Pharmacogenetics of dabigatran etexilate interindividual variability

•This is the first study that uses real world patients in oral anticoagulation.•Patients were enlisted in two experienced Italian Outpatient Anticoagulation Clinics.•Plasma dabigatran concentrations were measured using a LC–MS/MS method.•Statistical analysis was performed using different robust multivariate approaches.•The CES1 SNP rs8192935 significantly modulates dabigatran trough concentrations.

IntroductionDabigatran etexilate is given in fixed doses without coagulation monitoring for the prevention of blood clots in at risk adults. A high inter-individual variability in blood concentrations of the active metabolite of dabigatran has been reported. ABCB1 and CES1 exert an important effect in the metabolism of dabigatran etexilate and allele variants at these two loci are likely to play a pivotal role.To investigate whether screening for polymorphisms within the ABCB1 and the CES1 genes would explain a portion of the inter-individual variability in blood concentrations of the active metabolite of dabigatran.Material and methodsIn a cohort of patients who had atrial fibrillation and on anticoagulant prophylaxis with dabigatran etexilate, we investigated whether genotypes at rs4148738 (ABCB1), rs8192935 (CES1), and rs2244613 (CES1) loci would affect plasma dabigatran trough and peak concentrations.Results and discussionAmong 92 patients (median age: 72.0 years, range: 52–92) analyzed, no clinical variable or genotype was associated with a significant difference in dabigatran peak concentrations. As for trough concentrations, in addition to creatinine clearance, and sex a significant association with the CES1 SNP rs8192935 (p = 0.023) was detected. The mean adjusted plasma levels were higher among patients with the CC genotype (86.3 ng/dl) than in those carrying the T allele (62.1 ng/dl). No significant effect was found for the ABCB1 SNP rs4148738.The CES1 SNP rs8192935 significantly influenced the dabigatran trough concentrations and carriers of the T allele showed significantly lower concentrations than did carriers of the CC genotype.