Application of a Generic Physiologically Based Pharmacokinetic Model to the Estimation of Xenobiotic Levels in Human Plasma

Abstract

ABSTRACT:Estimation of xenobiotic kinetics in humans frequently relies upon extrapolation from experimental data generated in animals. In an accompanying paper, we have presented a unique, generic, physiologically based pharmacokinetic model and described its application to the prediction of rat plasma pharmacokinetics from in vitro data alone. Here we demonstrate the application of the same model, parameterized for human physiology, to the estimation of plasma pharmacokinetics in humans and report a comparative evaluation against some recently published predictive methods that involve scaling from in vivo animal data. The model was parameterized through an optimization process, using a training set of in vivo data taken from the literature, and validated using a separate test set of published in vivo data. On average, the vertical divergence of the predicted plasma concentrations from the observed data, on a semilog concentration-time plot, was 0.47 log unit. For the training set, more than 80% of the predicted values of a standardized measure of the area under the concentration-time curve were within 3-fold of the observed values; over 70% of the test set predictions were within the same margin. Furthermore, in terms of predicting human clearance for the test set, the model was found to match or exceed the performance of three published interspecies scaling methods, all of which showed a distinct bias toward overprediction. We conclude that the generic physiologically based pharmacokinetic model, as a means of integrating readily determined in vitro and/or in silico data, is potentially a powerful, cost-effective tool for predicting human xenobiotic kinetics in drug discovery and risk assessment.Physiologically based pharmacokinetic (PBPK) models are mathematical descriptions of the flow of blood throughout the body, developed for the simulation of xenobiotic absorption, distribution, and elimination. Such models have been used by scientists from a number of different disciplines who are interested in the simulation and prediction of exposure (Grass and Sinko, 2002;Leahy, 2003).The application of a generic form of a PBPK model to the prediction of xenobiotic plasma levels in rat following an intravenous dose has been reported in an accompanying publication (Brightman et al., 2006). Here we describe the work that we have done to parameterize the same PBPK model for humans and to assess the reliability of the model in estimating plasma levels of xenobiotics, where these values are known from experimentation. In addition, we draw comparisons with alternative methods for predicting human pharmacokinetic properties that involve extrapolation from experimental data generated in animals.Just as there are numerous published compound-specific PBPK models for the rat that use data derived from in vivo studies (Sugita et al., 1982;Igari et al., 1983;Tsuji et al., 1983;Bernareggi and Rowland, 1991;Kawai et al., 1994;Blakey et al., 1997), there are many examples of comparable PBPK models for humans that rely upon scaling f...

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