The EMA Qualification Opinion for CYP Inhibition‐Mediated Drug–Drug Interaction Predictions: Implications for PBPK Credibility Assessment in the Era of ICH M15

Clinical pharmacology and pharmacometrics teams are now being encouraged to implement the ICH M15 framework in drug development to support model-informed decisions in regulatory submissions. Although model performance is an important component of model evaluation, regulatory confidence also depends on the intended context of use (CoU) and the supporting level of evidence. This is particularly relevant for physiologically based pharmacokinetic (PBPK) modeling, where increasing regulatory application has strengthened the need for structured approaches to evaluate predictive performance, extrapolation, uncertainty, and model applicability. The Simcyp Simulator (V19R1) was recently qualified by the EMA for prediction of CYP-mediated drug-drug interactions (DDIs) involving six enzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5), competitive inhibition, and mechanism-based inhibition for both victim and perpetrator drugs across three CoUs. Qualification data demonstrated consistent predictive performance across the three CoUs, with average fold errors close to unity, absolute average fold errors ranging from 1.23 to 1.25, and 98.8% of 246 predictions falling within 2-fold of observed values. The opinion predates ICH M15; however, it does not provide either a mapping to its credibility concepts or an operational basis for extending platform-level evidence to a specific investigational drug. We address this gap with an explicit mapping of the qualification opinion onto ICH M15 credibility concepts and an integrated approach linking qualification evidence, drug-specific validation, predictive performance, uncertainty characterization, and prospective application, illustrating how confidence in PBPK-supported regulatory decisions can be established within an ICH M15-aligned framework.