Metabolic Drug-Drug Interactions: Perspective from FDA Medical and Clinical Pharmacology Reviewers

Abstract

Publisher Summary This chapter introduces with a case report on metabolic drug-drug interactions. These cases are examples of multitude of reports received. Clinically significant drug-drug interactions involving the cytochrome P450 enzymes are frequently reported and the potential for more to occur is substantial. Clinically significant drug-drug interactions may be avoidable by the thorough study and analysis of drug metabolism in the drug development phase. A number of institutions have invested in developing human liver banks to study mostly drug metabolism, to explain retrospectively drug-associated toxicity, or to predict potential drug–drug interactions and prospectively design rational clinical trials. The first step in establishing whether cytochrome P450 enzymes are involved with the formation of an unknown metabolite in human hepatic microsomal system is to conduct two definitive studies: formation of the unknown metabolite in the presence and absence of NADPH and inhibition of the unknown metabolite formation by carbon monoxide. The major contribution of the knowledge of drug metabolism lies in designing clinical studies to evaluate potential drug-drug interactions. In vitro assessment of drug metabolism, in addition to identifying the enzyme, can measure the enzyme kinetics ( K m , V max , K i , etc.). The therapeutic concentrations of the competing drugs, as well as the K m and K i values estimated using the in vitro system, plays a significant role in deciding and designing a rational protocol for the clinical study. In vitro metabolic studies cannot model all possible drug-drug interactions. It is not possible to review and design definitive experiments on all drugs already on the market for labeling revisions. Knowing the pathway involved in biotransformation, it is possible to predict a class of drugs that may have a similar interaction with the unknown drug.