Static Versus Dynamic Model Predictions of Competitive Inhibitory Metabolic Drug-Drug Interactions via Cytochromes P450: One Step Forward and Two Steps Backwards.

ABSTRACT:

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_{(presence of precipitant)}/AUC_(absence

SUBMITTER: Tiryannik I 

PROVIDER: S-EPMC11762507 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature