PBPK Models for CYP3A4 and P‐gp DDI Prediction: A Modeling Network of Rifampicin, Itraconazole, Clarithromycin, Midazolam, Alfentanil, and Digoxin

TLDR

According to current FDA and EMA guidance, physiologically based pharmacokinetic (PBPK) modeling is a powerful tool for exploring and quantitatively predicting drug‑drug interactions and may replace dedicated clinical trials. This study provides whole‑body PBPK models of rifampicin, itraconazole, clarithromycin, midazolam, alfentanil, and digoxin within the Open Systems Pharmacology Suite. The authors built independent whole‑body PBPK models for six drugs, coupled them with reported interaction parameters, evaluated them against 112 development and 57 prediction studies, and released the models as open‑source documentation. The models achieved 93 % of predicted AUC ratios and 94 % of Cmax ratios within twofold of observed values, establishing the OSP platform as a reliable tool for enzyme‑ and transporter‑mediated DDI prediction.

Abstract

According to current US Food and Drug Administration ( FDA ) and European Medicines Agency ( EMA ) guidance documents, physiologically based pharmacokinetic ( PBPK ) modeling is a powerful tool to explore and quantitatively predict drug‐drug interactions ( DDI s) and may offer an alternative to dedicated clinical trials. This study provides whole‐body PBPK models of rifampicin, itraconazole, clarithromycin, midazolam, alfentanil, and digoxin within the Open Systems Pharmacology ( OSP ) Suite. All models were built independently, coupled using reported interaction parameters, and mutually evaluated to verify their predictive performance by simulating published clinical DDI studies. In total, 112 studies were used for model development and 57 studies for DDI prediction. 93% of the predicted area under the plasma concentration‐time curve ( AUC ) ratios and 94% of the peak plasma concentration (C max ) ratios are within twofold of the observed values. This study lays a cornerstone for the qualification of the OSP platform with regard to reliable PBPK predictions of enzyme‐mediated and transporter‐mediated DDI s during model‐informed drug development. All presented models are provided open‐source and transparently documented.