Preclinical in vivo ADME studies in drug development: a critical review.

INTRODUCTION: The last two decades have brought many fundamental changes to the drug development process. One such change is the importance of preclinical pharmacokinetics, which has become an essential part of early drug discovery. Furthermore, bioanalytical methods have become more sensitive and the identification and quantitation of metabolites can now be carried out on limited amount of biological material. There has also been a change in regulatory expectations, which are now particularly focused on the safety of human metabolites. AREAS COVERED: The focus of this paper is on some 'traditional' in vivo ADME studies: excretion balance, metabolic profile and WBA in the toxicological species. These studies, performed with radiolabeled material, have a long history: and are a regular presence in submission dossiers. This paper reviews their value in the perspective of the contemporary drug development process. EXPERT OPINION: These experiments may sometimes still be relevant to explain toxicological findings or for other special purposes but should not be considered required pieces of the registration dossiers. An appropriate investigation of samples coming from safety evaluation and human Phase I studies and the knowledge generated during the lead optimization phase provide, in most instances, all the DMPK information needed to take decisions in the drug development process.