Comparison of Quantitative Prediction Methods for Drug–Drug Interactions Based on Cytochrome P450 Inhibition

Quantitative risk assessment prediction of drug-drug interactions (DDIs) caused by metabolic enzyme inhibition is essential in both new drug development and clinical practice. Regulatory guidance recommends three approaches: cutoff criteria that conservatively evaluate the potential for DDIs using minimal data and quantitative prediction using mechanistic static pharmacokinetic (MSPK) models and physiologically based pharmacokinetic (PBPK) models. In clinical settings, the CR-IR method is also applied, which predicts DDIs using the contribution ratio of cytochrome P450 (CYP) isoforms to substrate clearance together with the inhibition ratio of an inhibitor toward the corresponding CYP.