Clinical Review of the Pharmacogenomics of Direct Oral Anticoagulants
Abstract
Purpose
There is growing interest in the use of pharmacogenomics to optimize the safety and efficacy of anticoagulation therapy. While the pharmacogenomics of warfarin have been well-studied, the pharmacogenomics of direct oral anticoagulants (DOACs) continue to be a fledgling, but growing, field of interest. We present a pertinent clinical review of the present state of research on the pharmacogenomics of DOACs.
Methods and Results
The present article is a review of pertinent clinical and scientific research on the pharmacogenomics of DOACs between January 2008 and December 2017 using MEDLINE and the United States National Institutes of Health Clinical Trials Registry. Many studies have identified single-nucleotide polymorphisms (SNPs) in genes responsible for DOAC metabolism that impacted serum DOAC concentration but had uncertain clinical significance.
Conclusions
As such, there is currently no strong evidence for the use of pharmacogenomic testing in optimizing the safety and efficacy of DOAC therapy. Nonetheless, genes of interest have been identified for each DOAC that may be of potential clinical utility. Further research is currently underway to elucidate the value of pharmacogenomics in this increasingly prescribed therapy.
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References
- Aspden P, Wolcott JA, Bootman JL, Cronenwett LR. Preventing medication errors: quality chasm series. Washington, DC: The National Academic Press; 2007.
- Google Scholar
- Kitzmiller JP, Groen DK, Phelps MA, Sadee W. Pharmacogenomic testing: relevance in medical practice: why drugs work in some patients but not in others. Cleve Clin J Med. 2011;78(4):243–57.
- Article PubMed PubMed Central Google Scholar
- Ma Q, Lu AY. Pharmacogenetics, pharmacogenomics, and individualized medicine. Pharmacol Rev. 2011;63(2):437–59.
- Article CAS PubMed Google Scholar
- Li J, Wang S, Barone J, Malone B. Warfarin pharmacogenomics. P T. 2009;34(8):422–7.
- PubMed PubMed Central Google Scholar
- Militaru FC, Vesa SC, Pop TR, Buzoianu AD. Pharmacogenetics aspects of oral anticoagulants therapy. J Med Life. 2015;8(2):171–5.
- CAS PubMed PubMed Central Google Scholar
- Johnson JA, Caudle KE, Gong L, Whirl-Carrillo M, Stein CM, Scott SA, et al. Clinical pharmacogenetics implementation consortium (CPIC) guideline for pharmacogenetics-guided warfarin dosing: 2017 update. Clin Pharmacol Ther. 2017;102(3):397–404.
- Owen RP, Gong L, Sagreiya H, Klein TE, Altman RB. VKORC1 pharmacogenomics summary. Pharmacogenet Genomics. 2010;20(10):642–4.
- Article CAS PubMed PubMed Central Google Scholar
- Gouin-Thibault I, Delavenne X, Blanchard A, et al. Inter-individual variability in dabigatran and rivaroxaban exposure: contribution of ABCB1 genetic polymorphisms and interaction with clarithromycin. J Thromb Haemost. 2017;15:273-83
- Cavallari LH, Shin J, Perera MA. Role of pharmacogenomics in the management of traditional and novel oral anticoagulants. Pharmacotherapy. 2011;31(12):1192–207.
- Article CAS PubMed Google Scholar
- Ross S, Pare G. Pharmacogenetics of antiplatelets and anticoagulants: a report on clopidogrel, warfarin and dabigatran. Pharmacogenomics. 2013;14(13):1565–72.
- Article CAS PubMed Google Scholar
- Shi J, Wang X, Nguyen JH, Bleske BE, Liang Y, Liu L, et al. Dabigatran etexilate activation is affected by the CES1 genetic polymorphism G143E (rs71647871) and gender. Biochem Pharmacol. 2016;119:76–84.
- Article CAS PubMed PubMed Central Google Scholar
- Merali Z, Ross S, Pare G. The pharmacogenetics of carboxylesterases: CES1 and CES2 genetic variants and their clinical effect. Drug Metabol Drug Interact. 2014;29(3):143–51.
- Article CAS PubMed Google Scholar
- Gong IY, Mansell SE, Kim RB. Absence of both MDR1 (ABCB1) and breast cancer resistance protein (ABCG2) transporters significantly alters rivaroxaban disposition and central nervous system entry. Basic Clin Pharmacol Toxicol. 2013;112(3):164–70.
- Article CAS PubMed Google Scholar
- Mikkaichi T, Yoshigae Y, Masumoto H, Imaoka T, Rozehnal V, Fischer T, et al. Edoxaban transport via P-glycoprotein is a key factor for the drug's disposition. Drug Metab Dispos. 2014;42(4):520–8.
- Article PubMed Google Scholar
- Stollberger C, Finsterer J. Relevance of P-glycoprotein in stroke prevention with dabigatran, rivaroxaban, and apixaban. Herz. 2015;40(Suppl 2):140–5.
- Article PubMed Google Scholar
- Vandell AG, Lee J, Shi M, Rubets I, Brown KS, Walker JR. An integrated pharmacokinetic/pharmacogenomic analysis of ABCB1 and SLCO1B1 polymorphisms on edoxaban exposure. Pharmacogenomics J. 2016.
- Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos. 2008;36(2):386–99.
- Article CAS PubMed Google Scholar
- Mueck W, Schwers S, Stampfuss J. Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subjects, specific patient populations and relevance of coagulation monitoring. Thromb J. 2013;11(1):10.
- Article CAS PubMed PubMed Central Google Scholar
- Bathala MS, Masumoto H, Oguma T, He L, Lowrie C, Mendell J. Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans. Drug Metab Dispos. 2012;40(12):2250–5.
- Article CAS PubMed Google Scholar
- Stangier J, Rathgen K, Stahle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64(3):292–303.
- Article CAS PubMed PubMed Central Google Scholar
- Pare G, Eriksson N, Lehr T, Connolly S, Eikelboom J, Ezekowitz MD, et al. Genetic determinants of dabigatran plasma levels and their relation to bleeding. Circulation. 2013;127(13):1404–12.
- Article CAS PubMed Google Scholar
- Dimatteo C, D'Andrea G, Vecchione G, Paoletti O, Cappucci F, Tiscia GL, et al. Pharmacogenetics of dabigatran etexilate interindividual variability. Thromb Res. 2016;144:1–5.
- Article CAS PubMed Google Scholar
- Ing Lorenzini K, Daali Y, Fontana P, Desmeules J, Samer C. Rivaroxaban-induced hemorrhage associated with ABCB1 genetic defect. Front Pharmacol. 2016;7:494.
- Article PubMed PubMed Central Google Scholar
- Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol. 2013;76(3):455–66.
- Article CAS PubMed PubMed Central Google Scholar
- Dimatteo C, D’Andrea G, Vecchione G, Paoletti O, Tiscia GL, Santacroce R, et al. ABCB1 SNP rs4148738 modulation of apixaban interindividual variability. Thromb Res. 2016;145:24–6.
- Article CAS PubMed Google Scholar
- Ueshima S, Hira D, Fujii R, Kimura Y, Tomitsuka C, Yamane T, et al. Impact of ABCB1, ABCG2, and CYP3A5 polymorphisms on plasma trough concentrations of apixaban in Japanese patients with atrial fibrillation. Pharmacogenet Genomics. 2017;27(9):329–36.
- Article CAS PubMed Google Scholar
- ClinicalTrials.gov, Influence of ABCB1 polymorphisms on plasma concentrations of new oral anticoagulants in case of serious adverse events (Pgp NACO). 2014; National Library of Medicine: Bethesda.
Author information
Authors and Affiliations
- Department of Internal Medicine, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ, 85259, USA
- Andrew S. Tseng & Jacob T. Maddux
- College of Pharmacy, University of Arizona, 1295 N Martin Ave, Tucson, AZ, 85721, USA
- Reema D. Patel
- Midwestern University, 19555 N 59th Ave, Glendale, AZ, 85308, USA
- Heidi E. Quist
- Department of Pharmacy, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ, 85259, USA
- Adrijana Kekic & Christopher B. Grilli
- Division of Cardiovascular Diseases, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ, 85259, USA
- Fadi E. Shamoun
Corresponding author
Correspondence to Fadi E. Shamoun.
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Ethical Approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Conflict of Interest
The authors declare that they have conflicts of interest.