Drug-drug interaction by metabolites: Challenges and solutions during therapeutics innovation

The direct effects of drug metabolites on efficacy and safety have been evaluated carefully according to the regulatory guidelines by major authorities such as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, US Food and Drug Administration, and Chinese National Medical Product Administration. In recent years, there has been increasing interest in and concern about the effects of drug metabolites on drug-drug interactions (DDIs) by inhibiting or inducing the activities of drug metabolism enzyme and/or drug transporters, termed metabolite-mediated DDIs (Met DDIs). Actually, the clinical risks of Met DDIs had been identified as gemfibrozil and mibefradil; mibefradil was withdrawn from the market because of serious adverse reactions. This review will focus on (1) the recommendations of various regulatory agencies regarding Met DDIs, (2) strategies and methodologies for evaluating Met DDIs for supporting the registrations of investigational new drug applications and new drug applications, and (3) the prediction of Met DDIs with the application of in vitro/nonclinical/clinical data by using relevant silicon models such as physiologically based pharmacokinetic and population pharmacokinetic models. SIGNIFICANCE STATEMENT: Metabolite-mediated drug-drug interactions (Met DDIs) can significantly affect clinical safety and efficacy. This review comprehensively analyzes regulatory guidelines by major authorities (National Medical Product Administration, US Food and Drug Administration, Pharmaceuticals and Medical Devices Agency, European Medicines Agency, and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use), summarizing their consensus on proactive Met DDI risk assessment while highlighting key discrepancies in scope, thresholds, and implementation requirements. Furthermore, it presents a translational evaluation strategy-from early in vitro characterization to advanced modeling approaches (physiologically based pharmacokinetic/population pharmacokinetic simulations) and optimized clinical study designs-with critical support from multiple case studies that illustrate practical applications, challenges, and solutions in Met DDI risk mitigation.