Umehara, Kenichi, Harrell, Andrew, Morse, Bridget Louise, Prakash, Chandra, Hilgendorf, Constanze, Ballard, Eric, Huth, Felix, Badee, Justine Marine, Jiang, Licong, Vourvahis, Manoli, Pajkovic, Natasa, Parrott, Neil, Thakkar, Nilay, Marroum, Patrik, Laethem, Ronald, Xu, Shiyao and Chen, Yuan (2025) Future Directions in Drug-Drug Interaction Evaluations: Industry Perspective on the ICH M12 Guideline. Drug metabolism and pharmacokinetics.

Abstract

The ICH M12 Guideline, 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 identified key challenges across in vitro and clinical stages. 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 glucuronosyltransferase (UGT) and transporter inhibition or induction were contextualized. Clearance pathway evaluations for low turnover compounds and UGT or transporter substrates was 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 (OATP) inhibition due to nitrosamine contamination: reduced and non-selective induction by drugs like carbamazepine and phenytoin or 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, improve in vitro-in vivo correlations, and enhance drug development and patient safety.

Item Type:	Article
Keywords:	ICH M12, DDI, guideline
Date Deposited:	24 Feb 2026 00:45
Last Modified:	24 Feb 2026 00:45
URI:	https://oak.novartis.com/id/eprint/58734