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ER - TY - JOUR T1 - Interspecies extrapolation of physiological pharmacokinetic parameter distributions JF - Risk Analysis Y1 - 1996/12// SP - 741 EP - 754 A1 - Karen H. Watanabe A1 - Frédéric Y. Bois KW - benzene KW - interspecies extrapolation KW - Monte Carlo parameterization KW - physiologically-based pharmacokinetics AB - Three methods (multiplicative, additive, and allometric) were developed to extrapolate physiological model parameter distributions across species, specifically from rats to humans. In the multiplicative approach, the rat model parameters are multiplied by the ratio of the mean values between humans and rats. Additive scaling of the distributions is defined by adding the difference between the average human value and the average rat value to each rat value. Finally, allometric scaling relies on established extrapolation relationships using power functions of body weight. A physiologically-based pharmacokinetic model was fitted independently to rat and human benzene disposition data. Human model parameters obtained by extrapolation and by fitting were used to predict the total bone marrow exposure to benzene and the quantity of metabolites produced in bone marrow. We found that extrapolations poorly predict the human data relative to the human model. In addition, the prediction performance depends largely on the quantity of interest. The extrapolated models underpredict bone marrow exposure to benzene relative to the human model. Yet, predictions of the quantity of metabolite produced in bone marrow are closer to the human model predictions. These results indicate that the multiplicative and allometric techniques were able to extrapolate the model parameter distributions, but also that rats do not provide a good kinetic model of benzene disposition in humans. VL - 16 IS - 6 U1 -7.1

ER - TY - JOUR T1 - Physiological pharmacokinetic analysis using population modeling and informative prior distributions JF - Journal of the American Statistical Association Y1 - 1996/12// SP - 1400 EP - 1412 A1 - Andrew Gelman A1 - Frédéric Y. Bois A1 - Jiming Jiang KW - bayesian methods KW - hierarchical models KW - informative prior distributions KW - markov chain simulation KW - pharmacokinetics KW - posterior predictive checks KW - sensitivity analysis KW - tetrachloroethylene KW - toxicokinetics AB - We describe a general approach using Bayesian analysis for the estimation of parameters in physiological pharmacokinetic models. The chief statistical difficulty in estimation with these models is that any physiological model that is even approximately realistic will have a large number of parameters, often comparable to the number of observations in a typical pharmacokinetic experiment (e.g., 28 measurements and 15 parameters for each subject). In addition, the parameters are generally poorly identified, akin to the wellknown ill-conditioned problem of estimating a mixture of declining exponentials. Our modeling includes (a) hierarchical population modeling, which allows partial pooling of information among different experimental subjects; (b) a pharmacokinetic model including compartments for well-perfused tissues, poorly perfused tissues, fat, and the liver; and (c) informative prior distributions for population parameters, which is possible because the parameters represent real physiological variables. We discuss how to estimate the models using Bayesian posterior simulation, a method that automatically includes the uncertainty inherent in estimating such a large number of parameters. We also discuss how to check model fit and sensitivity to the prior distribution using posterior predictive simulationY We illustrate the application to the toxicokinetics of tetrachloroethylene (perchloroethylene [PERC]), the problem that motivated this work. VL - 91 U1 -7.1

ER - TY - JOUR T1 - Population toxicokinetics of benzene. Environmental Health Perspectives JF - Environmental Health Perspectives Y1 - 1996/12// SP - 1405 EP - 1411 A1 - Frédéric Y. Bois A1 - Elise T. Jackson A1 - Kaija Pekari A1 - Martyn T. Smith AB - In assessing the distribution and metabolism of toxic compounds in the body, measurements are not always feasible for ethical or technical reasons. Computer modeling offers a reasonable alternative, but the variability and complexity of biological systems pose unique challenges in model building and adjustment. Recent tools from population pharmacokinetics, Bayesian statistical inference, and physiological modeling can be brought together to solve these problems. As an example, we modeled the distribution and metabolism of benzene in humans. We derive statistical distributions for the parameters of a physiological model of benzene, on the basis of existing data. The model adequately fits both prior physiological information and experimental data. An estimate of the relationship between benzene exposure (up to 10 ppm) and fraction metabolized in the bone marrow is obtained and is shown to be linear for the subjects studied. Our median population estimate for the fraction of benzene metabolized, independent of exposure levels, is 52% (90% confidence interval, 47-67%). At levels approaching occupational inhalation exposure (continuous 1 ppm exposure), the estimated quantity metabolized in the bone marrow ranges from 2 to 40 mg/day. VL - 104 UR - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1469729/ IS - Suppl 6 U1 -7.1

ER - TY - JOUR T1 - Population toxicokinetics of tetrachloroethylene JF - Archives of Toxicology Y1 - 1996/ SP - 347 EP - 355 A1 - Frédéric Y. Bois A1 - Andrew Gelman A1 - Jiming Jiang A1 - Don Maszle A1 - Lauren Zeise A1 - George Alexeeff KW - human metabolism KW - pharmacokinetics KW - population toxicokinetics KW - tetrachloroethylene AB - In assessing the distribution and metabolism of toxic compounds in the body, measurements are not always feasible for ethical or technical reasons. Computer modeling oﬀers a reasonable alternative, but the variability and complexity of biological systems pose unique challenges in model building and adjustment. Recent tools from population pharmacokinetics, Bayesian statistical inference, and physiological modeling can be brought together to solve these problems. As an example, we modeled the distribution and metabolism of tetrachloroethylene (PERC) in humans. We derive statistical distributions for the parameters of a physiological model of PERC, on the basis of data from Monster et al. (1979). The model adequately ﬁts both prior physiological information and experimental data. An estimate of the relationship between PERC exposure and fraction metabolized is obtained. Our median population estimate for the fraction of inhaled tetrachloroethylene that is metabolized, at exposure levels exceeding current occupational standards, is 1.5% [95% conﬁdence interval (0.52%, 4.1%)]. At levels approaching ambient inhalation exposure (0.001 ppm), the median estimate of the fraction metabolized is much higher, at 36% [95% conﬁdence interval (15%, 58%)]. This disproportionality should be taken into account when deriving safe exposure limits for tetrachloroethylene and deserves to be veriﬁed by further experiments. VL - 70 U1 -7.1

ER - TY - JOUR T1 - Human interindividual variability in metabolism and risk: the example of 4-aminobiphenyl JF - Risk Analysis Y1 - 1995/ SP - 205 EP - 213 A1 - Frédéric Y. Bois A1 - Gail Krowech A1 - Lauren Zeise KW - 4-Aminobiphenyl KW - interindividual variability KW - Monte Carlo Simulations KW - population heterogeneity KW - toxicokinetics AB - We investigate, through modeling, the impact of interindividual heterogeneity in the metabolism of 4-aminobiphenyl (ABP) and in physiological factors on human cancer risk: A physiological pharmacokinetic model was used to quantify the time course of the formation of the proximate carcinogen, N-hydroxy-4-ABP and the DNA-binding of the active species in the bladder. The metabolic and physiologic model parameters were randomly varied, via Monte Carlo simulations, to reproduce interindividual variability. The sampling means for most parameters were scaled from values developed by Kadlubar et al. (Cancer Res., 51: 4371, 1991) for dogs; variances were obtained primarily from published human data (e.g., measurements of ABP N-oxidation, and arylamine N-acetylation in human liver tissue). In 500 simulations, theoretically representing 500 humans, DNA-adduct levels in the bladder of the most susceptible individuals are ten thousand times higher than for the least susceptible, and the 5th and 95th percentiles differ by a factor of 160. DNA binding for the most susceptible individual (with low urine pH, low N-acetylation and high N-oxidation activities) is theoretically one million-fold higher than for the least susceptible (with high urine pH, high N-acetylation and low N-oxidation activities). The simulations also suggest that the four factors contributing most significantly to interindividual differences in DNA-binding of ABP in human bladder are urine pH, ABP N-oxidation, ABP N-acetylation and urination frequency. VL - 15 IS - 2 U1 -7.1

JO - Risk Anal. ER - TY - JOUR T1 - Statistical and regulatory considerations for multiple measures in bioequivalence testing JF - Clinical Research and Regulatory Affairs Y1 - 1995/ SP - 249 EP - 265 A1 - Walter W. Hauck A1 - Terry Hyslop A1 - Sharon Anderson A1 - Frédéric Y. Bois A1 - Thomas N. Tozer VL - 12 U1 -7.1

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