The Importance of Pharmacokinetic/Toxicokinetic and Metabolic Information in Carcinogenicity Study Design

Abstract

A major challenge in the risk/benefit assessment of new chemical entities is the rational and reliable extrapolation of preclinical (nonclinical) safety evaluation data from animals to humans. Toxicity studies, core to the safety evaluation process, are designed to determine a no observed toxic effect level as well as an observed toxic effect level. Traditionally, these levels have been those of administered dose, and safety margins are derived as the ratio between the preclinical no observed toxic effect dose level in animals and the clinical (or environmental) dose level in humans. In reality, however, safety margins thus derived are often optimistic guesses because they do not take into account the respective systemic exposures to the test compound during the preclinical studies and eventual human clinical (or environmental) use. This paper has aimed to show that this undesirable position can be redressed by the application of toxicokinetics. The primary purpose of toxicokinetic studies is to determine the rate, extent and duration of systemic exposure of the test animal species to the test compound at the different dose levels employed during toxicity studies and to provide data for direct comparison with human exposure to the test compound. Another purpose is to search for possible changes in test compound kinetics arising during the repeated dose regimen of toxicity studies possibly as a consequence of pharmacological, biochemical, and/or toxicological effects exerted by the test compound. Toxicokinetics contributes to the design of toxicity studies (dose level, dose route, and/or dose regimen and animal species selection), but even more important, it is essential for the proper evaluation of the significance of results of toxicity studies. Thus toxicokinetic data can provide the foundation for improved safety evaluation.