BACKGROUND: Predicting metabolic drug-drug interactions (DDIs) via cytochrome P450 enzymes (CYP) is essential in drug development, but controversy has reemerged recently about whether in vitro-in vivo extrapolation (IVIVE) using static models can replace dynamic models for some regulatory filings and label recommendations. OBJECTIVE: The aim of this study was to determine if static and dynamic models are equivalent for the quantitative prediction of metabolic DDIs arising from competitive CYP inhibition. METHODS: Drug parameter spaces were varied to simulate 30,000 DDIs between hypothetical substrates and inhibitors of CYP3A4. Predicted area under the plasma concentration-time profile ratios for substrates (AUCr = AUC RESULTS: The highest rate of IMDR <
0.8 and IMDR >
1.25 discrepancies in the 'population' representative was 85.9% and 3.1%, respectively, when using C CONCLUSION: Static models are not equivalent to dynamic models for predicting metabolic DDIs via competitive CYP inhibition across diverse drug parameter spaces, particularly for vulnerable patients. Caution is warranted in drug development if static IVIVE approaches are used alone to evaluate metabolic DDI risks.