Pharmacogenetics of dabigatran etexilate interindividual variability

Dimatteo, Claudia; D’Andrea, Giovanna; Vecchione, Gennaro; Paoletti, Oriana; Cappucci, Filomena; Tiscia, Giovanni Luca; Buono, Matteo; Grandone, Elvira; Testa, Sophie; Margaglione, Maurizio

doi:10.1016/j.thromres.2016.05.025

Cited by 75 publications

(92 citation statements)

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“…Further in vitro study based on CES1-transfected cell lines demonstrated that the G143E is a loss-of-function variant for metabolisms of DABE, M1, and M2. However, contrary to that suggested by two previous clinical studies [4, 10], no association was found between the SNPs rs2244613 and rs8192935 and CES1 expression and activity on DABE activation. Thus, further study is warranted to elucidate the effect of these two CES1 SNPs on CES1 function and their consequent impact on DABE activation.…”

Section: Discussioncontrasting

confidence: 99%

“…Pare and associates conducted a genome-wide association study in RE-LY study participants, and reported that the CES1 SNPs rs2244613 and rs8192935 were associated with lower plasma concentrations of DAB, and the rs2244613 was also associated with a lower risk of bleeding [4]. In addition, a recently published clinical study showed that the SNP rs8192935 carriers exhibited significantly lower plasma trough concentrations of DAB relative to non-carriers [10]. …”

Section: Discussionmentioning

confidence: 99%

“…A genome-wide association study conducted by Pare and colleagues reported that the CES1 single-nucleotide polymorphisms (SNPs) rs2244613 and rs8192935 were associated with lower exposure to the active metabolite DAB in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) study participants, and the SNP rs2244613 was also associated with a lower risk of bleeding [4]. In addition, a recently published clinical study showed that the trough concentrations of DAB were significantly lower in the carriers of the SNP rs8192935 relative to the non-carriers [10]. Although there is ample evidence that CES1 genetic variants, such as the loss-of-function variant G143E (rs71647871) originally discovered in our laboratory [11], can markedly affect CES1 function and consequently alter pharmacokinetics and pharmacodynamics of various CES1 substrate drugs, it remains undetermined whether the SNPs rs2244613 and rs8192935 may affect the expression/activity of the CES1 enzyme.…”

Section: Introductionmentioning

confidence: 99%

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Dabigatran etexilate activation is affected by the CES1 genetic polymorphism G143E (rs71647871) and gender

Shi

Wang

Nguyen

et al. 2016

Biochemical Pharmacology

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The oral anticoagulant prodrug dabigatran etexilate (DABE) is sequentially metabolized by intestinal carboxylesterase 2 (CES2) and hepatic carboxylesterase 1 (CES1) to form its active metabolite dabigatran (DAB). A recent genome-wide association study reported that the CES1 single nucleotide polymorphisms (SNPs) rs2244613 and rs8192935 were associated with lower DAB plasma concentrations in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) study participants. In addition, gender differences in exposure to DAB were observed in clinical studies. The aim of this study was to examine the effect of CES1 genetic polymorphisms and gender on DABE activation using several in vitro approaches. The genotypes of the CES1 SNPs rs2244613, rs8192935, and the known loss-of-function CES1 variant rs71647871 (G143E), and the activation of DABE and its intermediate metabolites M1 and M2 were determined in 104 normal human liver samples. DABE, M1, and M2 activations were found to be impaired in human livers carrying the G143E variant. However, neither rs2244613 nor rs8192935 was associated with the activation in human livers. The incubation study of DABE with supernatant fractions (S9) prepared from the G143E-transfected cells showed that the G143E is a loss-of-function variant for DABE metabolism. Moreover, hepatic CES1 activity on M2 activation was significantly higher in female liver samples than male. Our data suggest that CES1 genetic variants and gender are important contributing factors to variability in DABE activation in humans. A personalized DABE treatment approach based on patient-specific CES1 genotypes and sex may have the potential to improve the efficacy and safety of DABE pharmacotherapy.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dabigatran etexilate activation is affected by the CES1 genetic polymorphism G143E (rs71647871) and gender

Shi

Wang

Nguyen

et al. 2016

Biochemical Pharmacology

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“…a difference of at least 30%. Our results concur with very recent data reporting a lack of effect of the ABCB1 SNP rs4148738 in 92 patients treated with dabigatran etexilate [40]. Taken together, our results demonstrate that the ABCB1 genetic variations encountered in approximately half of the Caucasian population are not major predictors of interindividual variability in dabigatran and rivaroxaban pharmacokinetics.…”

Section: Discussionsupporting

confidence: 92%

Interindividual variability in dabigatran and rivaroxaban exposure: contribution of ABCB1 genetic polymorphisms and interaction with clarithromycin

Gouin‐Thibault

Delavenne

Blanchard

et al. 2017

Journal of Thrombosis and Haemostasis

116

119

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Background The direct oral anticoagulants (DOACs) dabigatran and rivaroxaban are both substrates of the P-glycoprotein (P-gp) transporter, encoded by the ABCB1 gene. Rivaroxaban is metabolized by cytochrome P450 A4 (CYP3A4). Interindividual variability in DOAC exposure and frequent P-gp-associated drug-drug interactions have been described in patients. Objective To assess the influence of ABCB1 polymorphisms on the pharmacokinetics of dabigatran and rivaroxaban, associated or not with clarithromycin, a P-gp and CYP3A4 inhibitor. Methods Sixty healthy male volunteers, selected according to ABCB1 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 ABCB1 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. ABCB1 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 ABCB1 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 ABCB1 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/CYP3A4 inhibitor with dabigatran or rivaroxaban may warrant caution in patients at risk of overexposure.

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“…The available DOACs have shown both inter-individual and intra-individual pharmacokinetic variability [1][2][3][4]. Even less predictable drug concentrations have been associated with advanced age, renal insufficiency, and body weight extremes [5][6][7].…”

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confidence: 99%