Daniel Moj1, Hugo Maas2, André Schaeftlein1, Nina Hanke1, José David Gómez-Mantilla2, Thorsten Lehr3. 1. Clinical Pharmacy, Saarland University, Campus C2 2, 66123, Saarbruecken, Germany. 2. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. 3. Clinical Pharmacy, Saarland University, Campus C2 2, 66123, Saarbruecken, Germany. thorsten.lehr@mx.uni-saarland.de.
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 5'-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 profiles from 13 studies of healthy and renally impaired individuals after varying doses (0.1-300 mg), intravenous (dabigatran) and oral (dabigatran etexilate) administration, and different 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 satisfied 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 first 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.
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 5'-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 profiles from 13 studies of healthy and renally impaired individuals after varying doses (0.1-300 mg), intravenous (dabigatran) and oral (dabigatran etexilate) administration, and different 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 satisfied 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 first 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.
Authors: Kevin Hill; Ewa Sucha; Emily Rhodes; Marc Carrier; Amit X Garg; Ziv Harel; Gregory L Hundemer; Edward G Clark; Greg Knoll; Eric McArthur; Manish M Sood Journal: JAMA Intern Med Date: 2020-08-01 Impact factor: 21.873