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

Abstract

ABSTRACT:The routine assessment of xenobiotic in vivo kinetic behavior is currently dependent upon data obtained through animal experimentation, although in vitro surrogates for determining key absorption, distribution, metabolism, and elimination properties are available. Here we present a unique, generic, physiologically based pharmacokinetic (PBPK) model and demonstrate its application to the estimation of rat plasma pharmacokinetics, following intravenous dosing, from in vitro data alone. 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 in vivo discovery compound data. On average, the vertical divergence of the predicted plasma concentrations from the observed data, on a semilog concentration-time plot, was approximately 0.5 log unit. Around 70% of all the predicted values of a standardized measure of area under the concentration-time curve (AUC) were within 3-fold of the observed values, as were over 90% of the training set t 1/2 predictions and 60% of those for the test set; however, there was a tendency to overpredict t 1/2 for the test set compounds. The capability of the model to rank compounds according to a given criterion was also assessed: of the 25% of the test set compounds ranked by the model as having the largest values for AUC, 61% were correctly identified. These validation results lead us to conclude that the generic PBPK model is potentially a powerful and cost-effective tool for predicting the mammalian pharmacokinetics of a wide range of organic compounds, from readily available in vitro inputs only.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. The essential concepts were outlined over 60 years ago in a farsighted paper (Teorell, 1937) that presented many of the mathematical relationships required to simulate blood flow and tissue distribution.Simulation modeling ideas were developed further by Mapleson (1973), to explain the effect of anesthetics, and early attempts to apply the approach to drugs were published in the 1960s by Bellman et al. (1961). Probably the most important contributions in that period were made by Bischoff and Dedrick (1968), who demonstrated that PBPK models could be used for the a priori prediction of the pharmacokinetics of thiopental. During the following decades, developments were made by academics such as Rowland (Rowland, 1986), Sugiyama (Sugiyama and Ito, 1998), and Amidon (Yu and Amidon, 1999), as well as scientists working in the environmental health field, in particular Anderson and Clewell (Andersen et al., 2002). Recent reviews (Grass and Sinko, 2002;Leahy, 2003) have discussed the application of these approaches to the prediction of pharmacokinetics in drug discovery.It is of interest to us to apply the PBPK approach to the estimation of plasma levels in animals from in vitro d...

A Physiologically Based Pharmacokinetic Model for Capreomycin

“…To our knowledge, no PBPK models have been published for any antituberculosis drugs. Moreover, even existing PBPK models for antibiotics (9,10,16,32) have not included considerations of interindividual variabilities, an important consideration in the interpretation of ADME predictions for these drugs. The PBPK model for capreomycin disposition in mice developed in For an explanation of this abbreviation, see Table 2.…”

“…Although traditionally used for environmental toxicants, PBPK models are increasingly used for the prediction of absorption, distribution, metabolism, and excretion (ADME) of various drugs (45)(46)(47), including antibiotics (9,10,16,32). A relatively recent advance in PBPK modeling has been the incorporation of approaches for accounting for interindividual variabilities in anatomy, physiology, biochemistry, and chemical exposure (1,6,8,12,36,39).…”

Modelling and PBPK Simulation in Drug Discovery

“…Until recently, the use of PBPK modeling had been limited in drug discovery and development due to the mathematical complexity of the models and the large amounts of in vivo animal tissue concentration data required. However, advances in the prediction of hepatic metabolism (7)(8)(9)(10) and tissue distribution (11)(12)(13)(14)(15)(16)(17) from in vitro and in silico data have made these models more attractive (18)(19)(20)(21)(22)(23)(24)(25). PBPK models provide the opportunity to integrate key input parameters from different sources not only to estimate PK parameters and predict plasma and tissue concentration-time profiles but also to gain mechanistic insight into compound properties.…”

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

“…A generic PBPK model, which enables the prediction of the pharmacokinetic behavior of any given compound dosed intravenously in a specified human population, without recourse to data derived through in vivo studies, is presented herein. The compound-dependent inputs required by the model are the same as those listed previously (Brightman et al, 2006).Model Description. The PBPK model is based upon that published by Bernareggi and Rowland (1991), as shown in their Fig.…”

“…modification of the tissue distribution and elimination components, and comprises a series of compartments representing 14 major organs and tissues in the body, interconnected by further compartments representing arterial and venous blood pools, according to the principles developed by Bischoff and others (Bischoff, 1975). The additional features of the model, including adaptations to facilitate modeling of "diffusion-limited" distribution of an intravenously administered compound into the various tissues and organs, as well as the various processes involved in renal excretion, are described in detail in the accompanying paper discussing its application to the prediction of rat in vivo pharmacokinetics (Brightman et al, 2006).Model Parameters. The physiological parameters used in the model were obtained from the literature and are given in the Appendix (which is available online as supplemental data); these were scaled according to the actual body weights of the subjects used in the clinical studies being simulated.…”