Open AccessAssessing Potential Drug–Drug Interactions Between Dabigatran Etexilate and a P‐Glycoprotein Inhibitor in Renal Impairment Populations Using Physiologically Based Pharmacokinetic Modeling
Author(s) -
Doki Kosuke,
Neuhoff Sibylle,
RostamiHodjegan Amin,
Homma Masato
Publication year - 2019
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12382
Subject(s) - pharmacokinetics , dabigatran , pharmacology , drug , medicine , dosing , prodrug , verapamil , p glycoprotein , population , therapeutic drug monitoring , chemistry , warfarin , calcium , biochemistry , antibiotics , environmental health , multiple drug resistance , atrial fibrillation
Plasma concentrations of dabigatran, an active principle of prodrug dabigatran etexilate ( DABE ), are increased by renal impairment ( RI ) or coadministration of a P‐glycoprotein inhibitor. Because the combined effects of drug–drug interactions and RI have not been evaluated by means of clinical studies, the decision of DABE dosing for RI patients receiving P‐glycoprotein inhibitors is empirical at its best. We conducted virtual drug–drug interactions studies between DABE and the P‐glycoprotein inhibitor verapamil in RI populations using physiologically based pharmacokinetic modeling. The developed physiologically based pharmacokinetic model for DABE and dabigatran was used to predict trough dabigatran concentrations in the presence and absence of verapamil in virtual RI populations. The population‐based physiologically based pharmacokinetic model provided the most appropriate dosing regimen of DABE for likely clinical scenarios, such as drug–drug interactions in this RI population based on available knowledge of the systems changes and in the absence of actual clinical studies.