Emerging role of drug interaction studies in drug development: the good, the bad, and the unknown.

Significant scientific advancements in the last decade have armed researchers with tools to assess drug metabolism and the effects of drugs on metabolic pathways; however, most of this research has focused on cytochrome P450 isozymes. Early delineation of this information aids in the prediction of potential drug-drug interactions, which may ultimately determine whether a compound is pursued in the drug development process. The recent withdrawals of medications such as terfenadine, astemizole, cisapride, and mibefradil from the market demonstrate the relevance of this a priori approach--the risk of drug interactions was largely unrecognized prior to their approval by the Food and Drug Administration (FDA). Drug interaction studies for new drug applications (NDAs) field between 1987 and 1991 were largely in vivo studies with potential coadministered drugs, whereas for NDAs field between 1992 and 1997, the majority of studies involved metabolic mechanisms and in vitro methodology. Despite current limitations in the extrapolation of in vitro drug metabolism data to the in vivo environment, in vitro studies remain the mainstay of initial evaluations in this area primarily because of the high throughput nature of these investigations and the reduced cost compared with in vivo studies. The FDA has published several guidance documents in the area of drug metabolism and drug interaction studies in drug development with suggestions for in vitro as well as in vivo approaches to these investigations. Current and future research will likely focus on in vitro models for cytochrome P450 induction, Phase II metabolism, and drug transporters, and include validation and extrapolation of these approaches in vivo.