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Interindividual variability in dabigatran and rivaroxaban exposure: contribution of ABCB 1 genetic polymorphisms and interaction with clarithromycin
Author(s) -
GouinThibault I.,
Delavenne X.,
Blanchard A.,
Siguret V.,
Salem J. E.,
Narjoz C.,
Gaussem P.,
Beaune P.,
FunckBrentano C.,
Azizi M.,
Mismetti P.,
Loriot M. A.
Publication year - 2017
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.13577
Subject(s) - rivaroxaban , dabigatran , pharmacology , pharmacokinetics , medicine , pharmacogenetics , cyp2c19 , genotype , warfarin , atrial fibrillation , biology , cytochrome p450 , genetics , gene , metabolism
Essentials Rivaroxaban and dabigatran are substrates of the P‐glycoprotein (P‐gp) encoded by the ABCB1 gene. We tested the effect of ABCB1 polymorphisms and of a P‐gp inhibitor on both drugs' pharmacokinetics. The ABCB1 genotype was not a clinically relevant determinant of both drugs' pharmacokinetics. Administration of P‐gp inhibitors with dabigatran or rivaroxaban should be exercised with caution.Summary Background The direct oral anticoagulants ( DOAC s) dabigatran and rivaroxaban are both substrates of the P‐glycoprotein (P‐gp) transporter, encoded by the ABCB 1 gene. Rivaroxaban is metabolized by cytochrome P 450 A 4 ( CYP 3A4). Interindividual variability in DOAC exposure and frequent P‐gp‐associated drug–drug interactions have been described in patients. Objective To assess the influence of ABCB 1 polymorphisms on the pharmacokinetics of dabigatran and rivaroxaban, associated or not with clarithromycin, a P‐gp and CYP 3A4 inhibitor. Methods Sixty healthy male volunteers, selected according to ABCB 1 genotype (20 homozygous mutated, 20 heterozygous mutated, and 20 wild‐type for haplotype 2677‐3435), were included in this randomized, two‐center, crossover study. All received sequentially a single dose of dabigatran etexilate (300 mg) and rivaroxaban (40 mg) associated or not with clarithromycin. Peak plasma concentration and area under the curve ( AUC ) were compared across the three ABCB 1 genotypes. The effect of clarithromycin on dabigatran or rivaroxaban pharmacokinetics was assessed. Results Interindividual coefficients of variation for AUC were 77% for dabigatran and 51% for rivaroxaban. ABCB 1 genotype did not significantly affect drug pharmacokinetics: AUC ratios between mutant‐allele carriers and wild‐type volunteers were 1.27 (95% confidence interval [ CI ] 0.84–1.92) and 1.20 (95% CI 0.96–1.51) for dabigatran and rivaroxaban, respectively. Clarithromycin coadministration led to a two‐fold increase in both drugs’ AUC , irrespective of ABCB 1 genotype: ratios of geometric means were 2.0 (95% CI 1.15–3.60) and 1.94 (95% CI 1.42–2.63) for dabigatran and rivaroxaban, respectively. Conclusions ABCB 1 genotype is not a significant determinant of interindividual variability in dabigatran and rivaroxaban pharmacokinetics. The levels of one drug did not predict the levels of the other. Coadministration of a P‐gp/ CYP 3A4 inhibitor with dabigatran or rivaroxaban may warrant caution in patients at risk of overexposure.