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 m2, 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.

The Impact of ABCB1 and CES1 Polymorphisms on Dabigatran Pharmacokinetics in Healthy Chinese Subjects

“…Allele C of CES1 rs2244613 was associated with decreased dabigatran trough concentration and decreased risk of bleeding, but not to the peak concentration. 6 , 7 , 18 According to the RE-LY study in Chinese patients with non-valvular atrial fibrillation, dabigatran had a lower risk of bleeding than warfarin. 11 Based on these findings, it was reasonable to suppose that the genetic difference between Chinese and Caucasians may contributed to the differences in bleeding risk.…”

Closure Device-Related Thrombosis After Anticoagulation With Dabigatran in Patients Undergoing Percutaneous Left Atrial Appendage Closure: Case Reports and Literature Review

“…The common genetic variants of CES1 and ABCB1 have been identified to potentially account for the interindividual variations in dabigatran plasma levels which could lead to varied anticoagulation therapeutic responses ( Sychev et al., 2020 ). It has been proven that the single nucleotide polymorphism (SNP) in the CES1 gene (rs2244613) could alter dabigatran metabolism, leading to lower trough concentrations and increasing thrombosis risks ( Sychev et al., 2020 ). However, we did not investigate the two associated genetic variants in these four cases.…”

The CES1 Gene rs2244613 Minor Allele Impact on the Safety Profile of Dabigatran Etexilate: Meta-Analysis

“…Sychev и соавт. [14,15] Эти результаты могут свидетельствовать о перспективе использования данного полиморфизма в качестве генетической детерминанты безопасности дабигатрана, например, при коррекции дозы препарата у пациентов с повышенным риском геморрагических осложнений.…”