Prediction of CYP‐mediated DDIs involving inhibition: Approaches to address the requirements for system qualification of the Simcyp Simulator

Abstract Physiologically‐based pharmacokinetic (PBPK) modeling is being increasingly used in drug development to avoid unnecessary clinical drug–drug interaction (DDI) studies and inform drug labels. Thus, regulatory agencies are recommending, or indeed requesting, more rigorous demonstration of the prediction accuracy of PBPK platforms in the area of their intended use. We describe a framework for qualification of the Simcyp Simulator with respect to competitive and mechanism‐based inhibition (MBI) of CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5. Initially, a DDI matrix, consisting of a range of weak, moderate, and strong inhibitors and substrates with varying fraction metabolized by specific CYP enzymes that were susceptible to different degrees of inhibition, were identified. Simulations were run with 123 clinical DDI studies involving competitive inhibition and 78 clinical DDI studies involving MBI. For competitive inhibition, the overall prediction accuracy was good with an average fold error (AFE) of 0.91 and 0.92 for changes in the maximum plasma concentration (C max ) and area under the plasma concentration (AUC) time profile, respectively, as a consequence of the DDI. For MBI, an AFE of 1.03 was determined for both C max and AUC. The prediction accuracy was generally comparable across all CYP enzymes, irrespective of the isozyme and mechanism of inhibition. These findings provide confidence in application of the Simcyp Simulator (V19 R1) for assessment of the DDI potential of drugs in development either as inhibitors or victim drugs of CYP‐mediated interactions. The approach described herein and the identified DDI matrix can be used to qualify subsequent versions of the platform.