Showing papers on "Physiologically based pharmacokinetic modelling published in 2009"

The Simcyp® population-based ADME simulator

Abstract: The Simcyp population-based absorption, distribution, metabolism and excretion simulator is a platform and database for 'bottom-up' mechanistic modelling and simulation of the processes of oral absorption, tissue distribution, metabolism and excretion of drugs and drug candidates in healthy and disease populations. It combines experimental data generated routinely during preclinical drug discovery and development from in vitro enzyme and cellular systems and relevant physicochemical attributes of compound and dosage form with demographic, physiological and genetic information on different patient populations. The mechanistic approach implemented in the Simcyp Simulator allows simulation of complex absorption, distribution, metabolism and excretion outcomes, particularly those involving multiple drug interactions, parent drug and metabolite profiles and time- and dose-dependent phenomena such as auto-induction and auto-inhibition.This review describes the framework and organisation of the simulator and how it combines the different categories of information.

Modelling and PBPK Simulation in Drug Discovery

Abstract: Physiologically based pharmacokinetic (PBPK) models are composed of a series of differential equations and have been implemented in a number of commercial software packages. These models require species-specific and compound-specific input parameters and allow for the prediction of plasma and tissue concentration time profiles after intravenous and oral administration of compounds to animals and humans. PBPK models allow the early integration of a wide variety of preclinical data into a mechanistic quantitative framework. Use of PBPK models allows the experimenter to gain insights into the properties of a compound, helps to guide experimental efforts at the early stages of drug discovery, and enables the prediction of human plasma concentration time profiles with minimal (and in some cases no) animal data. In this review, the application and limitations of PBPK techniques in drug discovery are discussed. Specific reference is made to its utility (1) at the lead development stage for the prioritization of compounds for animal PK studies and (2) at the clinical candidate selection and “first in human” stages for the prediction of human PK.

Physiologically based pharmacokinetics (PBPK)

Abstract: Allometric scaling is widely used to predict human pharmacokinetic parameters from preclinical species, and many different approaches have been proposed over the years to improve its predictive performance. Nevertheless, prediction errors are commonly observed in the practical application of simple allometry, for example, in cases where the hepatic metabolic clearance is mainly determined by enzyme activities, which do not scale allometrically across species. Therefore, if good correlation was noted for some drugs, poor correlation was observed for others, highlighting the need for other conceptual approaches. Physiologically based pharmacokinetic (PBPK) models are now a well-established approach to conduct extrapolations across species and to generate simulations of pharmacokinetic profiles under various physiological conditions. While conventional pharmacokinetic models are defined by drug-related data themselves, PBPK models have richer information content and integrate information from various sources, including drug-dependent, physiological, and biological parameters as they vary in between species, subjects, or with age and disease state. Therefore, the biological and mechanistic bases of PBPK models allow the extrapolation of the kinetic behavior of drugs with regard to dose, route, and species. In addition, by providing a link between tissue concentrations and toxicological or pharmacological effects, PBPK modeling represents a framework for mechanistic pharmacokinetic-pharmacodynamic models.

Database for physiologically based pharmacokinetic (PBPK) modeling: physiological data for healthy and health-impaired elderly.

Abstract: Physiologically based pharmacokinetic (PBPK) models have increasingly been employed in chemical health risk assessments. By incorporating individual variability conferred by genetic polymorphisms, health conditions, and physiological changes during development and aging, PBPK models are ideal for predicting chemical disposition in various subpopulations of interest. In order to improve the parameterization of PBPK models for healthy and health-impaired elderly (herein defined as those aged 65 yr and older), physiological parameter values were obtained from the peer-reviewed literature, evaluated, and entered into a Microsoft ACCESS database. Database records include values for key age-specific model inputs such as ventilation rates, organ volumes and blood flows, glomerular filtration rates, and other clearance-related processes. In total, 528 publications were screened for relevant data, resulting in the inclusion of 155 publications comprising 1051 data records for healthy elderly adults and 115 data records for elderly with conditions such as diabetes, chronic obstructive pulmonary disease (COPD), obesity, heart disease, and renal disease. There are no consistent trends across parameters or their associated variance with age; the gross variance in body weight decreased with advancing age, whereas there was no change in variance for brain weight. The database contains some information to inform ethnic and gender differences in parameters; however, the majority of the published data pertain to Asian (mostly Japanese) and Caucasian males. As expected, the number of records tends to decrease with advancing age. In addition to a general lack of data for parameters in the elderly with various health conditions, there is also a dearth of information on blood and tissue composition in all elderly groups. Importantly, there are relatively few records for alveolar ventilation rate; therefore, the relationship between this parameter and cardiac output (usually assumed to be 1:1) in the elderly is not well informed by the database. Despite these limitations, the database represents a potentially useful resource for parameterizing PBPK models for the elderly to facilitate the prediction of dose metrics in older populations for application in risk assessment.

Prediction of pharmacokinetic profile of valsartan in human based on in vitro uptake transport data.

Abstract: The aim of this study was to evaluate a strategy based on a physiologically based pharmacokinetic (PBPK) model for the prediction of PK profiles in human using in vitro data when elimination of compounds relies on active transport processes. The strategy was first applied to rat in vivo and in vitro data in order to refine the PBPK model. The model could then be applied to human in vitro uptake transport data using valsartan as a probe substrate. Plated rat and human hepatocytes, and cell lines overexpressing human OATP1B1 and OATP1B3 were used for in vitro uptake experiments. The uptake rate of valsartan was higher for rat hepatocytes (K m,u = 28.4 ± 3.7 μM, V max = 1318 ± 176 pmol/mg/min and P dif = 1.21 ± 0.42 μl/mg/min) compared to human hepatocytes (K m,u = 44.4 ± 14.6 μM, V max = 304 ± 85 pmol/mg/min and P dif = 0.724 ± 0.271 μl/mg/min). OATP1B1 and 1B3 parameters were correlated to human hepatocyte data using experimentally established relative activity factors (RAF). Resulting PBPK simulations using those in vitro data were compared for plasma (human and rat) and bile (rat) concentration–time profiles following i.v. bolus administration of valsartan. An uncertainty analysis indicated that the scaled in vitro uptake clearance had to be adjusted with an additional empirical scaling factor of 5 to match the plasma concentrations and biliary excretion profiles. Applying this model, plasma clearances (CLP) for rat and human were predicted within two-fold relative to predictions based on respective in vitro data. The corrected hepatic uptake transport kinetic parameters enabled the prediction of valsartan in vivo PK profiles and plasma clearances, using PBPK modeling. Moreover, the interspecies difference in elimination rate observed in vivo was correctly reflected in the transport parameters determined in vitro. More data are needed to support more general applications of the proposed approach including its use for metabolized compounds.

Physiologically Based Pharmacokinetic Modelling

Abstract: This chapter presents the readers with a primer on the subject of physiologically based pharmacokinetic (PBPK) modelling. It discusses the theory and principles of PBPK modelling, and compares and contrasts it with classical pharmacokinetic modelling. It describes the multiple steps involved in developing PBPK models, and includes a compilation, with complete referencing, of published PBPK models for environmental chemicals that have been developed to date. The many applications of PBPK modelling to address issues in toxicology and health risk assessment are discussed with relevant examples. It concludes with some discussion of the problems and limitations in PBPK modelling, and offers some observations about future directions for this rapidly emerging field. Keywords: physiologically based pharmacokinetic modelling; principles; toxicological applications; risk assessment

Design and Application of Microfluidic Systems for In Vitro Pharmacokinetic Evaluation of Drug Candidates

Abstract: One of the fundamental challenges facing the development of new chemical entities within the pharmaceutical industry is the extrapolation of key in vivo parameters from in vitro cell culture assays and animal studies Development of microscale devices and screening assays incorporating primary human cells can potentially provide better, faster and more efficient prediction of in vivo toxicity and clinical drug performance With this goal in mind, large strides have been made in the area of microfluidics to provide in vitro surrogates that are designed to mimic the physiological architecture and dynamics More recent advancements have been made in the development of in vitro analogues to physiologically-based pharmacokinetic (PBPK) models - a mathematical model that represents the body as interconnected compartments specific for a particular organ In this review we highlight recent advancements in human hepatocyte microscale culture, and describe the next generation of integrated devices, whose potential allows for the high throughput assessment of drug metabolism, distribution and pharmacokinetics

The influence of genetic polymorphisms on population variability in six xenobiotic-metabolizing enzymes.

Abstract: This review provides variability statistics for polymorphic enzymes that are involved in the metabolism of xenobiotics. Six enzymes were evaluated: cytochrome P-450 (CYP) 2D6, CYP2E1, aldehyde dehydrogenase-2 (ALDH2), paraoxonase (PON1), glutathione transferases (GSTM1, GSTT1, and GSTP1), and N-acetyltransferases (NAT1 and NAT2). The polymorphisms were characterized with respect to (1) number and type of variants, (2) effects of polymorphisms on enzyme function, and (3) frequency of genotypes within specified human populations. This information was incorporated into Monte Carlo simulations to predict the population distribution and describe interindividual variability in enzyme activity. The results were assessed in terms of (1) role of these enzymes in toxicant activation and clearance, (2) molecular epidemiology evidence of health risk, and (3) comparing enzyme variability to that commonly assumed for pharmacokinetics. Overall, the Monte Carlo simulations indicated a large degree of interindividual variability in enzyme function, in some cases characterized by multimodal distributions. This study illustrates that polymorphic metabolizing systems are potentially important sources of pharmacokinetic variability, but there are a number of other factors including blood flow to liver and compensating pathways for clearance that affect how a specific polymorphism will alter internal dose and toxicity. This is best evaluated with the aid of physiologically based pharmacokinetic (PBPK) modeling. The population distribution of enzyme activity presented in this series of articles serves as inputs to such PBPK modeling analyses.

Physiologically Based Toxicokinetic (PBTK) Modeling in Ecotoxicology

Abstract: Physiologically based toxicokinetic [(PBTK), or alternatively referred to as physiologically based pharmacokinetic (PBPK)] models are quantitative descriptions of absorption, distribution, metabolism, and excretion of chemicals in biota. PBTK models are increasingly being used as an effective tool for designing toxicology experiments and for conducting extrapolations essential for risk assessments. This chapter describes the basic concepts, equations, parameters, and software essential for developing PBTK models. QSAR methods for estimating input parameters as well as data sources containing relevant parameters for model development in rats, mice, cattle, birds, and fish are summarized. Model templates for creating PBTK models in fish and terrestrial species are presented. Several examples of model simulations are presented along with a brief discussion of how PBTK models can be applied to make significant advances in ecotoxicology and ecotoxicological risk assessments.

A PBPK model for midazolam in four avian species.

Abstract: A physiologically based pharmacokinetic (PBPK) model was developed for midazolam in the chicken and extended to three other species. Physiological parameters included organ weights obtained from 10 birds of each species and blood flows obtained from the literature. Partition coefficients for midazolam in tissues vs. plasma were estimated from drug residue data obtained at slaughter. The avian models include separate compartments for venous plasma, liver, kidney, muscle, fat and all other tissues. An estimate of total body clearance from an earlier in vitro study was used as a starting value in the model, assuming almost complete removal of the parent compound by liver metabolism. The model was optimized for the chicken with plasma and tissue data from a pharmacokinetic study after intravenous midazolam (5 mg/kg) dose. To determine which parameters had the most influence on the goodness of fit, a sensitivity analysis was performed. The optimized chicken model was then modified for the turkey, pheasant and quail. The models were validated with midazolam plasma and tissue residue data in the turkey, pheasant and quail. The PBPK models in the turkey, pheasant and quail provided good predictions of the observed tissue residues in each species, in particular for liver and kidney.

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

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

Physiologically-based PK/PD modelling of therapeutic macromolecules.

Abstract: Therapeutic proteins are a diverse class of drugs consisting of naturally occurring or modified proteins, and due to their size and physico-chemical properties, they can pose challenges for the pharmacokinetic and pharmacodynamic studies. Physiologically-based pharmacokinetics (PBPK) modelling has been effective for early in silico prediction of pharmacokinetic properties of new drugs. The aim of the present workshop was to discuss the feasibility of PBPK modelling of macromolecules. The classical PBPK approach was discussed with a presentation of the successful example of PBPK modelling of cyclosporine A. PBPK model was performed with transport of the cyclosporine across cell membranes, affinity to plasma proteins and active membrane transporters included to describe drug transport between physiological compartments. For macromolecules, complex PBPK modelling or permeability-limited and/or target-mediated distribution was discussed. It was generally agreed that PBPK modelling was feasible and desirable. The role of the lymphatic system should be considered when absorption after extravascular administration is modelled. Target-mediated drug disposition was regarded as an important feature for generation of PK models. Complex PK-models may not be necessary when a limited number of organs are affected. More mechanistic PK/PD models will be relevant when adverse events/toxicity are included in the PK/PD modelling.

Prediction of Pharmacokinetic Profile of Valsartan in Humans Based on in vitro Uptake-Transport Data

Abstract: The aim of this study was to evaluate a strategy based on a physiologically based pharmacokinetic (PBPK) model for the prediction of PK profiles in human using in vitro data when elimination of compounds relies on active transport processes. The strategy was first applied to rat in vivo and in vitro data in order to refine the PBPK model. The model could then be applied to human in vitro uptake transport data using valsartan as a probe substrate. Plated rat and human hepatocytes, and cell lines overexpressing human OATP1B1 and OATP1B3 were used for in vitro uptake experiments. The uptake rate of valsartan was higher for rat hepatocytes (Km,u = 28.4 ± 3.7 μM, Vmax = 1318 ± 176 pmol/mg/min and Pdif = 1.21 ± 0.42 μl/mg/min) compared to human hepatocytes (Km,u = 44.4 ± 14.6 μM, Vmax = 304 ± 85 pmol/mg/min and Pdif = 0.724 ± 0.271 μl/mg/min). OATP1B1 and 1B3 parameters were correlated to human hepatocyte data using experimentally established relative activity factors (RAF). Resulting PBPK simulations using those in vitro data were compared for plasma (human and rat) and bile (rat) concentration–time profiles following i.v. bolus administration of valsartan. An uncertainty analysis indicated that the scaled in vitro uptake clearance had to be adjusted with an additional empirical scaling factor of 5 to match the plasma concentrations and biliary excretion profiles. Applying this model, plasma clearances (CLP) for rat and human were predicted within two-fold relative to predictions based on respective in vitro data. The corrected hepatic uptake transport kinetic parameters enabled the prediction of valsartan in vivo PK profiles and plasma clearances, using PBPK modeling. Moreover, the interspecies difference in elimination rate observed in vivo was correctly reflected in the transport parameters determined in vitro. More data are needed to support more general applications of the proposed approach including its use for metabolized compounds.

Trichloroethylene risk assessment: a review and commentary

Abstract: Trichloroethylene (TCE) is a widespread environmental contaminant that is carcinogenic when given in high, chronic doses to certain strains of mice and rats. The capacity of TCE to cause cancer in humans is less clear. The current maximum contaminant level (MCL) of 5 ppb (microg/L) is based on an US Environment Protection Agency (USEPA) policy decision rather than the underlying science. In view of major advances in understanding the etiology and mechanisms of chemically induced cancer, USEPA began in the late 1990s to revise its guidelines for cancer risk assessment. TCE was chosen as the pilot chemical. The USEPA (2005) final guidelines emphasized a "weight-of-evidence" approach with consideration of dose-response relationships, modes of action, and metabolic/toxicokinetic processes. Where adequate data are available to support reversible binding of the carcinogenic moiety to biological receptors as the initiating event (i.e., a threshold exists), a nonlinear approach is to be used. Otherwise, the default assumption of a linear (i.e., nonthreshold) dose-response is utilized. When validated physiologically based pharmacokinetic (PBPK) models are available, they are to be used to predict internal dosimetry as the basis for species and dose extrapolations. The present article reviews pertinent literature and discusses areas where research may resolve some outstanding issues and facilitate the reassessment process. Key research needs are proposed, including role of dichloroacetic acid (DCA) in TCE-induced liver tumorigenesis in humans; extension of current PBPK models to predict target organ deposition of trichloroacetic acid (TCA) and DCA in humans ingesting TCE in drinking water; use of human hepatocytes to ascertain metabolic rate constants for use in PBPK models that incorporate variability in metabolism of TCE by potentially sensitive subpopulations; measurement of the efficiency of first-pass elimination of trace levels of TCE in drinking water; and assessment of exogenous factors' (e.g., alcohol, drugs) ability to alter metabolic activation and risks at such low-level exposure.

Influence of physiological status on residues of lipophilic xenobiotics in livestock

Abstract: Data on the transfer of lipophilic xenobiotics from livestock feed and the environment to meat and milk are required for risk assessment purposes. Often, data are only available for lactating dairy cattle. Physiologically-based pharmacokinetic (PBPK) modeling has been used to explore differences between classes of food-producing animals. Blood and tissue levels of lipophilic xenobiotics under conditions approximating steady-state were simulated. Simulations of constant exposure were performed for lactating cows, non-lactating cattle, sheep, goats and swine. The tissue : blood partition coefficient, fat volume and fat blood flow were identified as critical determinants of predicted tissue concentrations. There may be significant breed differences in residues in milk and fat following exposure. Modeling was used to derive scaling factors that can be used to assist the extrapolation of transfer studies, carried out on lactating dairy cows, to other classes of cattle and different species.

Practical Anticipation of Human Efficacious Doses and Pharmacokinetics Using In Vitro and Preclinical In Vivo Data

Abstract: Accurate predictions of human pharmacokinetic and pharmacodynamic (PK/PD) profiles are critical in early drug development, as safe, efficacious, and “developable” dosing regimens of promising compounds have to be identified. While advantages of successful integration of preclinical PK/PD data in the “anticipation” of human doses (AHD) have been recognized, pharmaceutical scientists have faced difficulties with practical implementation, especially for PK/PD profile projections of compounds with challenging absorption, distribution, metabolism, excretion and formulation properties. In this article, practical projection approaches for formulation-dependent human PK/PD parameters and profiles of Biopharmaceutics Classification System classes I-IV drugs based on preclinical data are described. Case examples for “AHD” demonstrate the utility of preclinical and clinical PK/PD modeling for formulation risk identification, lead candidate differentiation, and prediction of clinical outcome. The application of allometric scaling methods and physiologically based pharmacokinetic approaches for clearance or volume of distribution projections is described using GastroPlus™. Methods to enhance prediction confidence such as in vitro–in vivo extrapolations in clearance predictions using in vitro microsomal data are discussed. Examples for integration of clinical PK/PD and formulation data from frontrunner compounds via “reverse pharmacology strategies” that minimize uncertainty with PK/PD predictions are included. The use of integrated softwares such as GastroPlus™ in combination with established PK projection methods allow the projection of formulation-dependent preclinical and human PK/PD profiles required for compound differentiation and development risk assessments.

Transport and dynamics of toxic pollutants in the natural environment and their effect on human health: research gaps and challenge

Abstract: The source–pathway–receptor (SPR) approach to human exposure and risk assessment contains considerable uncertainty when using the refined modelling approaches to pollutant transport and dispersal, not least in how compounds of concern might be prioritised, proxy or indicator substances identified and the basic environmental and toxicological data collected. The impact of external environmental variables, urban systems and lifestyle is still poorly understood. This determines exposure of individuals and there are a number of methods being developed to provide more reliable spatial assessments. Within the human body, the dynamics of pollutants and effects on target organs from diffuse, transient sources of exposure sets ambitious challenges for traditional risk assessment approaches. Considerable potential exists in the application of, e.g. physiologically based pharmacokinetic (PBPK) models. The reduction in uncertainties associated with the effects of contaminants on humans, transport and dynamics influencing exposure, implications of adult versus child exposure and lifestyle and the development of realistic toxicological and exposure data are all highlighted as urgent research needs. The potential to integrate environmental with toxicological models provides the next phase of research opportunity and should be used to drive empirical and model assessments.

Physiologically based pharmacokinetics of matrine in the rat after oral administration of pure chemical and ACAPHA.

Abstract: ACAPHA, a botanical drug for the treatment of human esophageal cancer in China, is under investigation as a lung cancer chemoprevention agent at the BC Cancer Agency (Vancouver, BC, Canada). Little or no information is available on the pharmacokinetics of ACAPHA in animals. The objectives of this study were as follows: to examine the disposition kinetics of matrine, a bioactive marker of ACAPHA in the rat; to develop a physiologically based pharmacokinetic (PBPK) model for pure matrine; and to characterize the absorption and clearance of crude matrine in ACAPHA-treated rats using the PBPK model. Pure matrine (15 mg/kg) or crude matrine in the form of ACAPHA (0.38 or 3.8 g/kg) was administered to the rat by gavages. The rats were sacrificed at different time points postdosing. Blood and major organs were removed from the rat, extracted with toluene/butanol, and quantified for matrine using gas chromatography-mass spectrometry. An 11-compartment, flow-limited PBPK model of matrine was developed. The PBPK model was able to simulate closely the empirical data of rats treated with pure matrine. Because the absorption and clearance of crude matrine in ACAPHA-treated rats could not be parameterized a priori, they were estimated by fitting the experimental data to the PBPK model. Results of the study show that pure matrine is absorbed and eliminated by the rat at faster rates than crude matrine. Moreover, the ACAPHA matrix may change the pharmacokinetics of matrine in the rat significantly. The PBPK model is a valuable tool to gain insights into the disposition kinetics of a botanical drug.

The implications of using a physiologically based pharmacokinetic (PBPK) model for pesticide risk assessment.

Abstract: BackgroundA physiologically based pharmacokinetic (PBPK) model would make it possible to simulate the dynamics of chemical absorption, distribution, metabolism, and elimination (ADME) from differen...

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

Abstract: 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 (111In-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, shall be included in the more accurate models.

Physiologically based pharmacokinetic (PBPK) modeling and simulation: applications in lead optimization.

Abstract: Physiologically based pharmacokinetics (PBPK) models are increasingly being used in the lead optimization (LO) process. Although there are currently few literature reports of the application of PBPK, the scope of PBPK modeling is expanding and there is a steady increase in the number of publications in this field. Recent publications covering four important areas of the application of PBPK modeling in LO have been reviewed.

Measurement and prediction of oral absorption.

Abstract: After defining oral absorption, this review article summarizes the influence of different physiological and physicochemical parameters on oral absorption explained according to the situation at BayerScheringPharma. Along the optimization process in industries, prediction of oral absorption is exemplified. In silico prediction of oral absorption in early stages of research is highlighted with three examples, i.e., a classification algorithm, a single parameter prediction, and a linear free-energy relationship. In vitro prediction of permeation using Caco-2 cell layers and physicochemical modeling is exemplified. The influence of solubility is shown by a concrete example, in particular, using physiologically based pharmacokinetic (PBPK) modeling and physicochemical parameters. For later stages, optimization examples of in vivo animal models stress the importance of excellent in vivo data and in vivo/in vivo correlations for the prediction of human oral absorption from animal experiments.

Development of a physiologically based pharmacokinetic (PBPK) model for methyl iodide in rats, rabbits, and humans.

Abstract: Methyl iodide (MeI) has been proposed as an alternative to methyl bromide as a pre-plant soil fumigant that does not deplete stratospheric ozone. In inhalation toxicity studies performed in animals as part of the registration process, three effects have been identified that warrant consideration in developing toxicity reference values for human risk assessment: nasal lesions (rat), acute neurotoxicity (rat), and fetal loss (rabbit). Uncertainties in the risk assessment can be reduced by using an internal measure of target tissue dose that is linked to the likely mode of action (MOA) for the toxicity of MeI, rather than the external exposure concentration. Physiologically based pharmacokinetic (PBPK) models have been developed for MeI and used to reduce uncertainties in the risk assessment extrapolations (e.g. interspecies, high to low dose, exposure scenario). PBPK model-derived human equivalent concentrations comparable to the animal study NOAELs (no observed adverse effect levels) for the endpoints of interest were developed for a 1-day, 24-hr exposure of bystanders or 8 hr/day exposure of workers. Variability analyses of the PBPK models support application of uncertainty factors (UF) of approximately 2 for intrahuman pharmacokinetic variability for the nasal effects and acute neurotoxicity.

Reconstructing exposures from small samples using physiologically based pharmacokinetic models and multiple biomarkers

Abstract: This study examines the use of physiologically based pharmacokinetic (PBPK) models for inferring exposure when the number of biomarker observations per individual is limited, as commonly occurs in population exposure surveys. The trade-off between sampling multiple biomarkers at a specific time versus fewer biomarkers at multiple time points was investigated, using a simulation-based approach based on a revised and updated chlorpyrifos PBPK model originally published. Two routes of exposure, oral and dermal, were studied as were varying levels of analytic measurement error. It is found that adding an additional biomarker at a given time point adds substantial additional information to the analysis, although not as much as the addition of another sampling time. Furthermore, the precision of the estimates of exposed dose scaled approximately with the analytic precision of the biomarker measurement. For acute exposure scenarios such as those considered here, the results of this study suggest that the number of biomarkers can be balanced against the number of sampling times to obtain the most efficient estimator after consideration of cost, intrusiveness, and other relevant factors.