Future directions in drug-drug interaction evaluations: Industry perspective on the ICH M12 guidance.

The ICH M12 Guidance, adopted by the International Council for Harmonisation in 2024, provides a global framework for assessing drug-drug interaction (DDI) risks mediated by metabolic enzymes and drug transporters. The DDI Discussion Group in the International Consortium for Innovation and Quality identifies key challenges in the guidance. In vitro challenges include accounting for protein binding, mitigating overestimations of DDI risks, and interpreting weak enzyme inhibition or induction effects. A case study explores cytochrome P450 (CYP) induction risks by major metabolites. The complexities of UDP-glucuronosyltransferase (UGT) and transporter inhibition or induction are contextualized. Clearance pathway evaluations for low turnover compounds and UGT or transporter substrates are also summarized for object DDIs. Clinically, challenges include the need for validated endogenous biomarkers to improve DDI risk assessments and finding alternatives to rifampin for CYP induction and Organic Anion Transporting polypeptide 1B (OATP1B) inhibition due to nitrosamine: reduced and non-selective induction by drugs like carbamazepine and phenytoin or non-selective OATP inhibition by cyclosporine. Further complexities involve therapeutic-protein DDIs, transporter-enzyme interplay and compounds acting as simultaneous inducers and time-dependent inhibitors. Addressing these gaps requires collaborative efforts to refine predictive models to improve in vitro-in vivo correlations, and to enhance drug development and patient safety.