Reaction phenotyping to assess victim drug-drug interaction risks

Introduction: Reaction phenotyping provides critical information regarding the fraction metabolized (f(m)) of drug candidates. It has become increasingly important in drug discovery and development as it can be used to assess victim drug-drug interaction potential, guide structural modification to reduce f(m), inform clinical study design, predict individual variability in pharmacokinetics, and evaluate the impact of genetic polymorphisms. Areas covered: The currently available in vitro and in vivo methods for reaction phenotyping are summarized along with their advantages, limitations and timings for application during the different stages of drug discovery and development. Challenges of reaction phenotyping for low clearance compounds, non-Cytochrome P450 (CYP) enzymes, extrahepatic contribution and atypical kinetics are highlighted and various approaches are discussed. Expert opinion: Certain areas of reaction phenotyping remain challenging with the current state of the science. In order to better define f(m) in this challenging space, there needs to be future advances in selective inhibitors and specific substrate reactions for non-CYP enzymes, availability of high quality and low cost recombinant enzymes, tissue distribution and in vitro-in vivo correlation, scaling factors for extrahepatic enzymes and the next generation of low clearance tools.