A Comprehensive Whole-Body Physiologically Based Pharmacokinetic Model of Dabigatran Etexilate, Dabigatran and Dabigatran Glucuronide in Healthy Adults and Renally Impaired Patients

Abstract

Background and Objectives The thrombin inhibitor dabigatran is administered as the prodrug dabigatran etexilate, which is a substrate of esterases and P-glycoprotein (P-gp). Dabigatran is eliminated via renal excretion but is also a substrate of uridine 5ʹ-diphospho (UDP)-glucuronosyltransferases (UGTs). The objective of this study was to build a physiologically based pharmacokinetic (PBPK) model comprising dabigatran etexilate, dabigatran, and dabigatran 1-O-acylglucuronide to describe the pharmacokinetics in healthy adults and renally impaired patients mechanistically. Methods Model development and evaluation were carried out using (i) physicochemical and absorption, distribution, metabolism, and excretion (ADME) parameter values of all three analytes; (ii) concentration–time profles from 13 studies of healthy and renally impaired individuals after varying doses (0.1–300 mg), intravenous (dabigatran) and oral (dabigatran etexilate) administration, and diferent formulations of dabigatran etexilate (capsule, solution); and (iii) drug–drug interaction studies of dabigatran with the P-gp perpetrators rifampin (inducer) and clarithromycin (inhibitor). Results A PBPK model of dabigatran was successfully developed. The predicted area under the plasma concentration–time curve, trough concentration, and half-life values of the assessed clinical studies satisfed the two-fold acceptance criterion. Metabolic clearances of dabigatran etexilate and dabigatran were implemented using data on carboxylesterase 1/2 enzymes and UGT subtype 2B15. In severe renal impairment, the UGT2B15 metabolism and the P-gp transport in the model were reduced to 67% and 65% of the rates in healthy adults. Conclusion This is the frst implementation of a PBPK model for dabigatran to distinguish between the prodrug, active moiety, and main active metabolite. Following adjustment of the UGT2B15 metabolism and P-gp transport rates, the PBPK model accurately predicts the pharmacokinetics in renally impaired patients.