Showing papers on "Physiologically based pharmacokinetic modelling published in 2006"

Development and evaluation of a generic physiologically based pharmacokinetic model for children.

Abstract: Clinical trials in children are being encouraged by regulatory authorities in light of the immense off-label and unlicensed use of drugs in the paediatric population. The use of in silico techniques for pharmacokinetic prediction will aid in the development of paediatric clinical trials by guiding dosing regimens, ensuring efficient blood sampling times, maximising therapeutic effect and potentially reducing the number of children required for the study. The goal of this study was to extend an existing physiologically based pharmacokinetic (PBPK) model for adults to reflect the age-related physiological changes in children from birth to 18 years of age and, in conjunction with a previously developed age-specific clearance model, to evaluate the accuracy of the paediatric PBPK model to predict paediatric plasma profiles. The age-dependence of bodyweight, height, organ weights, blood flows, interstitial space and vascular space were taken from the literature. Physiological parameters that were used in the PBPK model were checked against literature values to ensure consistency. These included cardiac output, portal vein flow, extracellular water, total body water, lipid and protein. Five model compounds (paracetamol [acetaminophen], alfentanil, morphine, theophylline and levofloxacin) were then examined by gathering the plasma concentration-time profiles, volumes of distribution and elimination half-lives from different ages of children and adults. First, the adult data were used to ensure accurate prediction of pharmacokinetic profiles. The model was then scaled to the specific age of children in the study, including the scaling of clearance, and the generated plasma concentration profiles, volumes of distribution and elimination half-lives were compared with literature values. Physiological scaling produced highly age-dependent cardiac output, portal vein flow, extracellular water, total body water, lipid and protein values that well represented literature data. The pharmacokinetic profiles in children for the five compounds were well predicted and the trends associated with age were evident. Thus, young neonates had plasma concentrations greater than the adults and older children had concentrations less than the adults. Eighty-three percent, 97% and 87% of the predicted plasma concentrations, volumes of distribution and elimination half-lives, respectively, were within 50% of the study reported values. There was no age-dependent bias for term neonates to 18 years of age when examining volumes of distribution and elimination half-lives. This study suggests that the developed paediatric PBPK model can be used to scale pharmacokinetics from adults. The accurate prediction of pharmacokinetic parameters in children will aid in the development of dosing regimens and sampling times, thus increasing the efficiency of paediatric clinical trials.

A Novel Strategy for Physiologically Based Predictions of Human Pharmacokinetics

Abstract: Background The major aim of this study was to develop a strategy for predicting human pharmacokinetics using physiologically based pharmacokinetic (PBPK) modelling. This was compared with allometry (of plasma concentration-time profiles using the Dedrick approach), in order to determine the best approaches and strategies for the prediction of human pharmacokinetics.

Use of a physiologically based pharmacokinetic model to identify exposures consistent with human biomonitoring data for chloroform.

Abstract: Biomonitoring data provide evidence of human exposure to environmental chemicals by quantifying the chemical or its metabolite in a biological matrix. To better understand the correlation between biomonitoring data and environmental exposure, physiologically based pharmacokinetic (PBPK) modeling can be of use. The objective of this study was to use a combined PBPK model with an exposure model for showering to estimate the intake concentrations of chloroform based on measured blood and exhaled breath concentrations of chloroform. First, the predictive ability of the combined model was evaluated with three published studies describing exhaled breath and blood concentrations in people exposed to chloroform under controlled showering events. Following that, a plausible exposure regimen was defined combining inhalation, ingestion, and dermal exposures associated with residential use of water containing typical concentrations of chloroform to simulate blood and exhaled breath concentrations of chloroform. Simulation results showed that inhalation and dermal exposure could contribute substantially to total chloroform exposure. Next, sensitivity analysis and Monte Carlo analysis were performed to investigate the sources of variability in model output. The variability in exposure conditions (e.g., shower duration) was shown to contribute more than the variability in pharmacokinetics (e.g., body weight) to the predicted variability in blood and exhaled breath concentrations of chloroform. Lastly, the model was used in a reverse dosimetry approach to estimate distributions of exposure consistent with concentrations of chloroform measured in human blood and exhaled breath.

Population-Based Analysis of Methadone Distribution and Metabolism Using an Age-Dependent Physiologically Based Pharmacokinetic Model

Abstract: Limited pharmacokinetic (PK) and pharmacodynamic (PD) data are available to use in methadone dosing recommendations in pediatric patients for either opioid abstinence or analgesia. Considering the extreme inter-individual variability of absorption and metabolism of methadone, population-based PK would be useful to provide insight into the relationship between dose, blood concentrations, and clinical effects of methadone. To address this need, an age-dependent physiologically based pharmacokinetic (PBPK) model has been constructed to systematically study methadone metabolism and PK. The model will facilitate the design of cost-effective studies that will evaluate methadone PK and PD relationships, and may be useful to guide methadone dosing in children. The PBPK model, which includes whole-body multi-organ distribution, plasma protein binding, metabolism, and clearance, is parameterized based on a database of pediatric PK parameters and data collected from clinical experiments. The model is further tailored and verified based on PK data from individual adults, then scaled appropriately to apply to children aged 0-24 months. Based on measured variability in CYP3A enzyme expression levels and plasma orosomucoid (ORM2) concentrations, a Monte-Carlo-based simulation of methadone kinetics in a pediatric population was performed. The simulation predicts extreme variability in plasma concentrations and clearance kinetics for methadone in the pediatric population, based on standard dosing protocols. In addition, it is shown that when doses are designed for individuals based on prior protein expression information, inter-individual variability in methadone kinetics may be greatly reduced.

Use of Probabilistic Modeling within a Physiologically Based Pharmacokinetic Model To Predict Sulfamethazine Residue Withdrawal Times in Edible Tissues in Swine

Abstract: The presence of antimicrobial agents in edible tissues of food-producing animals remains a major public health concern. Probabilistic modeling techniques incorporated into a physiologically based pharmacokinetic (PBPK) model were used to predict the amounts of sulfamethazine residues in edible tissues in swine. A PBPK model for sulfamethazine in swine was adapted to include an oral dosing route. The distributions for sensitive parameters were determined and were used in a Monte Carlo analysis to predict tissue residue times. Validation of the distributions was done by comparison of the results of a Monte Carlo analysis to those obtained with an external data set from the literature and an in vivo pilot study. The model was used to predict the upper limit of the 95% confidence interval of the 99th percentile of the population, as recommended by the U.S. Food and Drug Administration (FDA). The external data set was used to calculate the withdrawal time by using the tolerance limit algorithm designed by FDA. The withdrawal times obtained by both methods were compared to the labeled withdrawal time for the same dose. The Monte Carlo method predicted a withdrawal time of 21 days, based on the amounts of residues in the kidneys. The tolerance limit method applied to the time-limited data set predicted a withdrawal time of 12 days. The existing FDA label withdrawal time is 15 days. PBPK models can incorporate probabilistic modeling techniques that make them useful for prediction of tissue residue times. These models can be used to calculate the parameters required by FDA and explore those conditions where the established withdrawal time may not be sufficient.

Physiologically Based Synthetic Models of Hepatic Disposition

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

Use of a physiologically based pharmacokinetic model for rats to study the influence of body fat mass and induction of CYP1A2 on the pharmacokinetics of TCDD.

Abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly lipophilic chemical that distributes into adipose tissue, especially at low doses. However, at high doses TCDD sequesters in liver because it induces cytochrome P450 1A2 (CYP1A2) that binds TCDD. A physiologically based pharmacokinetic (PBPK) model was developed that included an inducible elimination rate of TCDD in the Sprague-Dawley rat. Objectives of this work were to characterize the influence of induction of CYP1A2 and adipose tissue mass fraction on the terminal elimination half-life (t1/2) of TCDD using this PBPK model. When the model assumes a fixed elimination of TCDD, t1/2 increases with dose, due to hepatic sequestration. Because experimental data indicate that the t1/2 of TCDD decreases with dose, the model was modified to include an inducible elimination rate. The PBPK model was then used to compare the t1/2 after an increase of adipose tissue mass fraction from 6.9 to 70%. The model suggests that at low exposures, increasing adipose tissue mass increases the terminal t1/2. However, at higher exposures, as CYP1A2 is induced, the relationship between adipose tissue mass and t1/2 reaches a plateau. This demonstrates that an inducible elimination rate is needed in a PBPK model in order to describe the pharmacokinetics of TCDD. At low exposures these models are more sensitive to parameters related to partitioning into adipose tissue.

Structural Identifiability of Physiologically Based Pharmacokinetic Models

Abstract: When starting a project in drug kinetics it is necessary to test a priori whether there is sufficient information in the experimental input-output design to estimate unique values of internal rate constants. This is an important test if the pharmacokinetics of a drug are to be characterised in some way by the parameter values estimated from the observed plasma or blood concentration profile. Various modifications of the well-perfused Physiologically Based Pharmacokinetic model (PBPK) are considered here. More complex PBPK models can be considered to consist of subsystems, representing groups of tissues, which are connected in parallel to the central compartment. A novel method of structural identifiability analysis is presented here that considers these subsystems individually. This makes analysis of subsequently modified models much simpler. It is found in a number of cases that these more complex systems remain globally identifiable and at worst reduce to locally identifiable for the additional parameters. A caveat is added about having more than one eliminating peripheral tissue.

Steady‐State Solutions to PBPK Models and Their Applications to Risk Assessment I: Route‐to‐Route Extrapolation of Volatile Chemicals

Abstract: Although analysis of in vivo pharmacokinetic data necessitates use of time-dependent physiologically-based pharmacokinetic (PBPK) models, risk assessment applications are often driven primarily by steady-state and/or integrated (e.g., AUC) dosimetry. To that end, we present an analysis of steady-state solutions to a PBPK model for a generic volatile chemical metabolized in the liver. We derive an equivalent model that is much simpler and contains many fewer parameters than the full PBPK model. The state of the system can be specified by two state variables-the rate of metabolism and the rate of clearance by exhalation. For a given oral dose rate or inhalation exposure concentration, the system state only depends on the blood-air partition coefficient, metabolic constants, and the rates of blood flow to the liver and of alveolar ventilation. At exposures where metabolism is close to linear, only the effective first-order metabolic rate is needed. Furthermore, in this case, the relationship between cumulative exposure and average internal dose (e.g., AUCs) remains the same for time-varying exposures. We apply our analysis to oral-inhalation route extrapolation, showing that for any dose metric, route equivalence only depends on the parameters that determine the system state. Even if the appropriate dose metric is unknown, bounds can be placed on the route-to-route equivalence with very limited data. We illustrate this analysis by showing that it reproduces exactly the PBPK-model-based route-to-route extrapolation in EPA's 2000 risk assessment for vinyl chloride. Overall, we find that in many cases, steady-state solutions exactly reproduce or closely approximate the solutions using the full PBPK model, while being substantially more transparent. Subsequent work will examine the utility of steady-state solutions for analyzing cross-species extrapolation and intraspecies variability.

Physiologically-Based Pharmacokinetic Modeling of Benzene in Humans: A Bayesian Approach

Abstract: Benzene is myelotoxic and leukemogenic in humans exposed at high doses (>1 ppm, more definitely above 10 ppm) for extended periods. However, leukemia risks at lower exposures are uncertain. Benzene occurs widely in the work environment and also indoor air, but mostly below 1 ppm, so assessing the leukemia risks at these low concentrations is important. Here, we describe a human physiologically-based pharmacokinetic (PBPK) model that quantifies tissue doses of benzene and its key metabolites, benzene oxide, phenol, and hydroquinone after inhalation and oral exposures. The model was integrated into a statistical framework that acknowledges sources of variation due to inherent intra- and interindividual variation, measurement error, and other data collection issues. A primary contribution of this work is the estimation of population distributions of key PBPK model parameters. We hypothesized that observed interindividual variability in the dosimetry of benzene and its metabolites resulted primarily from known or estimated variability in key metabolic parameters and that a statistical PBPK model that explicitly included variability in only those metabolic parameters would sufficiently describe the observed variability. We then identified parameter distributions for the PBPK model to characterize observed variability through the use of Markov chain Monte Carlo analysis applied to two data sets. The identified parameter distributions described most of the observed variability, but variability in physiological parameters such as organ weights may also be helpful to faithfully predict the observed human-population variability in benzene dosimetry.

Issues in the Pharmacokinetics of Trichloroethylene and Its Metabolites

Abstract: Much progress has been made in understanding the complex pharmacokinetics of trichloroethylene (TCE). Qualitatively, it is clear that TCE is metabolized to multiple metabolites either locally or into systemic circulation. Many of these metabolites are thought to have toxicologic importance. In addition, efforts to develop physiologically based pharmacokinetic (PBPK) models have led to a better quantitative assessment of the dosimetry of TCE and several of its metabolites. As part of a mini-monograph on key issues in the health risk assessment of TCE, this article is a review of a number of the current scientific issues in TCE pharmacokinetics and recent PBPK modeling efforts with a focus on literature published since 2000. Particular attention is paid to factors affecting PBPK modeling for application to risk assessment. Recent TCE PBPK modeling efforts, coupled with methodologic advances in characterizing uncertainty and variability, suggest that rigorous application of PBPK modeling to TCE risk assessment appears feasible at least for TCE and its major oxidative metabolites trichloroacetic acid and trichloroethanol. However, a number of basic structural hypotheses such as enterohepatic recirculation, plasma binding, and flow- or diffusion-limited treatment of tissue distribution require additional evaluation and analysis. Moreover, there are a number of metabolites of potential toxicologic interest, such as chloral, dichloroacetic acid, and those derived from glutathione conjugation, for which reliable pharmacokinetic data is sparse because of analytical difficulties or low concentrations in systemic circulation. It will be a challenge to develop reliable dosimetry for such cases.

Integrating in vitro ADMET data through generic physiologically based pharmacokinetic models.

Abstract: Early estimation of kinetics in man currently relies on extrapolation from experimental data generated in animals. Recent results from the application of a generic physiologically based model, Cloe PK) (Cyprotex), which is parameterised for human and rat physiology, to the estimation of plasma pharmacokinetics, are summarised in this paper. A comparison with predictive methods that involve scaling from in vivo animal data can also be made from recently published data. On average, the divergence of the predicted plasma concentrations from the observed data was 0.47 log units. For the external test set, > 70% of the predicted values of the AUC were within threefold of the observed values. Furthermore, the model was found to match or exceed the performance of three published interspecies scaling methods for estimating clearance, all of which showed a distinct bias towards overprediction. It is concluded that Cloe PK, as a means of integrating readily determined in vitro and/or in silico data, is a powerful, cost-effective tool for estimating exposure and kinetics in drug discovery and risk assessment that should, if widely adopted, lead to major reductions in the need for animal experimentation.

Application of physiology-based pharmacokinetic and pharmacodynamic modeling to individualized target-controlled propofol infusions.

Abstract: This study compared the ability of the physiology-based pharmacokinetic (PBPK) model with that of compartmental models used in propofol infusion devices to predict the pharmacokinetics and pharmacodynamics of propofol in various patient groups (children, pregnant women, young men, normal weight adults, and obese adults). With a PBPK model, loss of consciousness (LOC) and recovery of consciousness (ROC) corresponded to a narrow range of brain tissue concentrations (2.2-4.0 mg/L). With the compartmental models, predicted effect concentrations were also within a narrow range at LOC, but were outside the range at ROC. In individuals of normal weight, coefficients of variation (CV) of the predicted brain or effect concentrations at LOC were in a similar range-between 18% and 32%. In obese individuals, however, interindividual CV values for brain or effect concentrations were 41% (PBPK) and 93% (compartmental). This comparison suggests the increased flexibility of PBPK models over compartmental models, the latter of which rely heavily on the patient group from which the model was derived. The incorporation of PBPK models may provide target-controlled infusions with enhanced ability to predict response in a wide variety of patients.

Physiologically Based Pharmacokinetic Modeling of Organophosphorus and Carbamate Pesticides

Abstract: Publisher Summary The chapter illustrates the applications of physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) modeling to assess OP and potentially CM insecticide dosimetry, biological response, and risk in humans exposed to these insecticides. Pharmacokinetics continue to play an important role in assessing organophosphorus (OP) and carbamate (CM) insecticide dosimetry, biological response, and risk in humans exposed to these agents. Pharmacokinetic is concemed with the quantitative integration of absorption, distribution, metabolism, and excretion and can be used to provide insight into the toxicological responses associated with these insecticides. These two major classes of pesticides share a common toxicological mode of action associated with their ability to target and inhibit acetylcholinesterase (AChE). Pharmacokinetic is 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-, and gender-specific and dose-dependent differences in biological response. These studies have been conducted with OP and CM insecticides in multiple species, at various dose levels, and across different routes of exposure to understand how in vivo kinetics contributes to the observed toxicological response. Pharmacokinetic studies with these insecticides are also useful in facilitating extrapolation of dosimetry and biological response from animals to humans, and for the assessment of human health risk. In this regard, PBPK/PD models are being utilized to assess risk and understand the toxicological implications of known or suspected exposures to various OP and CM insecticides.

Physiologically-based pharmacokinetic modeling of genistein in rats, Part I: Model development.

Abstract: Genistein is a phytoestrogen-a plant-derived compound that binds to and activates the estrogen receptor-occurring at high levels in soy beans and food products, leading to widespread human exposure. The numerous scientific publications available describing genistein's dosimetry, mechanisms of action, and identified or putative health effects in both experimental animals and humans make it ideal for examination as an example of endocrine-active compound (EAC). We developed a physiologically-based pharmacokinetic (PBPK) model to quantify the internal, target-tissue dosimetry of genistein in adult rats. Complexities of the model include enterohepatic circulation, binding of both genistein and its conjugates to plasma proteins, and the multiple compartments used to describe transport through the bile duct and gastrointestinal tract. Other aspects of the model are simple perfusion-limited transport to the tissue groups and first-order rates of metabolism, uptake, and excretion. We describe here the model structure and initial calibration of the model by fitting to a large data set for Wistar rats. The model structure can be readily extrapolated to describe genistein dosimetry in humans or modified to describe the dosimetry of other phytoestrogens and phenolic EACs. The model does a fair job of capturing the pharmacokinetics. Although it does not describe the interindividual variability and we have not identified a single set of parameters that provide a good fit to the data for both oral and intravenous exposures, we believe it provides a good initial attempt at PBPK modeling for genistein, which can serve as a template for other phytoestrogens and in the design of future experiments and research that can be used to fill data gaps and better estimate model parameters.

Ordinary differential equation models for ethanol pharmacokinetic based on anatomy and physiology.

Abstract: Physiologically-based pharmacokinetic (PBPK) models have been used to describe the distribution and elim- ination characteristics of intravenous ethanol administration. Further, these models have been used to estimate the ethanol infusion profile required to prescribe a specific breath ethanol concentration time course in a specific human being, providing a platform upon which other pharmacokinetic and pharmaco- dynamic investigations are based. In these PBPK models, the equivalence of two different peripheral tissue models are shown and issues concerning the mass flow into the liver in comparison with ethanol metabolism in the liver are explained. I. INTRODUCTION

A physiologically based pharmacokinetic model for endosulfan in the male Sprague-Dawley rats.

Abstract: Endosulfan, an organochlorine (OC) insecticide belonging to the cyclodiene group, is one of the most commonly used pesticides to control pests in vegetables, cotton, and fruits. To date, no physiologically based pharmacokinetic (PBPK) model has been located for endosulfan in animal species and humans. The estimation by a mathematical model is essential since information on humans can scarcely be obtained experimentally. The PBPK model was constructed based on the pharmacokinetic data of our experiment following single oral administration of 14C-Endosulfan to male Sprague-Dawley rats. The model was parameterized by using reference physiological parameter values and partition coefficients that were determined in the experiment and optimized by manual adjustment until the best visual fit of the simulations with the experimental data were observed. The model was verified by simulating the disposition of 14C-Endosulfan in vivo after single and multiple oral dosages and comparing simulated results with experimental results. The model was further verified by using experimental data retrieved from the literature. The present model could reasonably predict target tissue dosimetries in rats. Simulation with three-time repeated administration of 14C-Endosulfan and experimental data retrieved from the literature by the constructed model fitted fairly well with the experimental results; thus suggesting that the newly developed PBPK model was developed. Sensitivity analyses were used to determine those input parameters with the greatest influence on endosulfan tissue concentrations. © 2006 Wiley Periodicals, Inc. Environ Toxicol 21: 464–478, 2006.

Pharmacokinetic Modelling of [2-13C]Uracil Metabolism in Normal and DPD-Deficient Dogs

Abstract: A physiologically based pharmacokinetic (PBPK) model to simulate the plasma concentration and 13CO2 exhalation after [2-13C]uracil administration to DPD-suppressed dogs was developed. Simulation using this PBPK model should be useful in clinical situations where DPD-deficient patients at risk are to be detected with [2-13C]uracil as an in vivo probe.