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Showing papers on "Physiologically based pharmacokinetic modelling published in 2004"


Journal ArticleDOI
TL;DR: The most important age-dependent pharmacokinetic factor appears to be the potential for decreased clearance of a toxic chemical in the perinatal period due to the immaturity of many metabolic enzyme systems, although this same factor may also reduce the production of a reactive metabolite.

183 citations


Journal ArticleDOI
TL;DR: This review provides special focus on the development of hepatic cytochrome P-450 enzymes (CYPs) in early life and how this information, along with many factors unique to children, can be applied to PBPK models for this receptor population.

162 citations


Journal ArticleDOI
TL;DR: The current analysis utilizes data for caffeine and theophylline, closely related xanthines that are both cytochrome P-450 (CYP) 1A2 substrates, in developing PBPK models for neonates and adults, and a stepwise approach for modeling environmental toxicants in children is proposed.
Abstract: Children's risks can differ from those in adults for numerous reasons, one being differences in the pharmacokinetic handling of chemicals. Immature metabolism and a variety of other factors in neonates can affect chemical disposition and clearance. These factors can be incorporated into physiologically based pharmacokinetic (PBPK) models that simulate the fate of environmental toxicants in both children and adults. PBPK models are most informative when supported by empirical data, but typically pediatric pharmacokinetic data for toxicants are not available. In contrast, pharmacokinetic data in children are readily available for therapeutic drugs. The current analysis utilizes data for caffeine and theophylline, closely related xanthines that are both cytochrome P-450 (CYP) 1A2 substrates, in developing PBPK models for neonates and adults. Model development involved scale-up of in vitro metabolic parameters to whole liver and adjusting metabolic function for the ontological pattern of CYP1A2 and other CYPs. Model runs were able to simulate the large differences in half-life and clearance between neonates and adults. Further, the models were able to reproduce the faster metabolic clearance of theophylline relative to caffeine in neonates. This differential between xanthines was found to be due primarily to an extra metabolic pathway available to theophylline, back-methylation to caffeine, that is not available to caffeine itself. This pathway is not observed in adults exemplifying the importance of secondary or novel routes of metabolism in the immature liver. Greater CYP2E1 metabolism of theophylline relative to caffeine in neonates also occurs. Neonatal PBPK models developed for these drugs may be adapted to other CYP1A2 substrates (e.g., arylamine toxicants). A stepwise approach for modeling environmental toxicants in children is proposed.

158 citations


Journal ArticleDOI
TL;DR: Relative drug exposure and absorption parameters suggest that BioResponse-DIM exhibited approximately 50% higher bioavailability than the crystalline formulation, and the established PBPK model should prove useful in the design and analysis of future preclinical studies aimed at evaluating the in vivo pharmacological effects of DIM.
Abstract: 3,3′-Diindolylmethane (DIM) is a naturally occurring indole, which is currently under investigation as a potential chemopreventive agent. The concentrations of DIM in plasma, liver, kidney, lung, heart, and brain tissues were determined following oral administration of two different formulations to mice (250 mg/kg). Mice were sacrificed periodically from 0 to 24 h after administration of either a crystalline or an absorption-enhanced formulation (Bio-Response-DIM; Indolplex) of DIM, and plasma and tissue concentrations were determined by high-performance liquid chromatography (UV detection, 280 nm). A physiologically based pharmacokinetic (PBPK) model was developed to characterize the pharmacokinetic properties of the two different formulations. The final model included parameters reflecting linear first-order absorption, systemic clearance, and distributional clearance in the remainder compartment, which were considered independent of formulation. All pharmacokinetic profiles from the two formulations were fitted simultaneously to estimate unknown model parameters. Plasma and tissue concentration-time profiles exhibited a rapid rise to peak values at 0.5 to 1 h, followed by a polyexponential decline with an extended terminal phase. These profiles were well described by the final model and unknown parameters were estimated with relatively low coefficients of variation. Relative drug exposure and absorption parameters suggest that BioResponse-DIM exhibited approximately 50% higher bioavailability than the crystalline formulation. Clearance of DIM was estimated as 7.18 ml/h. This is the first study to characterize the pharmacokinetics of DIM in mice, and the established PBPK model should prove useful in the design and analysis of future preclinical studies aimed at evaluating the in vivo pharmacological effects of DIM.

121 citations


Journal ArticleDOI
TL;DR: The PBPK/PD model was shown to quantitatively estimate target tissue dosimetry and cholinesterase inhibition following several routes of exposures and shows the potential utility of the model framework for other related organophosphate pesticides.
Abstract: Diazinon (DZN) is an organophosphorus pesticide with the possibility for widespread exposures. The toxicological effects of DZN are primarily mediated through the effects of its toxic metabolite, DZN-oxon on acetylcholinesterases, which results in accumulation of acetylcholine at neuronal junctions. A physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was developed to quantitatively assess the kinetics of DZN and its metabolites in blood and the inhibition of cholinesterases in plasma, RBC, brain, and diaphragm. Focused in vivo pharmacokinetic studies were conducted in male Sprague-Dawley rats and the data were used to refine the model. No overt toxicity was noted following doses up to 100mg/kg. However, cholinesterases in plasma, RBC, brain and diaphragm were substantially inhibited at doses of 50 mg/kg. In plasma, total cholinesterase was inhibited to less than 20% of control by 6 h post dosing with 100 mg/kg. Inhibition of brain acetylcholinesterase (AChE) following 100 mg/kg exposures was approximately 30% of control by 6 h. Diaphragm butyrylcholinesterase (BuChE) inhibition following 100 mg/kg dosing was to less than 20% of control by 6 h. The PBPK/PD model was used to describe the concentrations of DZN and its major, inactive metabolite, 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP) in plasma and urinary elimination of IMHP. The fit of the model to plasma, RBC, brain, and diaphragm total cholinesterase and BuChE activity was also assessed and the model was further validated by fitting data from the open literature for intraperitoneal, intravenous, and oral exposures to DZN. The model was shown to quantitatively estimate target tissue dosimetry and cholinesterase inhibition following several routes of exposures. This model further confirms the usefulness of the model structure previously validated for chlorpyrifos and shows the potential utility of the model framework for other related organophosphate pesticides.

112 citations


Journal ArticleDOI
TL;DR: A physiologically based pharmacokinetic model consisting of vein, artery, lung, liver, spleen, kidneys, heart, testes, muscle, brain, adipose tissue, stomach, and small intestine was developed to predict the tissue distribution and blood pharmacokinetics of bisphenol A in rats and humans.
Abstract: A physiologically based pharmacokinetic (PBPK) model consisting of vein, artery, lung, liver, spleen, kidneys, heart, testes, muscle, brain, adipose tissue, stomach, and small intestine was developed to predict the tissue distribution and blood pharmacokinetics of bisphenol A in rats and humans. To demonstrate the validity of the developed PBPK model, bisphenol A was administered to rats by multiple iv injections to steady state. The PBPK model predicted the steady-state levels of bisphenol A in blood and various tissues observed in rats after multiple iv injections. The PBPK model was further applied to predict blood and various tissue levels of bisphenol A in a 70 kg-human after single iv injection (5-mg dose) and multiple oral administrations to steady state (100-mg doses every 24 h). The simulated steady-state human blood levels (0.9–1.6 ng/ml) were comparable to basal blood levels of bisphenol A reported in literature (1.49 ng/ml). Furthermore, pharmacokinectic parameters of CL (116.6 L/h), V ss (141...

69 citations


Journal ArticleDOI
TL;DR: This model may provide a framework for the development of a human PBPK model to estimate fetal TCDD concentrations in human health risk assessments and overestimates the fetal concentrations by approximately a factor of two at low subchronic exposures, but does predict the fetal tissue concentrations within the range of the experimental data at the higher exposures.

55 citations


Journal ArticleDOI
TL;DR: A program is needed to require the development of physicochemical and biological data to support risk assessment methodologies involving QSAR and PBPK/PD models.
Abstract: A search of the scientific literature was carried out for physiochemical and biological data [i.e., IC50, LD50, Kp (cm/h) for percutaneous absorption, skin/water and tissue/blood partition coefficients, inhibition ki values, and metabolic parameters such as Vmax and Km] on 31 organophosphorus pesticides (OPs) to support the development of predictive quantitative structure–activity relationship (QSAR) and physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models for human risk assessment. Except for work on parathion, chlorpyrifos, and isofenphos, very few modeling data were found on the 31 OPs of interest. The available percutaneous absorption, partition coefficients and metabolic parameters were insufficient in number to develop predictive QSAR models. Metabolic kinetic parameters (Vmax, Km) varied according to enzyme source and the manner in which the enzymes were characterized. The metabolic activity of microsomes should be based on the kinetic activity of purified or cDNA-expr...

51 citations


Journal ArticleDOI
TL;DR: Physiologically based pharmacokinetic (PBPK) models for mixtures have become important tools for predicting conditions under which interactions are likely to alter the assumption of additivity and have permitted calculation of interaction thresholds with more confidence.

43 citations


Journal ArticleDOI
Walter Schmitt1, Stefan Willmann1
TL;DR: Physiology-based pharmacokinetic modeling is well recognized as a technology for mechanistically simulating and predicting the fate of substances in a mammalian body and contributes significantly to reach this goal.

40 citations


Journal ArticleDOI
TL;DR: The rationale for a state-of-the-science risk assessment for trichloroethylene (TCE) is presented and, based on consideration of the most plausible carcinogenic modes of action of TCE, a margin- of-exposure (MOE) approach would appear to be more appropriate.
Abstract: The guidelines for carcinogen risk assessment recently proposed by the U.S. Environmental Protection Agency (U.S. EPA) provide an increased opportunity for the consideration of pharmacokinetic and mechanistic data in the risk assessment process. However, the greater flexibility of the new guidelines can also make their actual implementation for a particular chemical highly problematic. To illuminate the process of performing a cancer risk assessment under the new guidelines, the rationale for a state-of-the-science risk assessment for trichloroethylene (TCE) is presented. For TCE, there is evidence of increased cell proliferation due to receptor interaction or cytotoxicity in every instance in which tumors are observed, and most tumors represent an increase in the incidence of a commonly observed, species-specific lesion. A physiologically based pharmacokinetic (PBPK) model was applied to estimate target tissue doses for the three principal animal tumors associated with TCE exposure: liver, lung, ...

Reference EntryDOI
15 Oct 2004
TL;DR: The general concept and background knowledge of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling is introduced and examples of application are provided.
Abstract: We introduce the general concept and background knowledge of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling. Examples of application of PBPK/PD modeling are provided. We illustrate the utility of PBPK/PD modeling, particularly in the pharmaceutical drug development process. We project future development on “second-generation” PBPK/PD modeling and In silico toxicology. An emphasis is given to introducing the concepts of PBPK/PD modeling rather than the details of its techniques and processes. Keywords: pharmacokinetic/pharmacodynamic (PBPK/PD) modeling; classical pharmacokinetics; differences; myths; data requirements; chemical interactions; application; validation; second-generation PBPK/PD model; reaction network modeling

Journal ArticleDOI
TL;DR: Computer toxicology methods provide a feasible alternative to establish interaction thresholds and a physiologically based pharmacokinetic (PBPK) model was developed to estimate an interaction threshold for the joint toxicity between chlorpyrifos and parathion in the rat.

Journal Article
TL;DR: The biochemical basis for the conceptual models used for physiologically based pharmacokinetic models is focused on, deferring detailed mathematical description of the models and simulation results to a separate paper.
Abstract: We propose an approach to modelling the joint effects of multiple genes involved in metabolic activation and detoxification of environmental exposures A physiologically based pharmacokinetic (PBPK) model is used, in which the various person-specific metabolic rates are related to measurements of the genotypes and/or phenotypes at the various stages of the relevant pathways Markov chain Monte Carlo (MCMC) methods are used to fit the model We illustrate the approach by application to case-control data on colorectal polyps in relation to consumption of well-done red meat and tobacco smoking via pathways involving heterocyclic amines (regulated by the genes CYP1A2, NAT1 and NAT2) and polycyclic aromatic hydrocarbons (regulated by the genes CYP1A1, EPHX1 (also called mEH) and GSTM3) In this chapter, we focus on the biochemical basis for our conceptual models, deferring detailed mathematical description of the models and simulation results to a separate paper

Journal ArticleDOI
TL;DR: A chemical lumping approach is used in a rat PBPK model for gasoline hydrocarbons to overcome the barrier to modeling more complex mixtures, and serves as a first example of how the engineering concept of chemical Lumping can be used in pharmacokinetics.
Abstract: Physiologically based pharmacokinetic (PBPK) models have often been used to describe the absorption, distribution, metabolism, and excretion of chemicals in animals but have been limited to single chemicals and simple mixtures due to the numerous parameters required in the models. To overcome the barrier to modeling more complex mixtures, we used a chemical lumping approach, used in the past in chemical engineering but not in pharmacokinetic modeling, in a rat PBPK model for gasoline hydrocarbons. Our previous gasoline model consisted of five individual components (benzene, toluene, ethylbenzene, xylene, and hexane) and a lumped chemical that included all remaining components of whole gasoline. Despite being comprised of hundreds of components, the lumped component could be described using a single set of chemical parameters that depended on the blend of gasoline. In the present study, we extend this approach to evaporative fractions of gasoline. The PBPK model described the pharmacokinetics of all of the volatility-weighted fractions of gasoline when differences in partitioning and metabolism between fractions were taken into account. Adjusting the ventilation rate parameter to account for respiratory depression at high exposures also allowed a much improved description of the data. At high exposure levels, gasoline components competitively inhibit each other's metabolism, and the model successfully accounted for binary interactions of this type, including between the lumped component and the five other chemicals. The model serves as a first example of how the engineering concept of chemical lumping can be used in pharmacokinetics.

Journal ArticleDOI
TL;DR: To aid in the development of age-specific PBPK models for experimental animals, information on physiological parameters in neonates and young animals is collected, through 60 days of age.
Abstract: Recent scientific and policy initiatives have resulted in increased interest in risk to fetuses, infants, and children and consideration of how such risks should be evaluated. A useful way of addressing this issue is to use physiologically based pharmacokinetic (PBPK) models to compare the tissue dose that children and adults receive for a given amount of a chemical ingested or inhaled. The response in children and adults for a given tissue dose can also be compared. To aid in the development of age-specific PBPK models for experimental animals, we have collected information on physiological parameters in neonates and young animals, through 60 days of age. Our effort focused on generic physiological values, such as tissue weight (termed tissue volume in the context of PBPK modeling), intake (alveolar ventilation, food intake, water intake), and flows (blood flows to tissues, bile flow, creatinine clearance, and glomerular filtration rate). To date, parameters for Sprague-Dawley rats and mice of mu...

Journal ArticleDOI
TL;DR: A physiologically-based pharmacokinetic (PBPK) modeling approach to describe the PKs of whole gasoline by isolating specific components for which a description is desired and treating the remaining components as a single lumped chemical.

Journal ArticleDOI
TL;DR: This manuscript presents the rational for and key considerations related to the inclusion of quantitative PK and PD data in assessing chemical risks.
Abstract: Risk assessment methodologies are being updated to allow the inclusion of numerical values for variance in pharmacokinetic (PK) measures and pharmacodynamic (PD) processes related to toxicity. The key PK measures and PD processes are identified from the results of carefully conducted and adequately reported studies. In some instances, studies with humans are not possible, and so the development of data useful for human PK evaluations and on PD processes in vitro or in silico represent an alternative. These results can be integrated under physiologic, anatomic, and biochemical constraints of the intact body through physiologically based pharmacokinetic (PBPK) modeling. This manuscript presents the rational for and key considerations related to the inclusion of quantitative PK and PD data in assessing chemical risks.

Journal ArticleDOI
TL;DR: A physiologically based pharmacokinetic model for investigating inter-individual and inter-racial variability in ethanol pharmacokinetics is presented and is proposed as suitable for the investigation of the effects of both acute and chronic ethanol exposure.
Abstract: A physiologically based pharmacokinetic model for investigating inter-individual and inter-racial variability in ethanol pharmacokinetics is presented. The model is a substantial modification of an existing model which described some genetic polymorphisms in the hepatic alcohol dehydrogenase enzymes. The model was modified to incorporate a description of ethanol absorption from the stomach and gastro-intestinal tract and the retardation of gastric emptying due to a concentration-dependent inhibition of gastric peristalsis. In addition, intra-venous and intra-arterial routes of administration were added to investigate whether the biological structure of the model provided a core which may be easily adapted for any route of exposure. The model is proposed as suitable for the investigation of the effects of both acute and chronic ethanol exposure.

Journal ArticleDOI
TL;DR: A statistical random effects model identified from a simplified one-compartment pharmacokinetic model is applied to establish the dynamic relationship between a biomarker and its corresponding external exposure, and incorporates inter-individual variations often ignored in the usual regression approach.
Abstract: Biological monitoring has gradually developed into a powerful tool in the identification and quantification of exposures to occupational and/or environmental hazards in environmental and occupational health studies. Aggregate individual exposure to pollutants and evidence for exploring dose-response relationship in the human bodies can be assessed through biomarker measurements. The existence of inter-individual differences among a study population, however, often hampers the relationship assessment between exposure and the biomarker. In this paper, a statistical random effects model identified from a simplified one-compartment pharmacokinetic model is applied to establish the dynamic relationship between a biomarker and its corresponding external exposure. This model avoids the complex parameter estimation problem encountered using a physiologically based pharmacokinetic (PBPK) model, and incorporates inter-individual variations often ignored in the usual regression approach. In addition, the relevant parameters for the generic kinetic process can be estimated directly. As a guideline for preliminary sampling strategy, tables of required sample sizes and the number of repeated measurements to achieve the desired statistical power and test efficiency are given. The currently established biological exposure indices (BEIs) for benzene and methyl chloroform are employed to illustrate the impact of inter- individual variations on the percentages of protection for workers exposed to the threshold limit value (TLV) of the corresponding chemical.

Journal ArticleDOI
TL;DR: It is asserted that a thorough analysis of the parameter-dependent sensitivity and identifiability characteristics can be used to plan efficient experimental protocols for the quantitative analysis of inhalation pharmacokinetics.
Abstract: A physiologically based pharmacokinetic (PBPK) model incorporating mixed enzyme inhibition was used to determine the mechanism of metabolic interactions occurring during simultaneous exposures to the organic solvents chloroform and trichloroethylene (TCE). Visualization-based sensitivity and identifiability analyses of the model were performed to determine the conditions under which four inhibitory parameters describing inhibitor binding could be estimated. The sensitivity methods were used to reduce the 4-parameter estimation problem into two distinct 2-parameter problems. The inhibitory parameters were then estimated from multiple closed-chamber gas-uptake experiments using graphical methods. The estimated values of the four inhibitory parameters predicted that chloroform and TCE interact in a competitive manner. Based on the model analysis, we present recommendations for the design of experiments for determination of inhibition mechanism in binary chemical mixtures. We assert that a thorough analysis of the parameter-dependent sensitivity and identifiability characteristics can be used to plan efficient experimental protocols for the quantitative analysis of inhalation pharmacokinetics.

Proceedings ArticleDOI
01 Jan 2004
TL;DR: A procedure for estimating the alcohol infusion profile required to produce a specific breath alcohol concentration (BrAC) time course using a PBPK model is described and a substantial improvement in all error statistics was obtained.
Abstract: A procedure for estimating the alcohol infusion profile required to produce a specific breath alcohol concentration (BrAC) time course using a PBPK model is described. Model parameter values are predicted from linear relationships to readily measurable physical characteristics or morphometrics. An algorithm to optimize this transformation, based upon recorded clinical experimental data, is provided. A substantial improvement in all error statistics, in relation to the original transform was obtained.


Patent
Walter Schmitt1, Stefan Willmann1, Edgar Diessel1, Ingmar Dorn1, Jens Burmeister1 
23 Sep 2004
TL;DR: In this paper, a method for determining the dose of at least one active agent based on a genetic analysis is proposed, which comprises analyzing specific genes for their nucleotide sequence or their expression levels of gene-specific proteins and/or RNA molecules.
Abstract: Method for determining the dose of at least one active agent based on a genetic analysis. The method comprises analyzing specific genes for their nucleotide sequence or their expression levels of gene-specific proteins and/or RNA molecules. The gene-specific data is assigned one or more relevant physiological functions of the human or animal body, in particular those which have an influence on the metabolism, absorption, excretion or distribution of the active agent in the body. The gene-specific data and the assigned physiological functions are then integrated into a physiology-based pharmacokinetic model (PBPK model). The PBPK model integrates pharmacokinetic data relating to one or more active agents. The PBPK model may also receive and evaluate patient-specific data directly inputted and combined with data from a knowledge database comprising known values of pharmacokinetic parameters. The PBPK's integration of these data provide a calculation of the individual dose of the active agent.

Journal ArticleDOI
TL;DR: Preliminary PBPK models could be developed for numerous pesticides based on commonly available data if properly validated with well-designed worker exposure studies, and may be useful in more complete assessments of risks to workers as well as members of the general public.

Journal ArticleDOI
TL;DR: The analysis of the nonlinear local disposition in loci is reviewed from two points of view, namely an indirect method involving physiologically based pharmacokinetics (PBPK) and a direct method using live animals.

Journal ArticleDOI
TL;DR: Developing the physiologically based pharmacokinetic model to describe the absorption, distribution, metabolism, and elimination of chlorobenzene in rats is the first step toward future extrapolations to apply to humans.
Abstract: A physiologically based pharmacokinetic (PBPK) model to describe the absorption, distribution, metabolism, and elimination of chlorobenzene in rats was developed. Partition coefficients were experimentally determined in rat tissues and blood samples using an in vitro vial equilibration technique. These solubility ratios were in agreement with previous reports. The in vivo metabolism of chlorobenzene was evaluated using groups of three F344 male rats exposed to initial chlorobenzene concentrations ranging from 82 to 6750 ppm in a closed, recirculating gas uptake system. An optimal fit of the family of uptake curves was obtained by adjusting Michaelis–Menten metabolic constants, Km (affinity) and Vmax (capacity), using the PBPK model. At the highest chamber concentration, the uptake curve could not be modeled without the addition of a first-order (Kfo) metabolic pathway. Pretreatment with pyrazole, an inhibitor of oxidative microsomal metabolism, had no impact on the slope of the uptake curve. The completed...

Journal ArticleDOI
TL;DR: This paper discusses dividing the overall variation into two sub-distributions representing pharmacokinetic (PK) and pharmacodynamic (PD) contributions to the variation among chemicals in the animal-to-human toxicologically equivalent dose.
Abstract: For a particular chemical, one can treat the chemical-by-chemical variation in relative doses for equal toxicity in experimental animals and humans as a characterization of the likelihoods of extrapolation factors of different magnitudes. An emerging approach to noncancer risk assessment is to use such empirical distributions in place of fixed Uncertainty Factors. This paper discusses dividing the overall variation into two sub-distributions representing pharmacokinetic (PK) and pharmacodynamic (PD) contributions to the variation among chemicals in the animal-to-human toxicologically equivalent dose. If a physiologically based pharmacokinetic model (PBPK model) is used to derive a compound specific adjustment factor (CSAF) for the pharmacokinetic component, the deconvolution of the PK and PD components allows one to remove the PK component (to be replaced with the CSAF), while retaining the uncertainty in pharmacodynamics that PBPK models do not address. One must then add back the uncertainty in ...

01 Jan 2004
TL;DR: A procedure for estimating the alcohol infusion profile required to produce a specific breath alcohol concentration (BrAC) time course using a PBPK model is described and a substantial improvement in all error statistics was obtained.
Abstract: A procedure for estimating the alcohol infusion profile required to produce a specific breath alcohol concentration (BrAC) time course using a PBPK model is described. Model parameter values are predicted from linear relationships to readily measurable physical characteristics or morphometrics. An algorithm to optimize this transformation, based upon recorded clinical experimental data, is provided. A substantial improvement in all error statistics, in relation to the original transform was obtained.

Journal ArticleDOI
TL;DR: The present contamination level is not safe enough, but further dose-response data is required for a quantitative risk assessment, and the PBPK model showed temporal patterns in concentrations in various tissues.