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PubMed2026

Decoding Nonlinearities in AAV-Based Gene Therapy Using PBPK Modelling.

The objective of this research was to develop a physiologically based pharmacokinetic (PBPK) model for AAV-based gene therapy, which can capture the nonlinearity observed in both viral vector and transgene product pharmacokinetics (PK) across a wide range of doses, while accounting for the effect of immunogenicity. To develop the PBPK model, previously published PK data generated in mice using AAV8 vector containing the transgene for a non-binding monoclonal antibody was used. Immunocompetent mice were administered with AAV at a wide range of doses (1E8, 1E9, 5E9, 1E10, 2E10, 1E11, 2E11, 1E12, and 1E13vg per mouse), and the PK of transgene and transgene product (i.e., antibody) in plasma and/or tissue was collected. The nonlinearity in transgene product concentrations was characterized using a saturable production process and a concentration-dependent antibody elimination rate was used to characterize the effect of anti-drug antibody (ADA) on transgene product. The model successfully described the PK of both the vector and the transgene product across all dose levels and accurately captured the sigmoidal dose-exposure-response relationship for AAV. Notably, the model described a dose-dependent ADA response, with the high dose group exhibiting an earlier onset and faster rate of transgene product elimination. Lower dose group showed delayed onset and minimal ADA-mediated elimination of transgene product. Overall, the PBPK model presented here effectively characterizes vector and transgene product kinetics in mice and demonstrates utility in preclinical-to-clinical translation and dose optimization of AAV-based gene therapies.

Animals↗

PubMed1989

Evaluation of uncertainty in input parameters to pharmacokinetic models and the resulting uncertainty in output.

Physiologically-based pharmacokinetic (PBPK) models may be used to predict the concentrations of parent chemical or metabolites in tissues, resulting from specified chemical exposures. An important application of PBPK modeling is in assessment of carcinogenic risks to humans, based on animal data. The parameters of a PBPK model may include metabolic parameters, blood/air and tissue/blood partition coefficients, and physiological parameters, such as organ weights and blood flow rates. Uncertainty in estimates of these parameters results in uncertainty regarding tissue concentrations and resulting risks. Data are reviewed relevant to the quantification of these uncertainties, for a PBPK model-based risk assessment for tetrachloroethylene. Probability distributions are developed to express uncertainty in model parameters, and uncertainties are propagated by a sequence of operations that simulates processes recognized as contributing to estimates of human risk. Distributions of PBPK model output and human risk estimates are used to characterize uncertainty resulting from uncertainty in model parameters.

Animals↗

PubMed1988

Linking indoor air and pharmacokinetic models to assess tetrachloroethylene risk.

Physiologically based pharmacokinetic (PBPK) models describing the uptake, metabolism, and excretion of xenobiotic compounds are now proposed for use in regulatory health-risk assessments. In this study we investigate the extent of PCE metabolism arising from domestic respiratory exposure to tetrachloroethylene (PCE) from ground water, as predicted using a PBPK model. Indoor exposure patterns we use as input to the PBPK model are realistic ones generated from a three-compartment model describing volatilization of PCE from domestic water into household air. Values we use for the metabolic parameters of the PBPK model are estimated from data on urinary metabolites in workers exposed to PCE. It is shown that for respiratory PCE exposure due to typical levels of PCE in ground water, use of time-weighted average air concentrations with a steady-state PBPK model yields estimates of total metabolized PCE similar to those obtained using completely dynamic modeling, despite considerable uncertainty in key exposure- and metabolic-model parameters. These findings suggest that, for PCE, risk estimation taking pharmacokinetics into account may be accomplished using a simple analytic approach.

Air Pollutants↗

PubMed1992

Reassessing benzene cancer risks using internal doses.

Human cancer risks from benzene exposure have previously been estimated by regulatory agencies based primarily on epidemiological data, with supporting evidence provided by animal bioassay data. This paper reexamines the animal-based risk assessments for benzene using physiologically-based pharmacokinetic (PBPK) models of benzene metabolism in animals and humans. It demonstrates that internal doses (interpreted as total benzene metabolites formed) from oral gavage experiments in mice are well predicted by a PBPK model developed by Travis et al. Both the data and the model outputs can also be accurately described by the simple nonlinear regression model total metabolites = 76.4x/(80.75 + x), where x = administered dose in mg/kg/day. Thus, PBPK modeling validates the use of such nonlinear regression models, previously used by Bailer and Hoel. An important finding is that refitting the linearized multistage (LMS) model family to internal doses and observed responses changes the maximum-likelihood estimate (MLE) dose-response curve for mice from linear-quadratic to cubic, leading to low-dose risk estimates smaller than in previous risk assessments. This is consistent with the conclusion for mice from the Bailer and Hoel analysis. An innovation in this paper is estimation of internal doses for humans based on a PBPK model (and the regression model approximating it) rather than on interspecies dose conversions. Estimates of human risks at low doses are reduced by the use of internal dose estimates when the estimates are obtained from a PBPK model, in contrast to Bailer and Hoel's findings based on interspecies dose conversion. Sensitivity analyses and comparisons with epidemiological data and risk models suggest that our finding of a nonlinear MLE dose-response curve at low doses is robust to changes in assumptions and more consistent with epidemiological data than earlier risk models.

Animals↗

PubMed1989

Pharmacokinetics for regulatory risk analysis: the case of 1,1,1-trichloroethane (methyl chloroform).

A methodology for using physiologically based pharmacokinetic (PBPK) models to derive predicted safe concentrations of noncarcinogens in drinking water for humans based on experimentally determined no observed adverse effect levels (NOAELs) in animals is presented and applied to the case of 1,1,1-trichloroethane (methyl chloroform, MC). For each toxic endpoint and lowest corresponding NOAEL identified for MC, we considered a set of toxicologically plausible options regarding the presumed toxic agent and the metric for effective dose to target tissue. A four-compartment PBPK model for rodents was used to estimate corresponding effective doses to the animals used to obtain the experimental NOAELs. A five-compartment PBPK model was then applied, in conjunction with a multiroute (inhalation, ingestion and dermal) human-exposure scenario, to calculate alternative concentrations of MC in drinking water predicted to result in corresponding effective doses to the same target tissues in humans. In the case of MC, the PBPK approach to interspecies and interroute extrapolation of toxicity data resulted in lower drinking water concentrations predicted to be nontoxic to humans than corresponding concentrations obtained using a traditional method for determining safe levels.

Animals↗

PubMed1992

Structure and parameterization of pharmacokinetic models: their impact on model predictions.

There has been an increasing interest in physiologically based pharmacokinetic (PBPK) models in the area of risk assessment. The use of these models raises two important issues: (1) How good are PBPK models for predicting experimental kinetic data? (2) How is the variability in the model output affected by the number of parameters and the structure of the model? To examine these issues, we compared a five-compartment PBPK model, a three-compartment PBPK model, and nonphysiological compartmental models of benzene pharmacokinetics. Monte Carlo simulations were used to take into account the variability of the parameters. The models were fitted to three sets of experimental data and a hypothetical experiment was simulated with each model to provide a uniform basis for comparison. Two main results are presented: (1) the difference is larger between the predictions of the same model fitted to different data sets than between the predictions of different models fitted to the dame data; and (2) the type of data used to fit the model has a larger effect on the variability of the predictions than the type of model and the number of parameters.

Animals↗

PubMed1992

A physiologically based pharmacokinetic model for nicotine and cotinine in man.

Physiologically based pharmacokinetic (PBPK) models have been developed describing the disposition kinetics of nicotine and its major metabolite, cotinine, in man. Separate 9-compartment, flow-limited PBPK models were initially created for nicotine and cotinine. The physiological basis for compartment designation and parameter selection has been provided; chemical-specific tissue-to-blood partition coefficients and elimination rates were derived from published human and animal data. The individual models were tested through simulations of published studies of nicotine and cotinine infusions in man using similar dosing protocols to those reported. Each model adequately predicted the time course of nicotine or cotinine concentrations in the blood and urine following the administration of nicotine or cotinine. These individual models were then linked through the liver compartments to form a nicotine-cotinine model capable of predicting the metabolic production and disposition of cotinine from administered nicotine. The potential for integrating this functional PBPK model with an appropriate pharmacodynamic model for the characterization of nicotine's physiological effects is discussed.

Cotinine↗

PubMed1988

Pharmacokinetics for regulatory risk analysis: the case of trichloroethylene.

Physiologically based pharmacokinetic (PBPK) models describing the uptake, metabolism, and excretion of volatile organic compounds (VOCs) are now proposed for use in regulatory health-risk assessment. A steady-state analysis of one such model is shown to provide simple, convenient predicted relationships between an applied dose and the corresponding toxicologically effective, metabolized dose for certain VOCs like trichloroethylene (TCE). A version of this PBPK model was fit to data on human metabolism of TCE to urinary metabolites in chronically exposed workers, yielding a direct estimate of PBPK parameters governing human capacity to metabolize TCE. It is shown that this estimate is consistent with others based on experimental studies of TCE metabolism in humans exposed to TCE by inhalation for short periods. These results are applied to human cancer-risk assessment using rodent bioassay data on TCE-induced tumorigenesis.

Carcinogenicity Tests↗

PubMed1992

A physiologically based pharmacokinetic model for nicotine disposition in the Sprague-Dawley rat.

A physiologically based pharmacokinetic (PBPK) model was developed to describe the disposition of nicotine in the Sprague-Dawley (SD) rat. Parameters for the model were either obtained from the literature (blood flows, organ volumes) or determined experimentally (partition coefficients). Nicotine metabolism was defined in the liver compartment by the first-order rate constants KNC and KNP which control the rate of nicotine metabolism to cotinine and "polar metabolites" (PM), respectively. These rate constants were estimated by optimizing the model fit to pharmacokinetic data obtained by administering an intraarterial (S)-[5-3H]nicotine bolus of 0.1 mg/kg to 6 rats. Model simulations that optimized for the appearance of cotinine in plasma estimated KNC and KNP to be 75.8 and 24.3 hr-1, respectively. Use of these constants in the model allowed us to accurately predict nicotine plasma kinetics and the fraction of the dose eliminated by renal (8.5%) and metabolic (91.5%) clearance. To validate the model's ability to predict tissue kinetics of nicotine, 21 male SD rats were administered 0.1 mg/kg (S)-[5-3H]nicotine intraarterially. At seven time points following treatment, 3 rats were euthanized and tissues were removed and analyzed for nicotine. Model-predicted nicotine tissue kinetics were in agreement with those determined experimentally in muscle, liver, skin, fat, and kidney. The brain, heart, and lung exhibited nonlinear nicotine elimination, suggesting that saturable nicotinic binding sites may be important in nicotine disposition in these organs. Inclusion of saturable receptor binding expressions in the mathematical description of these compartments resulted in better agreement with the experimental data. The Bmax and KD estimated by model simulations for these tissues were brain, 0.009 and 0.12; lung, 0.039 and 2.0; and heart, 0.039 nmol/tissue and 0.12 nM, respectively. This PBPK model can successfully describe the tissue and plasma kinetics of nicotine in the SD rat and will be a useful tool for pharmacologic studies in humans and experimental animals that require insight into the plasma or tissue concentration-effect relationship.

Animals↗

PubMed1991

Modelling of respiratory exchange of polar solvents.

Physiologically based pharmacokinetic (pbpk) models are frequently used to describe the kinetics of inhaled gases and vapours. In these models the conducting airways of the respiratory tract are generally assumed to act as inert tubes. The function of the inert tubes is merely to conduct the vapour to the alveolar regions where the actual exchange between ambient air and body takes place. Such an 'inert tube' model may be adequate to describe the inhalation and exhalation kinetics of inert vapours, for example non-polar solvents which have a low water solubility. Experimental data suggest, however, that the 'inert tube' model may be erroneous for polar solvents which have a high water solubility. To explore this possibility further a tentative pbpk model was developed. Model structure and parameters were obtained from the literature on lung anatomy and physiology and by visual fitting to experimental acetone, carbon dioxide, diethyl ether and ethanol data. The model was written and solved by spreadsheet programming on a personal computer. Simulations were carried out to illustrate the difference between end-exhaled and alveolar air and how water solubility and workload influence the uptake and excretion kinetics of polar solvents. It is concluded that the model is valuable for predicting the lung kinetics of polar vapours under various circumstances. It may therefore be useful in the development of biological monitoring methods based on breath sampling and help us to understand and to explain experimental data.

Computer Simulation↗

PubMed1990

Evaluation of estimations in vitro of tissue/blood distribution coefficients for organothiophosphate insecticides.

Physiologically based pharmacokinetic (PBPK) modeling of foreign chemicals is dependent on the accurate determination of their tissue/blood distribution coefficients, Kp (partition coefficients). The present study was undertaken to evaluate the validity of the in vitro estimation of the Kp values of the organothiophosphate insecticides parathion and methyl parathion by equilibrium dialysis. Data derived from previously published studies that utilized single-pass perfusions of mouse livers in situ with parathion or methyl parathion were analyzed to determine liver/perfusate Kp values from the equation Kp = (t 1/2ss) (Q)/(0.693) (VH), where Kp is the liver/perfusate distribution ratio, t 1/2ss is the half-life for approach to steady state of the chemical, VH is the liver volume, and Q is the perfusate flow rate. Kp values for methyl parathion were calculated to be 16.4 +/- 7.5 and 9.5 +/- 2.7 (mean +/- SD) for perfused livers and equilibrium dialysis, respectively, while estimates of Kp for parathion were 15.6 +/- 6.3 and 19.5 +/- 5.5 for perfused livers and equilibrium dialysis, respectively. These results indicate that equilibrium dialysis can be utilized to give an accurate estimate of tissue partitioning of parathion and methyl parathion from perfusate into perfused mouse livers.

Animals↗

PubMed1990

Extrapolation of animal toxicity to humans: interspecies comparisons in drug development.

Different methods for converting the dose-related toxicity of drugs from animals to humans are reviewed. Each method is analyzed with respect to its utility and limitations. Linear extrapolations from animals to humans based on body weight equivalence are shown to be inaccurate unless species-specific conversion factors are used. Extrapolations based on surface area equivalence are more accurate, do not require conversion factors, and may be used when pharmacokinetic data are not available. Ultimately, interspecies conversions are most reliable when pharmacokinetic data are available, assuming that toxic responses are comparable among species for similar blood levels. Two pharmacokinetic-based approaches may be used: direct use of plasma concentration or area under the concentration-time curve (AUC) and physiologically based pharmacokinetic (PBPK) models.

Animals↗

PubMed1991

Modeling benzene pharmacokinetics across three sets of animal data: parametric sensitivity and risk implications.

Typically, the uncertainty affecting the parameters of physiologically based pharmacokinetic (PBPK) models is ignored because it is not currently practical to adjust their values using classical parameter estimation techniques. This issue of parametric variability in a physiological model of benzene pharmacokinetics is addressed in this paper. Monte Carlo simulations were used to study the effects on the model output arising from variability in its parameters. The output was classified into two categories, depending on whether the output of the model on a particular run was judged to be generally consistent with published experimental data. Statistical techniques were used to examine sensitivity and interaction in the parameter space. The model was evaluated against the data from three different experiments in order to test for the structural adequacy of the model and the consistency of the experimental results. The regions of the parameter space associated with various inhalation and gavage experiments are distinct, and the model as presently structured cannot adequately represent the outcomes of all experiments. Our results suggest that further effort is required to discern between the structural adequacy of the model and the consistency of the experimental results. The impact of our results on the risk assessment process for benzene is also examined.

Animals↗