An important goal in drug development is to understand the effects of intrinsic and/or extrinsic factors (IEFs) on drug pharmacokinetics. Although clinical studies investigating a given IEF can accomplish this goal, they may not be feasible for all IEFs or for situations when multiple IEFs exist concurrently. Physiologically based pharmacokinetic (PBPK) models may serve as a complementary tool for forecasting the effects of IEFs. We developed PBPK models for four drugs that are eliminated by both cytochrome P450 (CYP)3A4 and CYP2D6, and evaluated model prediction of the effects of comedications and/or genetic polymorphism on drug exposure. PBPK models predicted 100 and ≥70% of the observed results when the conventional "twofold rule" and the more conservative 25% deviation cut point were applied, respectively. These findings suggest that PBPK models can be used to infer effects of individual or combined IEFs and should be considered to optimize studies that evaluate these factors, specifically drug interactions and genetic polymorphism of drug-metabolizing enzymes.