Genetic Determinants of Dabigatran Plasma Levels and Their Relation to Bleeding

Abstract

Background-Fixed-dose unmonitored treatment with dabigatran etexilate is effective and has a favorable safety profile in the prevention of stroke in atrial fibrillation patients compared with warfarin. We hypothesized that genetic variants could contribute to interindividual variability in blood concentrations of the active metabolite of dabigatran etexilate and influence the safety and efficacy of dabigatran. Methods and Results-We successfully conducted a genome-wide association study in 2944 Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) participants. The CES1 single-nucleotide polymorphism rs2244613 was associated with trough concentrations, and the ABCB1 single-nucleotide polymorphism rs4148738 and the CES1 singlenucleotide polymorphism rs8192935 were associated with peak concentrations at genome-wide significance (P<9×10 ) in dabigatran-treated participants, with a consistent but nonsignificant lower risk of major bleeding (odds ratio, 0.66; 95% confidence interval, 0.43-1.01). The interaction between treatment (warfarin versus all dabigatran) and carrier status was statistically significant (P=0.002), with carriers having less bleeding with dabigatran than warfarin (hazard ratio, 0.59; 95% confidence interval, 0.46-0.76; P=5.2×10 − 5) in contrast to no difference in noncarriers (hazard ratio, 0.96; 95% confidence interval, 0.81-1.14; P=0.65). There was no association with ischemic events, and neither rs4148738 nor rs8192935 was associated with bleeding or ischemic events. Conclusions-Genome-wide association analysis identified that carriage of the CES1 rs2244613 minor allele occurred in 32.8% of patients in RE-LY and was associated with lower exposure to active dabigatran metabolite. The presence of the polymorphism was associated with a lower risk of bleeding. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600. (Circulation.

Enhanced Elimination of Dabigatran Through Extracorporeal Methods

“…Dabigatran is a potent competitive thrombin inhibitor [2], inhibiting both fibrin-bound and unbound thrombin. Dabigatran has a low oral bioavailability, ranging from 3 to 7 % and is predominantly cleared (80 %) by the kidneys [1,2,29,35]. The recommended dosage for prevention of stroke in patients with nonvalvular AF and for treatment and secondary prevention of venous thromboembolism is 150 mg twice daily [1].…”

“…For example, a recent analysis demonstrated that the single-nucleotide polymorphism of carboxylesterase-1, rs2244613, was present in 32.8 % of subjects enrolled in the RE-LY trial, which was found to be protective as lower trough concentrations of dabigatran and correlate with a lower risk of bleeding [35]. In addition, polymorphisms in ABCB1, the gene that encodes P-glycoprotein, can influence the bioavailability of dabigatran [23,44].…”

Determination of dabigatran in plasma, serum, and urine samples: comparison of six methods

“…Despite the claim that dabigatran treatment does not to require laboratory-guided dose adjustment, due to the low bioavailability ( < 6.5%), predominant renal elimination ( > 80%) [7], and genetic variants' influence on the responses to dabigatran [9], assessing the intensity of anticoagulation may be useful in patients at risk of overdose and in highrisk (both for thromboembolism and for bleeding) patients in general [10]. The standard for measuring NOAC concentrations in biological fluids is high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS).…”

A population‐based study of the drug interaction between clopidogrel and angiotensin converting enzyme inhibitors

“…However, important pharmacologic differences exist among the drugs in this class. Most commonly prescribed ACE inhibitors (including ramipril, trandolapril, enalapril and perindopril) are prodrugs that are de‐esterified to active metabolites (ramiprilat, trandolaprilat, emalaprilat and perindoprilat, respectively) by the enzyme carboxylesterase 1 (CES1), an enzyme highly expressed in liver and increasingly appreciated as an important factor in drug metabolism 9, 10, 11, 12. In contrast, lisinopril and captopril are active ACE inhibitors that require no such bio‐activation 13.…”

“…In contrast, lisinopril and captopril are active ACE inhibitors that require no such bio‐activation 13. Genetic variation in CES1 has been shown to influence drug metabolism and may influence the antihypertensive effects of ACE inhibitors such as imidapril 11, 14, 15, 16, 17, 18.…”