Advances and challenges for drug interaction evaluation - Perspectives on the ICH M12 guideline

Drug-drug interaction (DDI) is an important factor to consider when determining the drug and optimal dose for individual patients. The DDI potential of an investigational drug is routinely evaluated during development. For pharmacokinetics-based DDIs, regional regulatory guidelines were developed providing recommendations on in vitro and clinical DDI evaluations. Recently, a globally harmonized DDI (M12) guideline was issued by the International Council for Harmonization (ICH) and adopted by regulatory agencies worldwide. The M12 guideline describes a stepwise, risk-based approach that leverages in vitro and clinical data and is facilitated by modeling tools and endogenous biomarker information. Compared to regional guidelines, several aspects were expanded or updated in the M12 guideline, including the utility of endogenous biomarkers and revisions of in vitro-to-in vivo extrapolation (IVIVE) criteria to predict the in vivo potential of CYP inhibition or induction. In this review, we provided the current status of M12 guideline implementation in the EU, Japan, and the US, clarified the scope of the guideline, described the application of biomarkers of transporters or enzymes in regulatory submissions and reviews, shared the rationale underlying the modifications of certain IVIVE criteria, and discussed some remaining challenges that need collaborative effort from academia, industry, and regulators to address.