Nonclinical Kinetics and Metabolism Studies in Support of the Safety Assessment of Drugs

Abstract

Animal studies on absorption, distribution, metabolism and excretion (ADME) play an important role in the discovery and selection of drugs as well as in supporting pharmacological studies. The majority of ADME studies, however, are performed to support toxicity studies and, ultimately, safety assessment. In reaching this goal, nonclinical kinetics and metabolism studies form the pier for the bridge between toxicokinetics and toxicity studies; the combination of ADME data with human pharmacokinetics is essential for a drug-exposure based safety evaluation. Lists of ADME studies to be performed in the various stages of drug development are presented and discussed; they comprise standard in-vivo and in-vitro studies as well as some optional studies. ADME studies, however, should always be tailor-made, that is, designed on a case-by-case basis; in line with a global strategy; and anticipating toxicological, pharmacological, and pharmacokinetic findings by a flexible step-by-step approach. The continuous interaction and combined efforts of a pharmaceutical company's departments of toxicology and pharmacokinetics, including a toxicokinetics group, will result in a faster registration of new chemical entities.