Assessing potential drug-drug interactions between dabigatran etexilate and a P-gp inhibitor in renal impairment population using PBPK modeling.

Plasma concentrations of dabigatran (DAB), an active principle of prodrug dabigatran etexilate (DABE), are increased by renal impairment (RI) or co-administration of a P-glycoprotein (P-gp) inhibitor. Since the combined effects of drug-drug interactions (DDIs) and RI have not been evaluated by means of clinical studies, the decision of DABE dosing for RI patients receiving P-gp inhibitors is empirical at its best. We conducted virtual DDI studies between DABE and the P-gp inhibitor verapamil in RI populations using physiologically-based pharmacokinetic (PBPK) modeling. The developed PBPK model for DABE and DAB was used to predict trough DAB concentrations in the presence and absence of verapamil in virtual RI populations. The population-based PBPK model provided the most appropriate dosing regimen of DABE for likely clinical scenarios, such as DDIs in this RI population based on available knowledge of the systems changes and in the absence of actual clinical studies. This article is protected by copyright. All rights reserved.