Development of physiologically based pharmacokinetic and physiologically based pharmacodymamic models for applications in toxicology and risk assessment

Abstract

Pharmacokinetics (PK) involves the study of the rates of absorption, distribution, excretion, and biotransformation of chemicals and their metabolites. PK models can be used to reconstruct extensive time-course data sets based on a small number of kinetic parameters. These models can be used to predict the results of new experiments and integrate studies on kinetics, disposition and metabolism in various animal species [1]. The 2 main approaches that have been pursued in developing PK models are: (1) data-based compartmental modeling; and (2) physiologically based compartmental modeling. Data-based models rely on the collection of time-course concentration data and fitting these data with mathematical models. Compartments in these models do not necessarily reflect the anatomy and physiology of the animal, and the kinetic constants derived from these models do not have obvious physiological or biochemical counterparts. In physiologically based pharmacokinetic (PBPK) models, compartments correspond more closely to actual anatomical structures, defined with respect to their volumes, blood flows, chemical binding (partitioning) characteristics, and ability to metabolize or excrete the compounds of interest. Because the kinetic parameters of these models reflect tissue blood flows, partitioning, and biochemical constants, these models are more readily scaled from one animal species to another [2]. PBPK models have been used to understand the disposition of chemicals in the body for almost 70 years. Their more widespread application in toxicology dates back only 15 years or so to models developed for polychlorinated biphenyls and other persistent lipophilic compounds. Quantitative applications of PBPK models in risk assessment date to the development of a number of PBPK models for methylene chloride in the mid 1980s. The burgeoning use of PBPK models in toxicology research and chemical risk assessment today is primarily related to their ability to make more accurate predictions of target tissue dose for different exposure situations in different animal species, including humans. This overview includes a discussion of the development of these PBPK models in toxicology and speculates about future applications of PBPK and physiologically based pharmacodynamic (PBPD) models in chemical risk assessment.