signals based on rhythm information, which consists of the combination of five rectangular pulses based on previous analyses of muscle synergy. Simulation results showed that our model establishes adaptive walking against perturbing forces and variations in the environment, with phase resetting playing important roles in increasing the robustness of responses, suggesting that this mechanism of regulation may contribute to the generation of adaptive human bipedal locomotion.

  5. Inversion analysis of estimating interannual variability and its uncertainties in biotic and abiotic parameters of a parsimonious physiologically based model after wind disturbance

    Science.gov (United States)

    Toda, M.; Yokozawa, M.; Richardson, A. D.; Kohyama, T.

    2011-12-01

    The effects of wind disturbance on interannual variability in ecosystem CO2 exchange have been assessed in two forests in northern Japan, i.e., a young, even-aged, monocultured, deciduous forest and an uneven-aged mixed forest of evergreen and deciduous trees, including some over 200 years old using eddy covariance (EC) measurements during 2004-2008. The EC measurements have indicated that photosynthetic recovery of trees after a huge typhoon occurred during early September in 2004 activated annual carbon uptake of both forests due to changes in physiological response of tree leaves during their growth stages. However, little have been resolved about what biotic and abiotic factors regulated interannual variability in heat, water and carbon exchange between an atmosphere and forests. In recent years, an inverse modeling analysis has been utilized as a powerful tool to estimate biotic and abiotic parameters that might affect heat, water and CO2 exchange between the atmosphere and forest of a parsimonious physiologically based model. We conducted the Bayesian inverse model analysis for the model with the EC measurements. The preliminary result showed that the above model-derived NEE values were consistent with observed ones on the hourly basis with optimized parameters by Baysian inversion. In the presentation, we would examine interannual variability in biotic and abiotic parameters related to heat, water and carbon exchange between the atmosphere and forests after disturbance by typhoon.

  6. Use of physiologically based kinetic (PBK) modeling to study interindividual human variation and species differences in plasma concentrations of quercetin and its metabolites.

    Science.gov (United States)

    Boonpawa, Rungnapa; Moradi, Nooshin; Spenkelink, Albertus; Rietjens, Ivonne M C M; Punt, Ans

    2015-12-15

    Biological activities of flavonoids in vivo ultimately depend on the systemic bioavailability of the aglycones and their metabolites. We aimed to develop physiologically based kinetic (PBK) models to predict plasma concentrations of the flavonoid quercetin and its metabolites in individual human subjects and to define species differences compared with male rat. The human models were developed based on in vitro metabolic parameters derived from incubations with pooled and 20 individual human tissue fractions and by fitting kinetic parameters to available in vivo data. The outcomes obtained were compared to a previously developed model for quercetin and its metabolites formation in male rat. Quercetin-3'-O-glucuronide was predicted to be the major circulating metabolite in 19 out of 20 individuals, while in male rat di- and tri-conjugates of quercetin containing a glucuronic acid, sulfate and/or methyl moieties are the major metabolites. Significant species differences occur in major circulating metabolites of quercetin suggesting that rat is not an adequate model to study effects of quercetin in man. The defined PBK models can be used to guide the experimental design of in vitro experiments with flavonoids, especially to better take into account the relevance of metabolism and the contribution of metabolites to the biological activity in humans.

  7. Physiologically-based, predictive analytics using the heart-rate-to-Systolic-Ratio significantly improves the timeliness and accuracy of sepsis prediction compared to SIRS.

    Science.gov (United States)

    Danner, Omar K; Hendren, Sandra; Santiago, Ethel; Nye, Brittany; Abraham, Prasad

    2017-04-01

    Enhancing the efficiency of diagnosis and treatment of severe sepsis by using physiologically-based, predictive analytical strategies has not been fully explored. We hypothesize assessment of heart-rate-to-systolic-ratio significantly increases the timeliness and accuracy of sepsis prediction after emergency department (ED) presentation. We evaluated the records of 53,313 ED patients from a large, urban teaching hospital between January and June 2015. The HR-to-systolic ratio was compared to SIRS criteria for sepsis prediction. There were 884 patients with discharge diagnoses of sepsis, severe sepsis, and/or septic shock. Variations in three presenting variables, heart rate, systolic BP and temperature were determined to be primary early predictors of sepsis with a 74% (654/884) accuracy compared to 34% (304/884) using SIRS criteria (p sepsis identification via detection of variations in HR-to-systolic ratio. This approach may lead to earlier sepsis workup and life-saving interventions. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Understanding Variability in Posaconazole Exposure Using an Integrated Population Pharmacokinetic Analysis

    OpenAIRE

    Dolton, Michael J; Brüggemann, Roger J. M.; Burger, David M.; McLachlan, Andrew J

    2014-01-01

    Posaconazole oral suspension is widely used for antifungal prophylaxis and treatment in immunocompromised patients, with highly variable pharmacokinetics reported in patients due to inconsistent oral absorption. This study aimed to characterize the pharmacokinetics of posaconazole in adults and investigate factors that influence posaconazole pharmacokinetics byusing a population pharmacokinetic approach. Nonlinear mixed-effects modeling was undertaken for two posaconazole studies in patients ...

  9. Pharmacokinetic evaluation of the equivalency of gavage, dietary, and drinking water exposure to manganese in F344 rats.

    Science.gov (United States)

    Foster, Melanie L; Bartnikas, Thomas B; Johnson, Laura C; Herrera, Carolina; Pettiglio, Michael A; Keene, Athena M; Taylor, Michael D; Dorman, David C

    2015-06-01

    Concerns exist as to whether individuals may be at greater risk for neurotoxicity following increased manganese (Mn) oral intake. The goals of this study were to determine the equivalence of 3 methods of oral exposure and the rate (mg Mn/kg/day) of exposure. Adult male rats were allocated to control diet (10 ppm), high manganese diet (200 ppm), manganese-supplemented drinking water, and manganese gavage treatment groups. Animals in the drinking water and gavage groups were given the 10 ppm manganese diet and supplemented with manganese chloride (MnCl(2)) in drinking water or once-daily gavage to provide a daily manganese intake equivalent to that seen in the high-manganese diet group. No statistically significant difference in body weight gain or terminal body weights was seen. Rats were anesthetized following 7 and 61 exposure days, and samples of bile and blood were collected. Rats were then euthanized and striatum, olfactory bulb, frontal cortex, cerebellum, liver, spleen, and femur samples were collected for chemical analysis. Hematocrit was unaffected by manganese exposure. Liver and bile manganese concentrations were elevated in all treatment groups on day 61 (relative to controls). Increased cerebellum manganese concentrations were seen in animals from the high-manganese diet group (day 61, relative to controls). Increased (relative to all treatment groups) femur, striatum, cerebellum, frontal cortex, and olfactory bulb manganese concentrations were also seen following gavage suggesting that dose rate is an important factor in the pharmacokinetics of oral manganese. These data will be used to refine physiologically based pharmacokinetic models, extending their utility for manganese risk assessment by including multiple dietary exposures. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  10. COMPARATIVE COMPUTATIONAL MODELING OF AIRFLOWS AND VAPOR DOSIMETY IN THE RESPIRATORY TRACTS OF RAT, MONKEY, AND HUMAN

    Energy Technology Data Exchange (ETDEWEB)

    Corley, Richard A.; Kabilan, Senthil; Kuprat, Andrew P.; Carson, James P.; Minard, Kevin R.; Jacob, Rick E.; Timchalk, Charles; Glenny, Robb W.; Pipavath, Sudhaker; Cox, Timothy C.; Wallis, Chris; Larson, Richard; Fanucchi, M.; Postlewait, Ed; Einstein, Daniel R.

    2012-07-01

    Coupling computational fluid dynamics (CFD) with physiologically based pharmacokinetic (PBPK) models is useful for predicting site-specific dosimetry of airborne materials in the respiratory tract and elucidating the importance of species differences in anatomy, physiology, and breathing patterns. Historically, these models were limited to discrete regions of the respiratory system. CFD/PBPK models have now been developed for the rat, monkey, and human that encompass airways from the nose or mouth to the lung. A PBPK model previously developed to describe acrolein uptake in nasal tissues was adapted to the extended airway models as an example application. Model parameters for each anatomic region were obtained from the literature, measured directly, or estimated from published data. Airflow and site-specific acrolein uptake patterns were determined under steadystate inhalation conditions to provide direct comparisons with prior data and nasalonly simulations. Results confirmed that regional uptake was dependent upon airflow rates and acrolein concentrations with nasal extraction efficiencies predicted to be greatest in the rat, followed by the monkey, then the human. For human oral-breathing simulations, acrolein uptake rates in oropharyngeal and laryngeal tissues were comparable to nasal tissues following nasal breathing under the same exposure conditions. For both breathing modes, higher uptake rates were predicted for lower tracheo-bronchial tissues of humans than either the rat or monkey. These extended airway models provide a unique foundation for comparing dosimetry across a significantly more extensive range of conducting airways in the rat, monkey, and human than prior CFD models.

  11. Pharmacokinetics of rilmenidine in healthy subjects

    Energy Technology Data Exchange (ETDEWEB)

    Genissel, P.; Bromet, N.; Fourtillan, J.B.; Mignot, A.; Albin, H.

    1988-02-24

    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.

  12. 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.

  13. 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.

  14. 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 pregnancy (568 ± 273 L/h, n = 8, P pregnancy (P pregnancy-induced changes in 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.

  15. 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.

  16. Drug pharmacokinetics and pharmacodynamics: Technological considerations

    Energy Technology Data Exchange (ETDEWEB)

    Fowler, J.S.; Volkow, N.D.; Wolf, A.P.

    1992-01-01

    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.

  17. Drug pharmacokinetics and pharmacodynamics: Technological considerations

    Energy Technology Data Exchange (ETDEWEB)

    Fowler, J.S.; Volkow, N.D.; Wolf, A.P.

    1992-12-31

    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.

  18. Pharmacokinetic and pharmacodynamic profile of ceftobiprole.

    Science.gov (United States)

    Lodise, Thomas P; Patel, Nimish; Renaud-Mutart, Amy; Gorodecky, Evgeny; Fritsche, Thomas R; Jones, Ronald N

    2008-05-01

    A new addition to our therapeutic armamentarium against antimicrobial-resistant pathogens is ceftobiprole, a novel broad-spectrum cephalosporin currently undergoing investigation for the treatment of complicated skin and skin structure infections (cSSSIs) and nosocomial pneumonia. Several qualities make ceftobiprole uniquely suited for early empiric use. A major advance from contemporary beta-lactams, ceftobiprole has a high affinity for the altered penicillin-binding protein (PBP) 2' (2a), making it active against methicillin-resistant staphylococci. It also binds avidly to the relevant PBPs of most Gram-positive and Gram-negative pathogens, and is resistant to hydrolysis by many beta-lactamases, making it uniquely suited for infections caused by Gram-positive and mixed Gram-negative organisms. This review summarizes the pharmacokinetic and pharmacodynamic profile of ceftobiprole and addresses in detail the population pharmacokinetic and Monte Carlo simulation analyses used to determine the candidate doses for the cSSSI and nosocomial pneumonia phase 3 clinical trials. This review will also address the ability of the selected dosing regimens in providing adequate free drug concentrations in excess of the MICs against a contemporary group of bacterial isolates from a global resistance surveillance study.

  19. Pharmacokinetics of sevoflurane uptake into the brain.

    Science.gov (United States)

    Turner, M J; McCulloch, T J; Kennedy, R R; Baker, A B

    2004-12-01

    Two recent studies have examined the pharmacokinetics of sevoflurane in adults. Lu et al.(Pharmacokinetics of sevoflurane uptake into the brain and body, Anaesthesia 2003; 58: 951-6) observed that jugular bulb sevoflurane concentration initially rose unexpectedly rapidly and then approached arterial concentrations unexpectedly slowly, suggesting that a blood-brain diffusion barrier exists. They also observed a large alveolar-arterial sevoflurane gradient, suggesting that an alveolar-arterial diffusion barrier exists. Nakamura et al. (Predicted sevoflurane partial pressure in the brain with an uptake and distribution model: Comparison with the measured value in internal jugular vein blood. Journal of Clinical Monitoring and Computing 1999; 15: 299-305) found no diffusion barriers. We used a computer model to analyse both data sets and show that the observations of Lu et al. can be explained by contamination of jugular samples with extracerebral blood. It is possible that the alveolar-arterial gradients observed by Lu et al. are due to discrepancies in conversions between blood concentrations and gas partial pressures. Our study suggests that there is no blood-brain diffusion barrier for sevoflurane and that the data of Lu et al. must be interpreted with caution.

  20. Benzodiazepines in epilepsy: pharmacology and pharmacokinetics.

    Science.gov (United States)

    Riss, J; Cloyd, J; Gates, J; Collins, S

    2008-08-01

    Benzodiazepines (BZDs) remain important agents in the management of epilepsy. They are drugs of first choice for status epilepticus and seizures associated with post-anoxic insult and are also frequently used in the treatment of febrile, acute repetitive and alcohol withdrawal seizures. Clinical advantages of these drugs include rapid onset of action, high efficacy rates and minimal toxicity. Benzodiazepines are used in a variety of clinical situations because they have a broad spectrum of clinical activity and can be administered via several routes. Potential shortcomings of BZDs include tolerance, withdrawal symptoms, adverse events, such as cognitive impairment and sedation, and drug interactions. Benzodiazepines differ in their pharmacologic effects and pharmacokinetic profiles, which dictate how the drugs are used. Among the approximately 35 BZDs available, a select few are used for the management of seizures and epilepsy: clobazam, clonazepam, clorazepate, diazepam, lorazepam and midazolam. Among these BZDs, clorazepate has a unique profile that includes a long half-life of its active metabolite and slow onset of tolerance. Additionally, the pharmacokinetic characteristics of clorazepate (particularly the sustained-release formulation) could theoretically help minimize adverse events. However, larger, controlled studies of clorazepate are needed to further examine its role in the treatment of patients with epilepsy.

  1. Adjustment of endogenous concentrations in pharmacokinetic modeling.

    Science.gov (United States)

    Bauer, Alexander; Wolfsegger, Martin J

    2014-12-01

    Estimating pharmacokinetic parameters in the presence of an endogenous concentration is not straightforward as cross-reactivity in the analytical methodology prevents differentiation between endogenous and dose-related exogenous concentrations. This article proposes a novel intuitive modeling approach which adequately adjusts for the endogenous concentration. Monte Carlo simulations were carried out based on a two-compartment population pharmacokinetic (PK) model fitted to real data following intravenous administration. A constant and a proportional error model were assumed. The performance of the novel model and the method of straightforward subtraction of the observed baseline concentration from post-dose concentrations were compared in terms of terminal half-life, area under the curve from 0 to infinity, and mean residence time. Mean bias in PK parameters was up to 4.5 times better with the novel model assuming a constant error model and up to 6.5 times better assuming a proportional error model. The simulation study indicates that this novel modeling approach results in less biased and more accurate PK estimates than straightforward subtraction of the observed baseline concentration and overcomes the limitations of previously published approaches.

  2. 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.

  3. The pharmacokinetics and pharmacodynamics of iron preparations.

    Science.gov (United States)

    Geisser, Peter; Burckhardt, Susanna

    2011-01-04

    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.

  4. [Therapeutic monitoring: analytic, pharmacokinetic and clinical aspects].

    Science.gov (United States)

    Marquet, P

    1999-01-01

    This paper gives an overview of present aspects and future prospects of therapeutic drug monitoring (TDM). The main aims of TDM are to avoid therapeutic failures due to bad compliance or too low dose of a given drug, as well as adverse or toxic effects due to an excessive dose. The therapeutic drugs frequently monitored depend on the country, but are generally few. For some of these drugs or for others, only patients at risk or belonging to particular sub-populations for a given drug, need TDM. A pre-analytical management is necessary, comprising a correct information of the physician, concerning the nature of the sample to collect and the clinical data necessary to the interpretation, as well as their recording; the control of the sample routing and storing conditions. Nowadays, drug analyses are essentially performed using immunochemical techniques, rapid and easy to operate but limited to a small number of drugs, and chromatographic methods, more specific and adaptable to almost any therapeutic drug and financially and technically more and more accessible. The interpretation of analytical results is a most important part of TDM, which requires knowledge of clinical data, precise collection time, co-administered treatments, and to dispose of a previously defined therapeutic range or target concentration, adapted to the population to which the patient belongs; the limitations of the analytical technique used must also be considered. Clinical pharmacokinetics is a further step in the use of analytical results, allowing the prediction of an efficient dose and administration schedule in one step, using a limited number of blood samples and generally a Bayesian estimation algorithm, readily available through commercial software dedicated to a few drugs in different reference populations. The pharmacokinetic characteristics of different populations and the validation of bayesian estimation have also been published for a number of drugs, sometimes by pharmaceutical

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

    Science.gov (United States)

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

    2017-02-01

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

  6. Development of a Combined In Vitro Physiologically Based Kinetic (PBK) and Monte Carlo Modelling Approach to Predict Interindividual Human Variation in Phenol-Induced Developmental Toxicity.

    Science.gov (United States)

    Strikwold, Marije; Spenkelink, Bert; Woutersen, Ruud A; Rietjens, Ivonne M C M; Punt, Ans

    2017-06-01

    With our recently developed in vitro physiologically based kinetic (PBK) modelling approach, we could extrapolate in vitro toxicity data to human toxicity values applying PBK-based reverse dosimetry. Ideally information on kinetic differences among human individuals within a population should be considered. In the present study, we demonstrated a modelling approach that integrated in vitro toxicity data, PBK modelling and Monte Carlo simulations to obtain insight in interindividual human kinetic variation and derive chemical specific adjustment factors (CSAFs) for phenol-induced developmental toxicity. The present study revealed that UGT1A6 is the primary enzyme responsible for the glucuronidation of phenol in humans followed by UGT1A9. Monte Carlo simulations were performed taking into account interindividual variation in glucuronidation by these specific UGTs and in the oral absorption coefficient. Linking Monte Carlo simulations with PBK modelling, population variability in the maximum plasma concentration of phenol for the human population could be predicted. This approach provided a CSAF for interindividual variation of 2.0 which covers the 99th percentile of the population, which is lower than the default safety factor of 3.16 for interindividual human kinetic differences. Dividing the dose-response curve data obtained with in vitro PBK-based reverse dosimetry, with the CSAF provided a dose-response curve that reflects the consequences of the interindividual variability in phenol kinetics for the developmental toxicity of phenol. The strength of the presented approach is that it provides insight in the effect of interindividual variation in kinetics for phenol-induced developmental toxicity, based on only in vitro and in silico testing. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  7. Prediction of in vivo developmental toxicity of all-trans-retinoic acid based on in vitro toxicity data and in silico physiologically based kinetic modeling.

    Science.gov (United States)

    Louisse, Jochem; Bosgra, Sieto; Blaauboer, Bas J; Rietjens, Ivonne M C M; Verwei, Miriam

    2015-07-01

    The use of laboratory animals for toxicity testing in chemical safety assessment meets increasing ethical, economic and legislative constraints. The development, validation and application of reliable alternatives for in vivo toxicity testing are therefore urgently needed. In order to use toxicity data obtained from in vitro assays for risk assessment, in vitro concentration-response data need to be translated into in vivo dose-response data that are needed to obtain points of departure for risk assessment, like a benchmark dose (BMD). In the present study, we translated in vitro concentration-response data of the retinoid all-trans-retinoic acid (ATRA), obtained in the differentiation assay of the embryonic stem cell test, into in vivo dose-response data using a physiologically based kinetic model for rat and human that is mainly based on kinetic model parameter values derived using in vitro techniques. The predicted in vivo dose-response data were used for BMD modeling, and the obtained BMDL10 values [lower limit of the 95 % confidence interval on the BMD at which a benchmark response equivalent to a 10 % effect size (BMR10) is reached (BMD10)] for rat were compared with BMDL10 values derived from in vivo developmental toxicity data in rats reported in the literature. The results show that the BMDL10 values from predicted dose-response data differ about sixfold from the BMDL10 values obtained from in vivo data, pointing at the feasibility of using a combined in vitro-in silico approach for defining a point of departure for toxicological risk assessment.

  8. A physiologically based in silico model for trans-2-hexenal detoxification and DNA adduct formation in human including interindividual variation indicates efficient detoxification and a negligible genotoxicity risk.

    Science.gov (United States)

    Kiwamoto, R; Spenkelink, A; Rietjens, I M C M; Punt, A

    2013-09-01

    A number of α,β-unsaturated aldehydes are present in food both as natural constituents and as flavouring agents. Their reaction with DNA due to their electrophilic α,β-unsaturated aldehyde moiety may result in genotoxicity as observed in some in vitro models, thereby raising a safety concern. A question that remains is whether in vivo detoxification would be efficient enough to prevent DNA adduct formation and genotoxicity. In this study, a human physiologically based kinetic/dynamic (PBK/D) model of trans-2-hexenal (2-hexenal), a selected model α,β-unsaturated aldehyde, was developed to examine dose-dependent detoxification and DNA adduct formation in humans upon dietary exposure. The kinetic model parameters for detoxification were quantified using relevant pooled human tissue fractions as well as tissue fractions from 11 different individual subjects. In addition, a Monte Carlo simulation was performed so that the impact of interindividual variation in 2-hexenal detoxification on the DNA adduct formation in the population as a whole could be examined. The PBK/D model revealed that DNA adduct formation due to 2-hexenal exposure was 0.039 adducts/10⁸ nucleotides (nt) at the estimated average 2-hexenal dietary intake (0.04 mg 2-hexenal/kg bw) and 0.18 adducts/10⁸ nt at the 95th percentile of the dietary intake (0.178 mg 2-hexenal/kg bw) in the most sensitive people. These levels are three orders of magnitude lower than natural background DNA adduct levels that have been reported in disease-free humans (6.8-110 adducts/10⁸ nt), suggesting that the genotoxicity risk for the human population at realistic dietary daily intakes of 2-hexenal may be negligible.

  9. Towards a physiology-based measure of pain: patterns of human brain activity distinguish painful from non-painful thermal stimulation.

    Directory of Open Access Journals (Sweden)

    Justin E Brown

    Full Text Available Pain often exists in the absence of observable injury; therefore, the gold standard for pain assessment has long been self-report. Because the inability to verbally communicate can prevent effective pain management, research efforts have focused on the development of a tool that accurately assesses pain without depending on self-report. Those previous efforts have not proven successful at substituting self-report with a clinically valid, physiology-based measure of pain. Recent neuroimaging data suggest that functional magnetic resonance imaging (fMRI and support vector machine (SVM learning can be jointly used to accurately assess cognitive states. Therefore, we hypothesized that an SVM trained on fMRI data can assess pain in the absence of self-report. In fMRI experiments, 24 individuals were presented painful and nonpainful thermal stimuli. Using eight individuals, we trained a linear SVM to distinguish these stimuli using whole-brain patterns of activity. We assessed the performance of this trained SVM model by testing it on 16 individuals whose data were not used for training. The whole-brain SVM was 81% accurate at distinguishing painful from non-painful stimuli (p<0.0000001. Using distance from the SVM hyperplane as a confidence measure, accuracy was further increased to 84%, albeit at the expense of excluding 15% of the stimuli that were the most difficult to classify. Overall performance of the SVM was primarily affected by activity in pain-processing regions of the brain including the primary somatosensory cortex, secondary somatosensory cortex, insular cortex, primary motor cortex, and cingulate cortex. Region of interest (ROI analyses revealed that whole-brain patterns of activity led to more accurate classification than localized activity from individual brain regions. Our findings demonstrate that fMRI with SVM learning can assess pain without requiring any communication from the person being tested. We outline tasks that should be

  10. Physiologically-based toxicokinetic model for cadmium using Markov-chain Monte Carlo analysis of concentrations in blood, urine, and kidney cortex from living kidney donors.

    Science.gov (United States)

    Fransson, Martin Niclas; Barregard, Lars; Sallsten, Gerd; Akerstrom, Magnus; Johanson, Gunnar

    2014-10-01

    The health effects of low-level chronic exposure to cadmium are increasingly recognized. To improve the risk assessment, it is essential to know the relation between cadmium intake, body burden, and biomarker levels of cadmium. We combined a physiologically-based toxicokinetic (PBTK) model for cadmium with a data set from healthy kidney donors to re-estimate the model parameters and to test the effects of gender and serum ferritin on systemic uptake. Cadmium levels in whole blood, blood plasma, kidney cortex, and urinary excretion from 82 men and women were used to calculate posterior distributions for model parameters using Markov-chain Monte Carlo analysis. For never- and ever-smokers combined, the daily systemic uptake was estimated at 0.0063 μg cadmium/kg body weight in men, with 35% increased uptake in women and a daily uptake of 1.2 μg for each pack-year per calendar year of smoking. The rate of urinary excretion from cadmium accumulated in the kidney was estimated at 0.000042 day(-1), corresponding to a half-life of 45 years in the kidneys. We have provided an improved model of cadmium kinetics. As the new parameter estimates derive from a single study with measurements in several compartments in each individual, these new estimates are likely to be more accurate than the previous ones where the data used originated from unrelated data sets. The estimated urinary excretion of cadmium accumulated in the kidneys was much lower than previous estimates, neglecting this finding may result in a marked under-prediction of the true kidney burden.

  11. Integrating in vitro data and physiologically based kinetic (PBK) modelling to assess the in vivo potential developmental toxicity of a series of phenols.

    Science.gov (United States)

    Strikwold, Marije; Spenkelink, Bert; de Haan, Laura H J; Woutersen, Ruud A; Punt, Ans; Rietjens, Ivonne M C M

    2017-05-01

    Toxicity outcomes derived in vitro do not always reflect in vivo toxicity values, which was previously observed for a series of phenols tested in the embryonic stem cell test (EST). Translation of in vitro data to the in vivo situation is therefore an important, but still limiting step for the use of in vitro toxicity outcomes in the safety assessment of chemicals. The aim of the present study was to translate in vitro embryotoxicity data for a series of phenols to in vivo developmental toxic potency values for the rat by physiologically based kinetic (PBK) modelling-based reverse dosimetry. To this purpose, PBK models were developed for each of the phenols. The models were parameterised with in vitro-derived values defining metabolism and transport of the compounds across the intestinal and placental barrier and with in silico predictions and data from the literature. Using PBK-based reverse dosimetry, in vitro concentration-response curves from the EST were translated into in vivo dose-response curves from which points of departure (PoDs) were derived. The predicted PoDs differed less than 3.6-fold from PoDs derived from in vivo toxicity data for the phenols available in the literature. Moreover, the in vitro PBK-based reverse dosimetry approach could overcome the large disparity that was observed previously between the in vitro and the in vivo relative potency of the series of phenols. In conclusion, this study shows another proof-of-principle that the in vitro PBK approach is a promising strategy for non-animal-based safety assessment of chemicals.

  12. Combining in vitro embryotoxicity data with physiologically based kinetic (PBK) modelling to define in vivo dose-response curves for developmental toxicity of phenol in rat and human.

    Science.gov (United States)

    Strikwold, Marije; Spenkelink, Bert; Woutersen, Ruud A; Rietjens, Ivonne M C M; Punt, Ans

    2013-09-01

    In vitro assays are often used for the hazard characterisation of compounds, but their application for quantitative risk assessment purposes is limited. This is because in vitro assays cannot provide a complete in vivo dose-response curve from which a point of departure (PoD) for risk assessment can be derived, like the no observed adverse effect level (NOAEL) or the 95 % lower confidence limit of the benchmark dose (BMDL). To overcome this constraint, the present study combined in vitro data with a physiologically based kinetic (PBK) model applying reverse dosimetry. To this end, embryotoxicity of phenol was evaluated in vitro using the embryonic stem cell test (EST), revealing a concentration-dependent inhibition of differentiation into beating cardiomyocytes. In addition, a PBK model was developed on the basis of in vitro and in silico data and data available from the literature only. After evaluating the PBK model performance, effective concentrations (ECx) obtained with the EST served as an input for in vivo plasma concentrations in the PBK model. Applying PBK-based reverse dosimetry provided in vivo external effective dose levels (EDx) from which an in vivo dose-response curve and a PoD for risk assessment were derived. The predicted PoD lies within the variation of the NOAELs obtained from in vivo developmental toxicity data from the literature. In conclusion, the present study showed that it was possible to accurately predict a PoD for the risk assessment of phenol using in vitro toxicity data combined with reverse PBK modelling.

  13. Pharmacokinetic Models for the Elimination of Drinking Water Contaminants from the Body,

    Science.gov (United States)

    1990-03-01

    for the MFO and GSH pathways in B6C3F1 mice .111-5 111-4 Log (total area under curve) for animals dosed with trichloroethylene in oil plotted against...values 8XE - Ethylene glycol monomethyl ethgr EPA = Environmental Protection Agency exp - Exponential function g - Gram GSH = Glutathione S-transferase...the laboratory are often available. The earliest PBPK models were developed for cancer I chemotherapeutic agents such as methotraxate and cisplatin

  14. The influence of cardiovascular physiology on dose/pharmacokinetic and pharmacokinetic/pharmacodynamic relationships.

    Science.gov (United States)

    Fagiolino, Pietro; Eiraldi, Rosa; Vázquez, Marta

    2006-01-01

    Inter- and intraindividual variability in the relationship between dose and clinical--or pharmacodynamic--response of a drug can be analysed in two steps: firstly, by considering the plasma pharmacokinetic response to a given dose and, secondly, by the connection between both pharmacokinetic and pharmacodynamic responses. As the cardiovascular system is the means of transport of endogenous and exogenous substances, blood flow fraction destined to each organ determines the relative mass of solute in plasma, which is constantly in contact with the tissue. Hence, not only the rate but also the extent of drug transfer would be increased when tissues are irrigated by a higher fraction of cardiac output. Aging and circadian rhythms present similar cardiac output distribution patterns when moving from young to aged adult and from nocturnal to diurnal hours. These two changes lead to an increased blood flow delivery to the extra-splanchnic-renal region in the elderly and in the morning, but with a decreased cardiac output in aged individuals and an increased one during the day. This scenario allows us to forecast substance concentrations outside the blood vessels, which are responsible for the extent of drug elimination and the intensity of drug effect. So available data on disposition and pharmacodynamics of drugs might be explained from another point of view that challenges current knowledge. Furthermore, the administration of cardiovascular active drugs might reverse the chronological sequence between pharmacokinetic and pharmacodynamic responses, since they could modify blood flow distribution.

  15. CYP3A5 polymorphism effect on cyclosporine pharmacokinetics in living donor renal transplant recipients: analysis by population pharmacokinetics.

    Science.gov (United States)

    Song, Joohan; Kim, Myeong Gyu; Choi, Boyoon; Han, Na Young; Yun, Hwi-Yeol; Yoon, Jeong-Hyun; Oh, Jung Mi

    2012-09-01

    Cyclosporine is often used to prevent allograft rejection in renal transplant recipients. However, cyclosporine has a narrow therapeutic window and large variability in its pharmacokinetics. Individual characteristics and genetic polymorphisms can cause the variation. Hence, it is important to determine the cause(s) of the variation in cyclosporine pharmacokinetics. To our knowledge, this is the first reported population pharmacokinetic study of cyclosporine in living donor renal transplant recipients that considered the genetic polymorphism as a covariate. To build a population pharmacokinetic model of cyclosporine in living donor renal transplant recipients and identify covariates including CYP3A5*3, ABCB1 genetic polymorphisms that affect cyclosporine pharmacokinetic parameters. Clinical characteristics and cyclosporine concentration data for 69 patients who received cyclosporine-based immunosuppressive therapy after living donor renal transplantation were collected retrospectively for up to 400 postoperative days. CYP3A5*1/*3 and ABCB1C1236T, G2677T/A, C3435T geno-typing was performed. A population pharmacokinetic analysis was conducted using a NONMEM program. After building the final model, 1000 bootstrappings were performed to validate the final model. In total, 2034 blood samples were collected. A 1-compartment open model with first-order absorption and elimination was chosen to describe the pharmacokinetics of cyclosporine. A population pharmacokinetic analysis showed that postoperative days, sex, and CYP3A5 genotype significantly affected the pharmacokinetics of cyclosporine. The final estimate of mean clearance was 56 L/h, and the mean volume of distribution was 4650 L. The interindividual variability for these parameters was 22.98% and 51.48%, respectively. Using the present model to calculate the dose of cyclosporine with CYP3A5 genotyping can be possible for the patients whose cyclosporine concentration is not within the therapeutic range even with

  16. Implications of mechanism-based inhibition of CYP2D6 for the pharmacokinetics and toxicity of MDMA.

    Science.gov (United States)

    Yang, Jiansong; Jamei, Masoud; Heydari, Amir; Yeo, Karen R; de la Torre, Rafael; Farré, Magí; Tucker, Geoffrey T; Rostami-Hodjegan, Amin

    2006-11-01

    The aim of this study was to model the in vivo kinetic consequences of mechanism-based inhibition (MBI) of CYP2D6 by 3,4 methylenedioxymethamphetamine (MDMA, ecstasy). A model with physiologically-based components of drug metabolism was developed, taking account of change in the hepatic content of active CYP2D6 due to MBI by MDMA. Based on the in vitro information, plasma concentration time profiles of MDMA after various doses were computed and compared with reported observations. The analysis suggested that a typical recreational MDMA dose could inactivate most hepatic CYP2D6 within an hour, and the return to a basal level of CYP2D6 could take at least 10 days. Thus, the genetic polymorphism of CYP2D6 and coadministration of CYP2D6 inhibitors may have less impact on MDMA pharmacokinetics and the risk of acute toxicity than previously thought. This is consistent with clinical observations that indicate no obvious link between inherited CYP2D6 deficiency and acute MDMA intoxication.

  17. Integrated exposure and dose modeling and analysis system. 1. Formulation and testing of microenvironmental and pharmacokinetic components

    Energy Technology Data Exchange (ETDEWEB)

    Georgopoulos, P.G.; Walia, A.; Roy, A.; Lioy, P.J. [Rutgers Univ. and Univ. of Medicine & Dentistry of New Jersey, Piscataway, NJ (United States)

    1997-01-01

    The conceptual and theoretical framework for a modular integrated Exposure and Dose Modeling and Analysis System (EDMAS) has been formulated, and its stepwise implementation and testing is currently in progress. This system aims to provide state-of-the art tools for performing integrated assessments of exposure and dose for individuals and populations. The integration of modeling components with each other as well as with available environmental, exposure, and toxicological databases in being accomplished with the use of computational tools that include interactive simulation environments, Geographical information Systems, and various data retrieval, management, statistical analysis, and visualization methods. This paper overviews the structure and modular nature of this integrated modeling system and focuses specifically on two of its components: (a) a hierarchy of physiologically based pharmacokinetic models (PBPKM), representing various levels of detail and sophistication, and (b) a family of microenvironmental models, that incorporate complex physical and chemical transformations. The deterministic implementation of these components is also presented here in two test applications: (i) a case study of benzene exposure indoors resulting from the volatilization of contaminated tap water and (ii) a case study of photochemical pollution infiltration indoors, in an office building environment. 77 refs., 6 figs., 2 tabs.

  18. Liposomal anticancer therapy: pharmacokinetic and clinical aspects.

    Science.gov (United States)

    Di Paolo, A

    2004-11-01

    Liposomes, which are vesicles composed of a phospholipid bilayer surrounding an aqueous milieu, represent a new strategy for anticancer drug delivery. Extravasation and accumulation of liposomal drugs within neoplastic tissues are possible because of the leaky vasculature and scarce lymphatic vessels of tumours (the enhanced permeability and retention effect). Furthermore, liposomal chemotherapeutic agents display distinctive pharmacokinetic characteristics, because they possess longer elimination half-lives, reduced clearance and smaller volume of distribution with respect to corresponding free drugs. Taken together, these features lead to highest levels of cytotoxic agents in tumours, as demonstrated in preclinical models and clinical trials, whereas healthy tissues are spared from toxicity. In fact, liposomal drugs (i.e., doxorubicin), alone or in combination with other cytotoxic agents, lead to improved clinical effectiveness and ameliorated toxicity profile with respect to corresponding free drugs when they are used for the treatment of metastatic breast and ovarian cancers, and Kaposi's sarcoma.

  19. Menorest: technical development and pharmacokinetic profile.

    Science.gov (United States)

    Marty, J P

    1996-04-01

    Transdermal application of oestradiol enables the use of lower doses than with the oral drug and avoids first-pass metabolism in the liver. First-generation transdermal delivery systems were of reservoir design. Menorest is one of a new generation of patches, in which oestradiol is dispersed in a micronized suspension throughout the adhesive matrix. This design results in a very thin patch with good cosmetic acceptability. Pharmacokinetic studies indicate that Menorest allows transdermal release of oestradiol at a constant and reproducible rate at doses from 25-100 micrograms/day. There is a linear relationship between the dose of oestradiol administered (which is determined by the surface area of the patch) and the plasma concentration of oestradiol. In contrast to the standard reference reservoir patch, Estraderm, Menorest maintains plasma oestradiol concentrations at or above the target level of 40 pg/ml throughout the 84-h dosing interval.

  20. 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...

  1. Pharmacokinetics and residues of enrofloxacin in chickens.

    Science.gov (United States)

    Anadón, A; Martínez-Larrañaga, M R; Díaz, M J; Bringas, P; Martínez, M A; Fernàndez-Cruz, M L; Fernández, M C; Fernández, R

    1995-04-01

    The pharmacokinetic properties of enrofloxacin were determined in broiler chickens after single IV and orally administered doses of 10 mg/kg of body weight. After IV and oral administrations, the plasma concentration-time graph was characteristic of a two-compartment open model. The elimination half-life and the mean +/- SEM residence time of enrofloxacin for plasma were 10.29 +/- 0.45 and 9.65 +/- 0.48 hours, respectively, after IV administration and 14.23 +/- 0.46 and 15.30 +/- 0.53 hours, respectively, after oral administration. After single oral administration, enrofloxacin was absorbed slowly, with time to reach maximal plasma concentration of 1.64 +/- 0.04 hours. Maximal plasma concentration was 2.44 +/- 0.06 micrograms/ml. Oral bioavailability was found to be 64.0 +/- 0.2%. Statistically significant differences between the 2 routes of administration were found for the pharmacokinetic variables--half-lives of the distribution and elimination phase and apparent volume of distribution and volume of distribution at steady state. In chickens, enrofloxacin was extensively metabolized into ciprofloxacin. Residues of enrofloxacin and the major metabolite ciprofloxacin in fat, kidney, liver, lungs, muscles, and skin were measured in chickens that received an orally administered dose of 10 mg/kg once daily for 4 days. The results indicate that enrofloxacin and ciprofloxacin residues were cleared slowly. Mean muscle, liver, and kidney concentrations of the metabolite ciprofloxacin ranging between 0.020 and 0.075 micrograms/g persisted on day 12 in chickens after dosing. However, at the time of slaughter (12 days), enrofloxacin residues were only detected in liver and mean +/- SEM concentration was 0.025 +/- 0.003 micrograms/g.

  2. 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.

  3. Pharmacokinetics of levobupivacaine following infant spinal anesthesia.

    Science.gov (United States)

    Frawley, Geoff; Hallett, Ben; Velkov, Tony; Bjorksten, Andrew

    2016-06-01

    Infant spinal anesthesia with levobupivacaine has been promoted as a technique to reduce both the risk of postoperative apnea and exposure to volatile anesthesia. There is, however, no pharmacokinetic data to support the currently recommended doses. Our aim was to determine whether infant levobupivacaine spinal anesthesia is associated with plasma concentrations consistent with a low risk of local anesthetic systemic toxicity. This was an open-label pharmacokinetic safety and tolerability study of levobupivacaine spinal anesthesia in infants spinal anesthetic with levobupivacaine 1 mg·kg(-1) in the left lateral position. Spinal anesthesia was successful in 25 (86.2%) of 29 infants (postmenstrual age 36-52 weeks; weight 2.2-4.7 kg). The median (IQR) total venous levobupivacaine plasma concentrations was 0.33 (0.25-0.42) μg·ml(-1) and unbound venous levobupivacaine was 19.5 (14.5-38) ng·ml(-1) . Median protein binding was 93.5 (91.4-96%). Alpha-1 acid glycoprotein concentrations were 0.25 (0.17-0.37) g·l(-1) and albumin concentrations were 29 (24-32) g·l(-1) . Total plasma concentrations and unbound (free) concentration of levobupivacaine were consistently lower than concentrations reported in cases of pediatric local anesthetic toxicity. In a small number of infants requiring a repeat spinal of 1 mg·kg(-1) was also associated with acceptable total and free concentrations. We conclude that levobupivacaine at 1 mg·kg(-1) is associated with no systemic side effects in infants receiving awake spinal anesthesia. © 2016 John Wiley & Sons Ltd.

  4. Clinical pharmacokinetic and pharmacodynamic profile of lacosamide.

    Science.gov (United States)

    Cawello, Willi

    2015-09-01

    Lacosamide-a third-generation antiepileptic drug available in multiple formulations-was first approved in 2008 as adjunctive therapy for partial-onset seizures (POS) in adults. In 2014, lacosamide was approved as monotherapy for POS by the US Food and Drug Administration (FDA). A loading dose administration was approved in 2013 by the European Medicines Agency and in 2014 by the FDA. Unlike traditional sodium channel blockers affecting fast inactivation, lacosamide selectively enhances sodium channel slow inactivation. This mechanism of action results in stabilization of hyperexcitable neuronal membranes, inhibition of neuronal firing and reduction in long-term channel availability without affecting physiological function. Lacosamide is rapidly absorbed, with maximum plasma concentrations reached 0.5-4 h after intake. Oral bioavailability is high (100 %) for a dose up to 800 mg. Bioavailability is irrespective of food intake. Variability in pharmacokinetic parameters is low (coefficients of variation almost all lacosamide is consistent in healthy subjects and across different patient populations studied. Lacosamide elimination from plasma occurs with a terminal half-life of approximately 13 h in young subjects and 14-16 h in elderly subjects; this difference does not impact the dose regimen. Lacosamide produces a pharmacodynamic effect that is closely correlated with its plasma concentration. The pharmacokinetic and pharmacodynamic relationship for reduction of seizure frequency can be described by a maximum effect (E max) model. Lacosamide does not induce or inhibit cytochrome P450 enzymes or known drug transporter systems, has low protein binding of less than 15 % and, because it has multiple elimination pathways, it has no clinically relevant interactions with commonly prescribed medications.

  5. Pharmacokinetics of moxidectin and doramectin in goats.

    Science.gov (United States)

    Escudero, E; Carceles, C M; Diaz, M S; Sutra, J F; Galtier, P; Alvinerie, M

    1999-10-01

    The pharmacokinetic behaviour of doramectin after a single subcutaneous administration and moxidectin following a single subcutaneous or oral drench were studied in goats at a dosage of 0.2 mg kg(-1). The drug plasma concentration-time data were analysed by compartmental pharmacokinetics and non-compartmental methods. Maximum plasma concentrations of moxidectin were attained earlier and to a greater extent than doramectin (shorter t(max) and greater C(max) and AUC than doramectin). MRT of doramectin (4.91 +/- 0.07 days) was also significantly shorter than that of moxidectin (12.43 +/- 1.28 days). Then, the exposure of animals to doramectin in comparison with moxidectin was significantly shorter. The apparent absorption rate of moxidectin was not significantly different after oral and subcutaneous administration but the extent of absorption, reflected in the peak concentration (C(max)) and the area under the concentration-time curve (AUC), of the subcutaneous injection (24.27 +/- 1.99 ng ml(-1) and 136.72 +/- 7.35 ng d ml(-1) respectively) was significantly greater than that of the oral administration (15.53 +/- 1.27 ng ml(-1) and 36.72 +/- 4.05 ng d ml(-1) respectively). The mean residence time (MRT) of moxidectin didn't differ significantly when administered orally or subcutaneously. Therefore low oral bioavailability and the early emergence of resistance in this minor species may be related. These results deserve to be correlated with efficacy studies for refining dosage requirements of endectocides in this species.

  6. 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.

  7. Pharmacokinetics of intrarectal omeprazole in alpacas.

    Science.gov (United States)

    Marmulak, T; Stanley, S; Kass, P H; Wiebe, V; McKemie, D; Pusterla, N

    2010-08-01

    The purpose of this study was to evaluate the pharmacokinetics of omeprazole in three different vehicles when administered rectally to six alpacas. Alpacas were given single doses of omeprazole (4 mg/kg) in a double-blinded, randomized cross-over design with a 1 week washout period. Omeprazole formulations consisted of (1) Treatment A: omeprazole paste mixed in surgical lubricant (2) Treatment B: omeprazole capsule contents in 8.4% sodium bicarbonate and (3) Treatment C: omeprazole capsule contents in surgical lubricant and 8.4% sodium bicarbonate solution. Plasma samples were drawn at 0, 5, 10, 15, 30, 45, 60, 90, 120, 180, 300 and 480 min. Omeprazole plasma concentrations were determined by high-pressure liquid chromatography-mass spectrometry. Pharmacokinetic results demonstrated median peak plasma concentrations (C(max)) of 7.35 (3.2-15.2), 7.30 (1.7-10.9) and 8.65 (1.8-19.3) ng/mL and median area under the concentration curve (AUC((0-180))) of 747 (237-1681) min x ng/mL, 552.9 (39-1063) min x ng/mL, and 972 (107-1841) min x ng/mL for treatments A, B and C, respectively. The median half-lives were similar between groups: 38, 50, and 53 min. As a result of the low measured omeprazole plasma concentrations, it is assumed that rectal absorption of omeprazole is poor in alpacas and not an effective route of administration.

  8. Pharmacokinetics of Intranasal Scopolamine Gel Formulation (Inscop)

    Science.gov (United States)

    Boyd, Jason L.; Du, Brian; Daniels, Vernie; Simmons, Rita; Buckey, Jay; Putcha, Lakshmi

    2009-01-01

    Space Motion Sickness (SMS) is commonly experienced by astronauts and often requires treatment with medications during early flight days of space missions. Orally administered scopolamine is commonly used by astronauts to prevent SMS. Bioavailability of oral (PO) SMS medications is often low and highly variable. Intranasal (IN) administration of medications achieves higher and more reliable bioavailability than from an equivalent PO dose. Methods: To test the safety and reliability of INSCOP, two clinical studies were performed, a dose escalation study and a comparison study administering INSCOP during normal ambulation and head down tilt bedrest. Efficacy was evaluated by testing INSCOP with two, different motion sickness inducing paradigms. Results: Preliminary results indicate that INSCOP demonstrates linear pharmacokinetics and a low side effect profile. In head down tilt bedrest, relative bioavailability of INSCOP was increased for females at both doses (0.2 and 0.4 mg) and for males at the higher dose (0.4 mg) but is reduced at the lower dose (0.2 mg) compared to normal ambulation. INSCOP displays gender specific differences during ABR. One of the treatment efficacy trials conducted at Dartmouth Hitchcock Medical Center demonstrated that INSCOP is efficacious at both doses (0.2 and 0.4 mg) in suppressing motion sickness symptoms as indicated by longer chair ride times with INSCOP administration than with placebo, and efficacy increases with dose. Similar results were seen using another motion sickness simulator, the motion simulator dome, at the Naval Aerospace Medical Research Laboratory, with significantly increased time in the dome in motion-susceptible subjects when using INSCOP compared to untreated controls. Conclusion: Higher bioavailability, linear pharmacokinetics, a low incidence of side effects, and a favorable efficacy profile make INSCOP a desirable formulation for prophylactic and rescue treatment of astronauts in space and military personnel on

  9. Pharmacokinetics of fenoterol in pregnant women.

    Science.gov (United States)

    von Mandach, U; Böni, R; Danko, J; Huch, R; Huch, A

    1995-02-01

    The beta 2-sympathomimetic drug fenoterol (fenoterol hydrobromide, CAS 1944-12-3, Partusisten) is routinely used to inhibit uterine contractions (tocolysis). Investigations of plasma concentrations of those receiving i.v. or oral tocolysis often show different results, both within particular groups of pregnant women and in comparison with non-pregnant persons. The aim of this study was to determine the pharmacokinetics of fenoterol in pregnant women, an important factor which so far had not been known. Four healthy pregnant women with similar weight and gestational age and all with premature labor were administered a continuous intravenous infusion of 4 micrograms fenoterol/min. During and up to 24 hours after the end of the infusion, venous blood samples were taken in order to determine the fenoterol plasma concentrations by radioimmunoassay. From a steady state concentration (css) of 2242 +/- 391 pg/ml (x +/- S.E.), a non-linear two-phased plasma elimination was seen with half-lives t1/2 of 11.40 min and 4.87 h. The area under the plasma concentration-time curve (AUC0-12h) was 6.27 ng/ml x h. The total clearance (Cltot) was 114.8 l/h. These data are nearly the same as the data already known for healthy non-pregnant (male) volunteers. The deviations which are seen in the plasma concentrations in pregnant women in comparison to non-pregnant persons during or after continuous i.v. infusion can therefore not be caused by differences in the pharmacokinetics. Other factors, however, such as body weight and/or gestational age, might influence the results.

  10. Pharmacokinetics of a novel closantel/ivermectin injection in cattle.

    Science.gov (United States)

    Cromie, L; Ferry, M; Couper, A; Fields, C; Taylor, S M

    2006-06-01

    Two studies are described on the pharmacokinetics of a combination anthelmintic consisting of ivermectin and closantel for use in cattle. In the first, the pharmacokinetics of both active drugs in the combination were compared with the formulation with either ivermectin or closantel removed. No differences in the pharmacokinetics were observed, indicating that neither the absorption nor distribution of ivermectin or closantel in the combination were influenced by the presence of the other. In the second study the pharmacokinetics of ivermectin and closantel in the combination product were compared with control formulations of each. No difference was found between the closantel formulations. With ivermectin it was noted that absorption and excretion were more rapid and Cmax higher in the combination, although the AUC of both formulations were not significantly different.

  11. 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.

  12. Pharmacokinetically guided dosing of (high-dose) chemotherapeutic agents

    NARCIS (Netherlands)

    Attema-de Jonge, M.E. (Milly Ellen)

    2004-01-01

    Due to variation in drug distribution, metabolism and elimination processes between patients, systemic exposure to chemotherapeutic agents may be highly variable from patient to patient after administration of similar doses. This pharmacokinetic variability may explain in part the large variability

  13. 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.

  14. Pharmacokinetics of sodium meclofenamate in pre-ruminant cattle

    OpenAIRE

    E.J. Picco; D.C. Diaz David; Encinas,T.; Rubio,M.R.; J.C. Boggio

    2004-01-01

    The pharmacokinetic profile of sodium meclofenamate, a non-steroidal antiinflammatory drug, was determined in six pre-ruminant calves after intravenous and intramuscular administration at a dose of 2.2mg/kg of body weight. Meclofenamate concentrations were measured using a high performance liquid chromatography assay. The pharmacokinetics of sodium meclofenamate after intravenous and intramuscular administration to calves were characterised by a rapid distribution phase (t½alpha ), 15.45&plus...

  15. Preparation and In Vivo Pharmacokinetics of the Tongshu Suppository

    OpenAIRE

    Guoqiang Liu; Leilei Dong; Kuan Lu; Sisi Liu; Yingying Zheng

    2016-01-01

    Astragalus polysaccharide (APS) (used for intestinal protection) was added to formulate the Tongshu suppository to improve the pharmacokinetics of Aceclofenac, which were assessed in New Zealand rabbits using an orthogonal experimental design. The single-agent Aceclofenac was taken as the control formulation. The concentration-time and drug release curves were drawn, and T max (min), C max (μg·mL−1), AUC0→∞ , and MRT were compared using a pharmacokinetic systems program. The formulated Tongsh...

  16. Metabolic pathways and pharmacokinetics of natural medicines with low permeability.

    Science.gov (United States)

    Zeng, Mei; Yang, Lan; He, Dan; Li, Yao; Shi, Mingxin; Zhang, Jingqing

    2017-09-14

    Drug metabolism plays an important role in the drug disposal process. Differences in pharmacokinetics among individuals are the basis for personalized medicine. Natural medicines, formed by long-term evolution of nature, prioritize the action of a target protein with a drug. Natural medicines are valued for structural diversity, low toxicity, low cost, and definite biological activities. Metabolic pathway and pharmacokinetic research of natural medicines is highly beneficial for clinical dose adjustment and the development of personalized medicine. This review was performed using a systematic search of all available literature. It provides an overview and discussion of metabolic pathways and the pharmacokinetics of natural medicines with low permeability. The related enzymes and factors affecting them are analyzed. The series of metabolic reactions, including phase I reactions(oxidation hydrolysis, and reduction reactions) and phase II reactions (binding reactions), catalyzed by intracellular metabolic enzymes (such as CYP450, esterase, SULT, and UGT enzymes) in tissues (such as liver and gastro-intestinal tract) or in the body fluid environment were examined. The administration route, drug dose, and delivery system had a large influence on absorption, metabolism, and pharmacokinetics. Natural medicines with low permeability had distinctive metabolisms and pharmacokinetics. The metabolic and in vivo kinetic properties were favorably modified by choosing suitable drug delivery systems, administration routes and drug doses, among other variables. This study provides valuable information for clinicians and pharmacists to guide patients safe, effective, and rational drug use. The research of metabolism and pharmacokinetics is significant in guiding personalized clinical medicine.

  17. Pharmacokinetics, Pharmacodynamics and Population Pharmacokinetic/Pharmacodynamic Modelling of Bilastine, a Second-Generation Antihistamine, in Healthy Japanese Subjects

    OpenAIRE

    Togawa, Michinori; Yamaya, Hidetoshi; Rodríguez, Mónica; Nagashima, Hirotaka

    2016-01-01

    Background and objectives Bilastine is a novel second-generation antihistamine for the symptomatic treatment of allergic rhinitis and urticaria. The objective of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of bilastine following single and multiple oral doses in healthy Japanese subjects. The pharmacokinetic and pharmacodynamic profiles were compared with those reported in Caucasian subjects. Methods In a single-blind, randomized, placebo-controlled, pa...

  18. Pharmacokinetic studies of neuromuscular blocking agents: good clinical research practice (GCRP).

    Science.gov (United States)

    Viby-Mogensen, J; Ostergaard, D; Donati, F; Fisher, D; Hunter, J; Kampmann, J P; Kopman, A; Proost, J H; Rasmussen, S N; Skovgaard, L T; Varin, F; Wright, P M

    2000-11-01

    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 for good clinical research practice (GCRP) in pharmacokinetic studies of neuromuscular blocking agents is presented. Guidelines include: design of the study; relevant patient groups to investigate; test drug administration, sampling and analysis; pharmacokinetic analysis; pharmacokinetic/pharmacodynamic modeling; population pharmacokinetics; statistics; and presentation of pharmacokinetic data. The guidelines are intended to aid those working in this research area; it is hoped that they will assist researchers, editors of scientific papers, and pharmaceutical companies in improving the quality of pharmacokinetic studies.

  19. The effect of azithromycin on ivermectin pharmacokinetics--a population pharmacokinetic model analysis.

    Directory of Open Access Journals (Sweden)

    Ahmed El-Tahtawy

    Full Text Available BACKGROUND: A recent drug interaction study reported that when azithromycin was administered with the combination of ivermectin and albendazole, there were modest increases in ivermectin pharmacokinetic parameters. Data from this study were reanalyzed to further explore this observation. A compartmental model was developed and 1,000 interaction studies were simulated to explore extreme high ivermectin values that might occur. METHODS AND FINDINGS: A two-compartment pharmacokinetic model with first-order elimination and absorption was developed. The chosen final model had 7 fixed-effect parameters and 8 random-effect parameters. Because some of the modeling parameters and their variances were not distributed normally, a second mixture model was developed to further explore these data. The mixture model had two additional fixed parameters and identified two populations, A (55% of subjects, where there was no change in bioavailability, and B (45% of subjects, where ivermectin bioavailability was increased 37%. Simulations of the data using both models were similar, and showed that the highest ivermectin concentrations fell in the range of 115-201 ng/mL. CONCLUSIONS: This is the first pharmacokinetic model of ivermectin. It demonstrates the utility of two modeling approaches to explore drug interactions, especially where there may be population heterogeneity. The mechanism for the interaction was identified (an increase in bioavailability in one subpopulation. Simulations show that the maximum ivermectin exposures that might be observed during co-administration with azithromycin are below those previously shown to be safe and well tolerated. These analyses support further study of co-administration of azithromycin with the widely used agents ivermectin and albendazole, under field conditions in disease control programs.

  20. The design and fabrication of three-chamber microscale cell culture analog devices with integrated dissolved oxygen sensors.

    Science.gov (United States)

    Sin, Aaron; Chin, Katherine C; Jamil, Muhammad F; Kostov, Yordan; Rao, Govind; Shuler, Michael L

    2004-01-01

    Whole animal testing is an essential part in evaluating the toxicological and pharmacological profiles of chemicals and pharmaceuticals, but these experiments are expensive and cumbersome. A cell culture analog (CCA) system, when used in conjunction with a physiologically based pharmacokinetic (PBPK) model, provides an in vitro supplement to animal studies and the possibility of a human surrogate for predicting human response in clinical trials. A PBPK model mathematically simulates animal metabolism by modeling the absorption, distribution, metabolism, and elimination kinetics of a chemical in interconnected tissue compartments. A CCA uses mammalian cells cultured in interconnected chambers to physically represent the corresponding PBPK. These compartments are connected by recirculating tissue culture medium that acts as a blood surrogate. The purpose of this article is to describe the design and basic operation of the microscale manifestation of such a system. Microscale CCAs offer the potential for inexpensive, relatively high throughput evaluation of chemicals while minimizing demand for reagents and cells. Using microfabrication technology, a three-chamber ("lung"-"liver"-"other") microscale cell culture analog (microCCA) device was fabricated on a 1 in. (2.54 cm) square silicon chip. With a design flow rate of 1.76 microL/min, this microCCA device achieves approximate physiological liquid-to-cell ratio and hydrodynamic shear stress while replicating the liquid residence time parameters in the PBPK model. A dissolved oxygen sensor based on collision quenching of a fluorescent ruthenium complex by oxygen molecules was integrated into the system, demonstrating the potential to integrate real-time sensors into such devices.

  1. Antinociceptive effects, metabolism and disposition of ketamine in ponies under target-controlled drug infusion

    Science.gov (United States)

    Knobloch, M.; Portier, C.J.; Levionnois, O.L.; Theurillat, R.; Thormann, W.; Spadavecchia, C.; Mevissen, M.

    2007-01-01

    Ketamine is widely used as an anesthetic in a variety of drug combinations in human and veterinary medicine. Recently, it gained new interest for use in long-term pain therapy administered in sub-anesthetic doses in humans and animals. The purpose of this study was to develop a physiologically based pharmacokinetic (PBPk) model for ketamine in ponies and to investigate the effect of low-dose ketamine infusion on the amplitude and the duration of the nociceptive withdrawal reflex (NWR). A target-controlled infusion (TCI) of ketamine with a target plasma level of 1 μg/ml S-ketamine over 120 min under isoflurane anesthesia was performed in Shetland ponies. A quantitative electromyographic assessment of the NWR was done before, during and after the TCI. Plasma levels of R-/S-ketamine and R-/S-norketamine were determined by enantioselective capillary electrophoresis. These data and two additional data sets from bolus studies were used to build a PBPk model for ketamine in ponies. The peak-to-peak amplitude and the duration of the NWR decreased significantly during TCI and returned slowly toward baseline values after the end of TCI. The PBPk model provides reliable prediction of plasma and tissue levels of R- and S-ketamine and R- and S-norketamine. Furthermore, biotransformation of ketamine takes place in the liver and in the lung via first-pass metabolism. Plasma concentrations of S-norketamine were higher compared to R-norketamine during TCI at all time points. Analysis of the data suggested identical biotransformation rates from the parent compounds to the principle metabolites (R- and S-norketamine) but different downstream metabolism to further metabolites. The PBPk model can provide predictions of R- and S-ketamine and norketamine concentrations in other clinical settings (e.g. horses). PMID:16919695

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

    Science.gov (United States)

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

    2017-03-01

    Pazopanib is a multi-targeted anticancer tyrosine kinase inhibitor. This study was conducted to develop a population pharmacokinetic (popPK) model describing the complex pharmacokinetics of pazopanib in cancer patients. Pharmacokinetic data were available from 96 patients from three clinical studies. A multi-compartment model including (i) a complex absorption profile, (ii) the potential non-linear dose-concentration relationship and (iii) the potential long-term decrease in exposure was developed. A two-compartment model best described pazopanib pharmacokinetics. The absorption phase was modelled by two first-order processes: 36 % (relative standard error [RSE] 34 %) of the administered dose was absorbed with a relatively fast rate (0.4 h(-1) [RSE 31 %]); after a lag time of 1.0 h (RSE 6 %), the remaining dose was absorbed at a slower rate (0.1 h(-1) [RSE 28 %]). The relative bioavailability (rF) at a dose of 200 mg was fixed to 1. With an increasing dose, the rF was strongly reduced, which was modelled with an E max (maximum effect) model (E max was fixed to 1, the dose at half of maximum effect was estimated as 480 mg [RSE 23 %]). Interestingly, the plasma exposure to pazopanib also decreased over time, modelled on rF with a maximum magnitude of 50 % (RSE 27 %) and a first-order decay constant of 0.15 day(-1) (RSE 43 %). The inter-patient and intra-patient variability on rF were estimated as 36 % (RSE 16 %) and 75 % (RSE 22 %), respectively. A popPK model for pazopanib was developed that illustrated the complex absorption process, the non-linear dose-concentration relationship, the high inter-patient and intra-patient variability, and the first-order decay of pazopanib concentration over time. The developed popPK model can be used in clinical practice to screen covariates and guide therapeutic drug monitoring.

  3. Clinical pharmacokinetics of antibacterial drugs in neonates.

    Science.gov (United States)

    Paap, C M; Nahata, M C

    1990-10-01

    Neonatal patients are surviving longer due to the rapid advances in medical knowledge and technology. Our understanding of the developmental physiology of both preterm and full term neonates has also increased. It is now apparent that differences in body composition and organ function significantly affect the pharmacokinetics of antibacterial drugs in neonates, and dosage modifications are required to optimise antimicrobial therapy. The penicillins and cephalosporins are frequently used in neonates. Although ampicillin has replaced benzylpenicillin (penicillin G) for empirical treatment of neonatal sepsis, many of the other penicillins may be used in neonates for the management of various infections. Increased volume of distribution (Vd) and decreased total body clearance (CL) affect the disposition of penicillins and cephalosporins. Decreased renal clearance (CLR) due to decreased glomerular filtration and tubular secretion is responsible for the decreased CL for most of the beta-lactams. Aminoglycoside Vd is affected by the increased total body water content and extracellular fluid volume of neonates. The increased Vd, in part, accounts for the extended elimination half-life (t1/2) observed in neonates. Aminoglycoside CL is dependent on renal glomerular filtration which is markedly decreased in neonates, especially those preterm. These drugs appear to be less nephrotoxic and ototoxic in neonates than in older patients, and the role of serum concentration monitoring should be limited to specific neonatal patients. Other antibiotics such as vancomycin, teicoplanin, chloramphenicol, rifampicin, erythromycin, clindamycin, metronidazole and cotrimoxazole (trimethoprim plus sulfamethoxazole) may be used in certain clinical situations. The emergence of staphylococcal resistance to penicillins has increased the need for vancomycin. With the exceptions of vancomycin and chloramphenicol, the efficacy and safety of these other agents in neonates have not been established

  4. Population pharmacokinetics of olprinone in healthy male volunteers

    Directory of Open Access Journals (Sweden)

    Kunisawa T

    2014-03-01

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

  5. Pharmacokinetics of SPECT radiopharmaceuticals for imaging hypoxic tissues.

    Science.gov (United States)

    Wiebe, L I; Stypinski, D

    1996-09-01

    Although hypoxia has been known for decades to play an important role in the outcome of radiotherapy in oncology, and inspite of the contribution of hypoxia to a myriad of pathologies that involve vascular disease, the selective imaging of hypoxic tissue has attained prominence only within the past decade. Contemporary research in the hypoxia imaging field is based largely on radiosensitizer research of the 1960's and 1970's. Early sensitizer research identified a family of nitro-organic compounds, the N-1 substituted 2-nitroimidazoles as candidate drugs. The early champion, and still the reference standard for therapeutic radiosensitization of hypoxic tumor cells is misonidazole (MISO). Its peripheral neurotoxicity led to failure in clinical studies, but its biological, biophysical and biochemical properties have been investigated in detail and serve as a basis for further design, not only of sensitizers, but of diagnostic radiopharmaceuticals for imaging tissue hypoxia. Pharmacokinetic characterization of radiopharmaceuticals, specifically radiopharmaceuticals for imaging tissue hypoxia, has not been a central theme in their development. The advent of PET, through which quantitative determinations first became possible, opened the field for both descriptive and analytical radiopharmacokinetic studies. In SPECT, however, this approach is still undergoing refinement. This paper addresses some of the underlying issues in radiopharmaceutical pharmacokinetics. There is a paucity of published radiopharmacokinetic data for SPECT hypoxia imaging agents. Consequently, the pharmacokinetic issues for MISO are presented as a basis for development of pharmacokinetics for the chemically-related imaging agents. Properties of an hypoxia marker are described from a pharmacokinetic viewpoint, a theoretical model for descriptive pharmacokinetics is introduced and finally, recent pharmacokinetic studies from our laboratory are described.

  6. Pharmacokinetics of valacyclovir in the adult horse.

    Science.gov (United States)

    Maxwell, L K; Bentz, B G; Bourne, D W A; Erkert, R S

    2008-08-01

    Recent outbreaks of equine herpes virus type-1 infections have stimulated renewed interest in the use of effective antiherpetic drugs in horses. The purpose of this study was to investigate the pharmacokinetics of valacyclovir (VCV), the prodrug of acyclovir (ACV), in horses. Six adult horses were used in a randomized cross-over design. Treatments consisted of 10 mg/kg ACV infused intravenously, 5 g (7.7-11.7 mg/kg) VCV delivered intragastrically (IG) and 15 g (22.7-34.1 mg/kg) VCV administered IG. Serum samples were obtained at predetermined times for acyclovir assay using high-performance liquid chromatography. Following the administration of 5 g VCV, the mean observed maximum serum ACV concentration (C(max)) was 1.45 +/- 0.38 (SD) microg/mL, at 0.74 +/- 0.43 h. At a dose of 15 g VCV, the mean C(max) was 5.26 +/- 2.82 microg/mL, at 1 +/- 0.27 h. The mean bioavailability of ACV from oral VCV was 60 +/- 12% after 5 g of VCV and 48 +/- 12% after 15 g VCV, and did not differ significantly between dose rates (P > 0.05). Superposition suggested that a loading dose of 27 mg/kg VCV every 8 h for 2 days, followed by a maintenance dose of 18 mg/kg every 12 h, will maintain effective serum ACV concentrations.

  7. [Pharmacokinetics of zinc acexamate (ZAC) in rats].

    Science.gov (United States)

    Li, H Y; Liu, X M; Ji, X J

    1995-01-01

    Zinc acexamate (ZAC) is a new antiulcer drug. This paper reports the pharmacokinetics of ZAC in rats after single oral administration. The concentrations in biological samples were detected by spectrophotometry. This study shows that the concentration-time curve of ZAC in blood conformed to a single-compartment open model after 250, 500 and 750 ng.kg-1 ig. ZAC absorption was fast and the peak plasma level appeared in 1.5 h. The Cmax, AUC and CL/F were shown to be dose dependent. Two hours after oral administration of ZAC to normal rats, the highest level of ZAC was present in the gastrointestinal tract, while appreciable ZAC was present in the kidney, liver, plasma and lung. The level of ZAC in heart, spleen and brain was lower, no drug was detected in muscles and uterus. Six hours after oral administration, the drug concentration in various tissues decreased rapidly, but that of the gastrointestinal decreased very slowly. Feces excretion was an important route of excretion. ZAC excretion was about 11.7% of the administered dosage in feces within 48 h period, and the excreted amount from urine and bile was very small.

  8. Tyramine pharmacokinetics and reduced bioavailability with food.

    Science.gov (United States)

    VanDenBerg, Chad M; Blob, Lawrence F; Kemper, Eva M; Azzaro, Albert J

    2003-06-01

    Tyramine challenge studies have demonstrated that it requires approximately twice the amount of tyramine administered with a meal compared to administration after a fast to elicit the same effect, suggesting a reduction in bioavailability of tyramine when administered with food. The pharmacokinetics of tyramine when administered in a fasted versus a fed state were studied. A single 200-mg dose of tyramine was administered orally to healthy subjects both after an overnight fast and during a meal. Systemic exposure to tyramine was reduced by 53% (p tyramine was reduced by 72% (p Tyramine maximum serum concentration was observed between 20 minutes and 1 hour when the dose was administered after an overnight fast and appeared to be delayed and/or prolonged by administration during a meal. Tyramine oral clearance was 135 +/- 55.4 L/min, maximum observed serum concentration was 37.7 +/- 26.01 ng/mL, and tyramine elimination half-life was 0.533 (range: 0.330-0.668) hours after administration to fasted subjects. Tyramine bioavailability was significantly reduced when administered with a meal compared to after a fast. The results suggest that larger amounts of dietary tyramine will be required to induce a pressor response equivalent to that following encapsulated tyramine administered in the fasted state.

  9. Clinical Pharmacokinetics and Pharmacodynamics of Bosutinib.

    Science.gov (United States)

    Abbas, Richat; Hsyu, Poe-Hirr

    2016-10-01

    Chronic myeloid leukemia (CML) is a clonal myeloproliferative stem cell disorder. Bosutinib is an oral, once-daily SRC/ABL tyrosine kinase inhibitor with very potent inhibitory activity. Bosutinib is effective against all phases of intolerant or resistant Philadelphia chromosome-positive CML that do not harbor the T315I or V299LABL kinase domain mutations. Peak plasma concentrations of bosutinib occur at 4-6 h following oral administration, and dose-proportional increases in exposure are observed at doses ranging from 200 to 800 mg. Absorption of bosutinib increases with food. Bosutinib is distributed extensively into the tissues. It is highly plasma protein bound (94 %) and is primarily metabolized in the liver by cytochrome P450 3A4. Bosutinib is well tolerated overall and has a unique but manageable toxicity profile. This article provides a review of the available clinical pharmacokinetic, pharmacodynamic, and drug-drug interaction data on bosutinib in healthy subjects, patients with CML, and special populations.

  10. Ocular pharmacokinetics of thiamphenicol in rabbits.

    Science.gov (United States)

    Aldana, I; Fos, D; Gonzalez Peñas, E; Gazzaniga, A; Gianesello, V; Ceppi Monti, N; Figini, P G; Zato, M A; Bruseghini, L; Esteras, A

    1992-10-01

    The ocular pharmacokinetics of thiamphenicol (TAP, CAS 15318-45-3) was studied in rabbits by means of the assessment of its ocular and systemic absorption, and urinary excretion after instillation of 0.5% TAP eye drops. TAP concentrations in aqueous humor, plasma and urine were evaluated by a coupled LC/GC method (detection limit = 0.1 ng/ml), because the necessity to have a technique much more sensitive than the traditional chromatographic ones available in order to quantify the very low drug concentrations in biological fluids produced by the ocular treatment, and generally by a topical administration. The intravenous route was chosen as reference and allowed the absolute bioavailability to be estimated. TAP proved to be well absorbed through the cornea with the peak aqueous humor concentration of 110 ng/ml at 45 min following the instillation. The good ocular absorption of TAP was confirmed by the plasma concentrations observed after instillation of 0.5% eye drops. In any case, these concentrations were more than 1000 times lower than those observed after the intravenous treatment at the dose normally used for infectious diseases, allowing to exclude any systemic toxicity of TAP eye drops. The absolute ocular bioavailability was 16.2% when estimated from the AUC values and 34.0% from the cumulative urinary excretion values.

  11. [Pharmacokinetic interactions of telaprevir with other drugs].

    Science.gov (United States)

    Berenguer Berenguer, Juan; González-García, Juan

    2013-07-01

    Telaprevir is a new direct-acting antiviral drug for the treatment of hepatitis C virus (HCV) infection and is both a substrate and an inhibitor of cytochrome P450 (CYP450) isoenzymes. With the introduction of this new drug, assessment of drug-drug interactions has become a key factor in the evaluation of patients under treatment for HCV infection. During the treatment of this infection, many patients require other drugs to mitigate the adverse effects of anti-HCV drugs and to control other comorbidities. Moreover, most patients coinfected with HIV and HCV require antiretroviral therapy during treatment for HCV. Physicians should therefore be familiar with the pharmacokinetic properties of direct-acting antivirals for HCV treatment and their potential drug-drug interactions. The present article reviews the available information to date on the interactions of telaprevir with other drugs and provides recommendations for daily clinical practice. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  12. 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.

  13. Pattern Recognition in Pharmacokinetic Data Analysis.

    Science.gov (United States)

    Gabrielsson, Johan; Meibohm, Bernd; Weiner, Daniel

    2016-01-01

    Pattern recognition is a key element in pharmacokinetic data analyses when first selecting a model to be regressed to data. We call this process going from data to insight and it is an important aspect of exploratory data analysis (EDA). But there are very few formal ways or strategies that scientists typically use when the experiment has been done and data collected. This report deals with identifying the properties of a kinetic model by dissecting the pattern that concentration-time data reveal. Pattern recognition is a pivotal activity when modeling kinetic data, because a rigorous strategy is essential for dissecting the determinants behind concentration-time courses. First, we extend a commonly used relationship for calculation of the number of potential model parameters by simultaneously utilizing all concentration-time courses. Then, a set of points to consider are proposed that specifically addresses exploratory data analyses, number of phases in the concentration-time course, baseline behavior, time delays, peak shifts with increasing doses, flip-flop phenomena, saturation, and other potential nonlinearities that an experienced eye catches in the data. Finally, we set up a series of equations related to the patterns. In other words, we look at what causes the shapes that make up the concentration-time course and propose a strategy to construct a model. By practicing pattern recognition, one can significantly improve the quality and timeliness of data analysis and model building. A consequence of this is a better understanding of the complete concentration-time profile.

  14. Persistent Pharmacokinetic Challenges to Pediatric Drug Development

    Directory of Open Access Journals (Sweden)

    Daniel eSage

    2014-08-01

    Full Text Available The development of new therapeutic agents for the mitigation of pediatric disorders is largely hindered by the inability for investigators to assess pediatric pharmacokinetics (PK in healthy patients due to substantial safety concerns. Pediatric patients are a clinical moving target for drug delivery due to changes in absorption, distribution, metabolism and excretion (ADME and the potential for PK related toxicological (T events to occur throughout development. These changes in ADMET can have profound effects on drug delivery, and may lead to toxic or sub-therapeutic outcomes. Ethical, economical, logistical, and technical barriers have resulted in insufficient investigation of these changes by industrial, regulatory, and academic bodies, leading to the classification of pediatric patients as therapeutic orphans. In response to these concerns, regulatory agencies have incentivized investigation into these ontogenic changes and their effects on drug delivery in pediatric populations. The intent of this review is to briefly present a synopsis of the development changes that occur in pediatric patients, discuss the effects of these changes on ADME and drug delivery strategies, highlight the hurdles that are still being faced, and present some opportunities to overcome these challenges.

  15. In Vitro-In Vivo Extrapolation of Intestinal Availability for Carboxylesterase Substrates Using Portal Vein-Cannulated Monkey.

    Science.gov (United States)

    Trapa, Patrick E; Beaumont, Kevin; Atkinson, Karen; Eng, Heather; King-Ahmad, Amanda; Scott, Dennis O; Maurer, Tristan S; Di, Li

    2017-03-01

    Prediction of intestinal availability (FaFg) of carboxylesterase (CES) substrates is of critical importance in designing oral prodrugs with optimal properties, projecting human pharmacokinetics and dose, and estimating drug-drug interaction potentials. A set of ester prodrugs were evaluated using in vitro permeability (parallel artificial membrane permeability assay and Madin-Darby canine kidney cell line-low efflux) and intestinal stability (intestine S9) assays, as well as in vivo portal vein-cannulated cynomolgus monkey. In vitro-in vivo extrapolation (IVIVE) of FaFg was developed with a number of modeling approaches, including a full physiologically based pharmacokinetic (PBPK) model as well as a simplified competitive-rate analytical solution. Both methods converged as in the PBPK simulations enterocyte blood flow behaved as a sink, a key assumption in the competitive-rate analysis. For this specific compound set, the straightforward analytical solution therefore can be used to generate in vivo predictions. Strong IVIVE of FaFg was observed for cynomolgus monkey with R(2) of 0.71-0.93. The results suggested in vitro assays can be used to predict in vivo FaFg for CES substrates with high confidence. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  16. Understanding variability in posaconazole exposure using an integrated population pharmacokinetic analysis

    NARCIS (Netherlands)

    Dolton, M.J.; Bruggemann, R.J.M.; Burger, D.M.; McLachlan, A.J.

    2014-01-01

    Posaconazole oral suspension is widely used for antifungal prophylaxis and treatment in immunocompromised patients, with highly variable pharmacokinetics reported in patients due to inconsistent oral absorption. This study aimed to characterize the pharmacokinetics of posaconazole in adults and inve

  17. The pharmacokinetics, safety and efficacy of boosted saquinavir tablets in HIV type-1-infected pregnant women.

    NARCIS (Netherlands)

    Lugt, J. van der; Colbers, A.; Molto, J.; Hawkins, D.; Ende, M. van der; Vogel, M.; Wyen, C.; Schutz, M.; Koopmans, P.; Ruxrungtham, K.; Richter, C.; Burger, D.M.

    2009-01-01

    BACKGROUND: Pregnancy affects the pharmacokinetics of most protease inhibitors. Saquinavir, when administered in a tablet formulation, has not been studied extensively in this setting. METHODS: A pharmacokinetic, prospective, multicentre trial of HIV type-1-infected pregnant women treated with saqui

  18. The influence of labour on the pharmacokinetics of intravenously administered amoxicillin in pregnant women

    NARCIS (Netherlands)

    A.F. Muller (Alex); P.J. Dörr (Joep); J.W. Mouton (Johan); J. de Jongh (Joost); P.M. Oostvogel (Paul); E.A.P. Steegers (Eric); R.A. Voskuyl (Robert); M. Danhof (Meindert)

    2008-01-01

    textabstractAIMS: Many physiological changes take place during pregnancy and labour. These might change the pharmacokinetics of amoxicillin, necessitating adjustment of the dose for prevention of neonatal infections. We investigated the influence of labour on the pharmacokinetics of amoxicillin.

  19. Pharmacokinetics and pharmacodynamics of mivacurium in young adult and elderly patients

    DEFF Research Database (Denmark)

    Østergaard, Doris; Viby-Mogensen, Jørgen; Pedersen, N.A.

    2002-01-01

    age factors; butyrylcholinesterase; cholinesterase; dose-response curves; enzymes; metabolites; mivacurium; neuromuscular relaxants; pharmacodynamics; pharmacokinetics; pharmacology; pseudocholinesterase; stereoisomers......age factors; butyrylcholinesterase; cholinesterase; dose-response curves; enzymes; metabolites; mivacurium; neuromuscular relaxants; pharmacodynamics; pharmacokinetics; pharmacology; pseudocholinesterase; stereoisomers...

  20. Evaluation of methods for estimating population pharmacokinetics parameters. I. Michaelis-Menten model: routine clinical pharmacokinetic data.

    Science.gov (United States)

    Sheiner, L B; Beal, S L

    1980-12-01

    Individual pharmacokinetic par parameters quantify the pharmacokinetics of an individual, while population pharmacokinetic parameters quantify population mean kinetics, interindividual variability, and residual intraindividual variability plus measurement error. Individual pharmacokinetics are estimated by fitting individual data to a pharmacokinetic model. Population pharmacokinetic parameters are estimated either by fitting all individual's data together as though there was no individual kinetic differences (the naive pooled data approach), or by fitting each individual's data separately, and then combining the individual parameter estimates (the two-stage approach). A third approach, NONMEM, takes a middle course between these, and avoids shortcomings of each of them. A data set consisting of 124 steady-state phenytoin concentration-dosage pairs from 49 patients, obtained in the routine course of their therapy, was analyzed by each method. The resulting population parameter estimates differ considerably (population mean Km, for example, is estimated as 1.57, 5.36, and 4.44 micrograms/ml by the naive pooled data, two-stage, and NONMEN approaches, respectively). Simulations of the data were analyzed to investigate these differences. The simulations indicate that the pooled data approach fails to estimate variabilities and produces imprecise estimates of mean kinetics. The two-stage approach produces good estimates of mean kinetics, but biased and imprecise estimates of interindividual variability. NONMEN produces accurate and precise estimates of all parameters, and also reasonable confidence intervals for them. This performance is exactly what is expected from theoretical considerations and provides empirical support for the use of NONMEM when estimating population pharmacokinetics from routine type patient data.

  1. Use of unbound volumes of drug distribution in pharmacokinetic calculations.

    Science.gov (United States)

    Stepensky, David

    2011-01-18

    Volume of drug distribution is a primary pharmacokinetic parameter. This study assessed effects of drugs' plasma protein binding and tissue distribution on volume of drug distribution and identified the most appropriate ways for its calculation. Effects of the distribution factors on the unbound and total drug plasma concentrations and on the corresponding volumes of distribution were studied using pharmacokinetic modeling and simulation approach based on in vitro and in vivo concentration vs. time data of diazepam, a model drug with extensive plasma protein binding and tissue distribution. Pharmacokinetics of diazepam were appropriately described by three-compartment pharmacokinetic model that incorporated the processes of plasma protein binding and tissue permeation. According to this model, displacement of the drug from plasma proteins increases the unbound (but not the total) plasma concentrations and induces faster drug elimination from the body. The distribution pattern of the drug in the body and the time course of unbound (pharmacologically active) drug concentrations correlated with the unbound volumes of distribution, but not with the total volumes of distribution. In conclusion, unbound volumes of distribution appropriately describe the drug distribution pattern and the time course of unbound drug concentrations and are recommended for use as primary pharmacokinetic parameters in pharmaceutical research. Copyright © 2010 Elsevier B.V. All rights reserved.

  2. Pharmacokinetics of BMEDA after Intravenous Administration in Beagle Dogs

    Directory of Open Access Journals (Sweden)

    Chih-Hsien Chang

    2014-01-01

    Full Text Available The pharmacokinetics of N,N-bis(2-mercapatoethly-N',N'-diethylenediamine (BMEDA, a molecule that can form a chelate with rhenium-188 (188Re to produce the 188Re-BMEDA-liposomes, was studied. In this work, beagles received a single injection of BMEDA, at doses of 1, 2, or 5 mg/kg; the concentration of BMEDA in the beagles’ plasma was then analyzed and determined by liquid chromatography-mass spectrometry/mass spectrometry. Based on the pharmacokinetic parameters of BMEDA, we found that male and female animals shared similar patterns indicating that the pharmacokinetics of BMEDA is independent of gender differences. In addition, the pharmacokinetics of BMEDA was seen to be non-linear because the increase of mean AUC0–t and AUC0–∞ values tend to be greater than dose proportional while the mean Vss and CL values of BMEDA appeared to be dose dependent. The information on the pharmacokinetics of BMEDA generated from this study will serve as a basis to design appropriate pharmacology and toxicology studies for future human use.

  3. A self-regulating cell culture analog device to mimic animal and human toxicological responses.

    Science.gov (United States)

    Shuler, M L; Ghanem, A; Quick, D; Wong, M C; Miller, P

    1996-10-05

    The overall goal of this project is the development of a new methodology for translating advances in molecular level understanding of toxicological responses into a predictive tool for dose response in whole animals and humans exposed to single compounds or mixtures of compounds. The methodology incorporates a mechanistic cellular level model into a PBPK (physiologically based pharmacokinetic) model which simultaneously guides the development of an in vitro cell culture analog (CCA) to the PBPK. Where the PBPK specifies an organ, (e.g., liver) the in vitro or CCA system contains a compartment with the appropriate cell or cell population (e.g., hepatocytes for the liver). The CCA has significant advantages over other in vitro systems and PBPK systems used independently for evaluating metabolic responses to drugs or potentially toxic chemicals where the exchange of metabolites between organs is likely to be important. The CCA system is superior to a PBPK because an a priori description of complete metabolism is not required and secondary, unexpected interactions can be detected. The CCA system, unlike other in vitro systems, gives a dynamic response that realistically simulates in vivo interactions between organs. Furthermore, the CCA allows dosing on the same basis as animal tests (e.g., milligrams per kilogram of body mass equivalent). Because the construction of a CCA is guided by a PBPK, this approach allows extrapolation to low doses and across species, including extrapolation to humans. We have constructed a prototype system and have conducted proof-of-concept experiments using naphthalene as a test chemical. These experiments clearly demonstrate the ability to generate a reactive metabolite in one compartment and detect its effects (on LDH release and glutathione depletion) in a second compartment. However, this prototype device would be expensive to replicate and requires nearly constant supervision from a trained investigator. For this concept to replace

  4. 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.

  5. Atomoxetine pharmacogenetics: associations with pharmacokinetics, treatment response and tolerability.

    Science.gov (United States)

    Brown, Jacob T; Bishop, Jeffrey R

    2015-01-01

    Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder and is predominantly metabolized by the CYP2D6 enzyme. Differences in pharmacokinetic parameters as well as clinical treatment outcomes across CYP2D6 genotype groups have resulted in dosing recommendations within the product label, but clinical studies supporting the use of genotype guided dosing are currently lacking. Furthermore, pharmacokinetic and clinical studies have primarily focused on extensive as compared with poor metabolizers, with little information known about other metabolizer categories as well as genes involved in the pharmacodynamics of atomoxetine. This review describes the pharmacogenetic associations with atomoxetine pharmacokinetics, treatment response and tolerability with considerations for the clinical utility of this information.

  6. Pharmacokinetics of Remifentanil: a three-compartmental modeling approach

    Science.gov (United States)

    Cascone, Sara; Lamberti, Gaetano; Titomanlio, Giuseppe; Piazza, Ornella

    Remifentanil is a new opioid derivative drug characterized by a fast onset and by a short time of action, since it is rapidly degraded by esterases in blood and other tissues. Its pharmacokinetic and pharmacodynamics properties make remifentanil a very interesting molecule in the field of 0anesthesia. However a complete and versatile pharmacokinetic description of remifentanil still lacks. In this work a three-compartmental model has been developed to describe the pharmacokinetics of remifentanil both in the case in which it is administered by intravenous constant-rate infusion and by bolus injection. The model curves have been compared with experimental data published in scientific papers and the model parameters have been optimized to describe both ways of administration. The ad hoc model is adaptable and potentially useful for predictive purposes. PMID:24251247

  7. Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

    Science.gov (United States)

    Gao, Wenqing; Kim, Juhyun; Dalton, James T.

    2007-01-01

    Testosterone and structurally related anabolic steroids have been used to treat hypogonadism, muscle wasting, osteoporosis, male contraception, cancer cachexia, anemia, and hormone replacement therapy in aging men or age-related frailty; while antiandrogens may be useful for treatment of conditions like acne, alopecia (male-pattern baldness), hirsutism, benign prostatic hyperplasia (BPH) and prostate cancer. However, the undesirable physicochemical and pharmacokinetic properties of steroidal androgen receptor (AR) ligands limited their clinical use. Nonsteroidal AR ligands with improved pharmacological and pharmacokinetic properties have been developed to overcome these problems. This review focuses on the pharmacokinetics, metabolism, and pharmacology of clinically used and emerging nonsteroidal AR ligands, including antagonists, agonists, and selective androgen receptor modulators. PMID:16841196

  8. Pharmacokinetics of oral and intravenous melatonin in healthy volunteers

    DEFF Research Database (Denmark)

    Andersen, Lars Peter Holst; Werner, Mads Utke; Rosenkilde, Mette Marie

    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...

  9. Pharmacokinetics of high-dose intravenous melatonin in humans

    DEFF Research Database (Denmark)

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

    2016-01-01

    This crossover study investigated the pharmacokinetics and adverse effects of high-dose intravenous melatonin. Volunteers participated in 3 identical study sessions, receiving an intravenous bolus of 10 mg melatonin, 100 mg melatonin, and placebo. Blood samples were collected at baseline and 0, 60......, 120, 180, 240, 300, 360, and 420 minutes after the bolus. Quantitative determination of plasma melatonin concentrations was performed using a radioimmunoassay technique. Pharmacokinetic parameters were estimated by a compartmental pharmacokinetic analysis. Adverse effects included assessments...... of sedation and registration of other symptoms. Sedation, evaluated as simple reaction times, was measured at baseline and 120, 180, 300, and 420 minutes after the bolus. Twelve male volunteers completed the study. Median (IQR) Cmax after the bolus injections of 10 mg and 100 mg of melatonin were 221...

  10. Pharmacokinetics of metronidazole in pregnant patients with bacterial vaginosis.

    Science.gov (United States)

    Wang, Xin; Nanovskaya, Tatiana N; Zhan, Ying; Abdel-Rahman, Susan M; Jasek, Marlo; Hankins, Gary D V; Ahmed, Mahmoud S

    2011-03-01

    The present study was undertaken to investigate the pharmacokinetics of metronidazole in pregnant patients with bacterial vaginosis. Twenty patients received metronidazole (Flagyl ®, Pfizer, 235 East 42nd Street, NY, NY 10017) oral dose 500 mg twice a day for 3 consecutive days. Pharmacokinetic analyses of metronidazole were performed after a single oral dose on the morning of day 4. Although absolute estimates of metronidazole total body exposure were highest in women during early term pregnancy, weight-corrected estimates of exposure maximum plasma drug concentration (C(max)) and the area under the plasma concentration-versus-time curve (AUC(0-12)), along with apparent oral clearance and distribution volume, were not significantly different between women at early, middle, and late stages of pregnancy and were in the range of reported values for nonpregnant patients receiving a similar dose. The pharmacokinetic profile of metronidazole did not change at the different time points assessed during pregnancy.

  11. Pharmacokinetic studies of antipsychotics in healthy volunteers versus patients.

    Science.gov (United States)

    Cutler, N R

    2001-01-01

    In clinical trials of dopamine-blocking antipsychotics, significant adverse events may occur in healthy volunteers at dose levels that are well tolerated by schizophrenic patients. Because of these differences in tolerability, bioequivalence and pharmacokinetic studies of antipsychotics should be performed in schizophrenic patients rather than in healthy volunteers. When clozapine is the drug being investigated, pharmacokinetic and bioequivalence studies should be carried out in real-life dosage conditions because the half-life of clozapine increases with multiple doses. Under real-life conditions, the evaluation of multiple doses of clozapine in a population of schizophrenic patients can provide direct therapeutic relevance to bioavailability findings. This article discusses patient recruitment and informed consent in pharmacokinetic trials of schizophrenia, issues in studying antipsychotic agents in healthy volunteers versus schizophrenic patients, and a bioequivalency study of Clozaril (Novartis Pharmaceuticals) and generic clozapine (Creighton [Sandoz]) in schizophrenic patients.

  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. Pharmacokinetics and safety of intravitreal caspofungin.

    Science.gov (United States)

    Shen, Ying-Cheng; Liang, Chiao-Ying; Wang, Chun-Yuan; Lin, Keng-Hung; Hsu, Min-Yen; Yuen, Hon-Leung; Wei, Li-Chen

    2014-12-01

    Caspofungin exhibits potent antifungal activities against Candida and Aspergillus species. The elimination rate and retinal toxicity of caspofungin were determined in this study to assess its pharmacokinetics and safety in the treatment of fungal endophthalmitis. Intravitreal injections of 50 μg/0.1 ml of caspofungin were administered to rabbits. Levels of caspofungin in the vitreous and aqueous humors were determined using high-performance liquid chromatography (HPLC) at selected time intervals (10 min and 1, 2, 4, 8, 16, 24, and 48 h), and the half-lives were calculated. Eyes were intravitreally injected with caspofungin to obtain concentrations of 10 μg/ml, 50 μg/ml, 100 μg/ml, and 200 μg/ml. Electroretinograms were recorded 4 weeks after injections, and the injected eyes were examined histologically. The concentrations of intravitreal caspofungin at various time points exhibited an exponential decay with a half-life of 6.28 h. The mean vitreous concentration was 6.06 ± 1.76 μg/ml 1 h after intravitreal injection, and this declined to 0.47 ± 0.15 μg/ml at 24 h. The mean aqueous concentration showed undetectable levels at all time points. There were no statistical differences in scotopic a-wave and b-wave responses between control eyes and caspofungin-injected eyes. No focal necrosis or other abnormality in retinal histology was observed. Intravitreal caspofungin injection may be considered to be an alternative treatment for fungal endophthalmitis based on its antifungal activity, lower retinal toxicity, and lower elimination rate in the vitreous. More clinical data are needed to determine its potential role as primary therapy for fungal endophthalmitis.

  14. Metabolism and pharmacokinetics of indacaterol in humans.

    Science.gov (United States)

    Kagan, Mark; Dain, Jeremy; Peng, Lana; Reynolds, Christine

    2012-09-01

    The metabolism, pharmacokinetics, and excretion of [(14)C]indacaterol were investigated in healthy male subjects. Although indacaterol is administered to patients via inhalation, the dose in this study was administered orally. This was done to avoid the complications and concerns associated with the administration of a radiolabeled compound via the inhalation route. The submilligram doses administered in this study made metabolite identification and structural elucidation by mass spectrometry especially challenging. In serum, the mean t(max), C(max), and AUC(0-last) values were 1.75 h, 0.47 ng/ml, and 1.81 ng · h/ml for indacaterol and 2.5 h, 1.4 ngEq/ml, and 27.2 ngEq · h/ml for total radioactivity. Unmodified indacaterol was the most abundant drug-related compound in the serum, contributing 30% to the total radioactivity in the AUC(0-24h) pools, whereas monohydroxylated indacaterol (P26.9), the glucuronide conjugate of P26.9 (P19), and the 8-O-glucuronide conjugate of indacaterol (P37) were the most abundant metabolites, with each contributing 4 to 13%. In addition, the N-glucuronide (2-amino) conjugate (P37.7) and two metabolites (P38.2 and P39) that resulted from the cleavage about the aminoethanol group linking the hydroxyquinolinone and diethylindane moieties had a combined contribution of 12.5%. For all four subjects in the study, ≥90% of the radioactivity dose was recovered in the excreta (85% in feces and 10% in urine, mean values). In feces, unmodified indacaterol and metabolite P26.9 were the most abundant drug-related compounds (54 and 17% of the dose, respectively). In urine, unmodified indacaterol accounted for ∼0.3% of the dose, with no single metabolite accounting for >1.3%.

  15. Clinical pharmacokinetics of fibric acid derivatives (fibrates).

    Science.gov (United States)

    Miller, D B; Spence, J D

    1998-02-01

    Beginning with the description of clofibrate in 1962, derivatives of fibric acid (fibrates) have been used clinically to treat dyslipidaemias. Subsequently, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate and long-acting forms of gemfibrozil, fenofibrate and bezafibrate have been developed. Clinically, this class of drugs appears to be most useful in lipoprotein disorders characte