Genetic Determinants of Dabigatran Plasma Levels and Their Relation to Bleeding

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 single-nucleotide polymorphism rs8192935 were associated with peak concentrations at genome-wide significance (P<9×10−8) with a gene-dose effect. Each minor allele of the CES1 single-nucleotide polymorphism rs2244613 was associated with lower trough concentrations (15% decrease per allele; 95% confidence interval, 10–19; P=1.2×10−8) and a lower risk of any bleeding (odds ratio, 0.67; 95% confidence interval, 0.55–0.82; P=7×10−5) 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.

[1]  Bill Bynum,et al.  Lancet , 2015, The Lancet.

[2]  W. Baker,et al.  Systematic Review and Adjusted Indirect Comparison Meta-Analysis of Oral Anticoagulants in Atrial Fibrillation , 2012, Circulation. Cardiovascular quality and outcomes.

[3]  John Spertus,et al.  Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study , 2012, The Lancet.

[4]  E. Antman,et al.  Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation , 2012, Thrombosis and Haemostasis.

[5]  S. Yusuf,et al.  Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non‐valvular atrial fibrillation from the RE‐LY trial , 2011, Journal of thrombosis and haemostasis : JTH.

[6]  S. Yusuf,et al.  Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation: An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial , 2011, Circulation.

[7]  P. Visscher,et al.  GCTA: a tool for genome-wide complex trait analysis. , 2011, American journal of human genetics.

[8]  G. Abecasis,et al.  MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes , 2010, Genetic epidemiology.

[9]  Sharon R Grossman,et al.  Integrating common and rare genetic variation in diverse human populations , 2010, Nature.

[10]  Michael Boehnke,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[11]  Thorsten Lehr,et al.  Integration of high-throughput genotyping data into pharmacometric analyses using nonlinear mixed effects modeling , 2010, Pharmacogenetics and genomics.

[12]  K. Rathgen,et al.  Influence of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Oral Dabigatran Etexilate , 2010, Clinical pharmacokinetics.

[13]  S. Yusuf,et al.  Dabigatran versus warfarin in patients with atrial fibrillation. , 2009, The New England journal of medicine.

[14]  S. Yusuf,et al.  Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. , 2009, American heart journal.

[15]  A. Clemens,et al.  Pharmacology, Pharmacokinetics, and Pharmacodynamics of Dabigatran Etexilate, an Oral Direct Thrombin Inhibitor , 2009, Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis.

[16]  Julie A. Johnson,et al.  Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis. , 2008, American journal of human genetics.

[17]  David S. Miller,et al.  Modulation of P-Glycoprotein at the Blood-Brain Barrier: Opportunities to Improve Central Nervous System Pharmacotherapy , 2008, Pharmacological Reviews.

[18]  T. Ebner,et al.  The Metabolism and Disposition of the Oral Direct Thrombin Inhibitor, Dabigatran, in Humans , 2008, Drug Metabolism and Disposition.

[19]  K. Rathgen,et al.  Pharmacokinetics and Pharmacodynamics of the Direct Oral Thrombin Inhibitor Dabigatran in Healthy Elderly Subjects , 2008, Clinical pharmacokinetics.

[20]  Zhaohui S. Qin,et al.  A second generation human haplotype map of over 3.1 million SNPs , 2007, Nature.

[21]  K. Rathgen,et al.  The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. , 2007, British journal of clinical pharmacology.

[22]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[23]  Tomomi Kimura,et al.  A Single Nucleotide Polymorphism in the Carboxylesterase Gene Is Associated with the Responsiveness to Imidapril Medication and the Promoter Activity , 2005, Hypertension Research.

[24]  S. Tokudome,et al.  IDENTIFICATION OF THE CYTOSOLIC CARBOXYLESTERASE CATALYZING THE 5′-DEOXY-5-FLUOROCYTIDINE FORMATION FROM CAPECITABINE IN HUMAN LIVER , 2004, Drug Metabolism and Disposition.

[25]  R. Ho,et al.  (Section A: Molecular, Structural, and Cellular Biology of Drug Transporters) The Role of MDR1 Genetic Polymorphisms in Interindividual Variability in P-glycoprotein Expression and Function , 2004 .

[26]  Lee Yong Lim,et al.  Herbal Modulation of P‐Glycoprotein , 2004, Drug metabolism reviews.

[27]  R. Ho,et al.  The role of MDR1 genetic polymorphisms in interindividual variability in P-glycoprotein expression and function. , 2004, Current drug metabolism.

[28]  M. Redinbo,et al.  Human carboxylesterase 1: from drug metabolism to drug discovery. , 2003, Biochemical Society transactions.

[29]  P. Taylor,et al.  Current progress on esterases: from molecular structure to function. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[30]  M. Wierdl,et al.  Structural constraints affect the metabolism of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) by carboxylesterases. , 2001, Molecular pharmacology.

[31]  W. Bosron,et al.  Binding and hydrolysis of meperidine by human liver carboxylesterase hCE-1. , 1999, The Journal of pharmacology and experimental therapeutics.

[32]  P. Houghton,et al.  Comparison of activation of CPT-11 by rabbit and human carboxylesterases for use in enzyme/prodrug therapy. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[33]  J Zhang,et al.  Purification and Cloning of a Broad Substrate Specificity Human Liver Carboxylesterase That Catalyzes the Hydrolysis of Cocaine and Heroin* , 1997, The Journal of Biological Chemistry.