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. Simulation

SUBMITTER: Kilford PJ 

PROVIDER: S-EPMC9286715 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature