Effect of CES1 and ABCB1 genotypes on the pharmacokinetics and clinical outcomes of dabigatran etexilate in patients with atrial fibrillation and chronic kidney disease

Abstract

Background

Despite the well-studied safety profile of dabigatran, its interactions with genetic polymorphism parameters are poorly understood, especially in patients with moderate chronic kidney disease (CKD). The study assessed whether genetic factors can contribute to CKD and alter dabigatran concentration.

Methods

Patients with atrial fibrillation (AF) and stage 3 CKD treated with dabigatran 110 or 150 mg have been included in the study. Real-time polymerase chain reaction was used to evaluate single-nucleotide polymorphisms of the ABCB1 gene ( rs1045642 and rs4148738) and CES1 gene ( rs2244613). A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index.

Results

A total of 96 patients aged 51–89 years (median age: 75 years) were evaluated. Patients on a reduced regimen of 110 mg twice a day were older (79.8 vs. 67.9, p < 0.0001) and had lower creatinine clearance (49.7 vs. 62.3 mL/min/1.73 m ², p = 0.015). Patients with the rs2244613 CC genotype had lower C/D values (70% reduction in the mean C/D vs. AA genotype, p = 0.001). Linear stepwise regression has shown the CKD epidemiology collaboration to be the only significant predictor of C/D among genetic factors and kidney function characteristics. During the median follow-up of 15 months, there were 15 bleedings in 13 patients.

Conclusions

Polymorphism of CES1 rs2244613 can contribute to the safety of dabigatran in patients with AF and CKD. There was no influence of the aforementioned polymorphisms of ABCB1 on dabigatran trough plasma concentrations and C/D. Kidney function is a mainstay of clinical decision-making on direct oral anticoagulant (DOAC) dose, and further knowledge should be accumulated on the role of genetic factors.