Pharmacogenetics of Direct Oral Anticoagulants: A Systematic Review.

Johanna Raymond,Thibault Cousin,Fabien Lamoureux,Julien Wils,Laurent Imbert,Thomas Duflot,Rémi Varin

doi:10.3390/jpm11010037

Abstract

Dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban are direct oral anticoagulants (DOACs). Their inter-individual variability in pharmacodynamics and pharmacokinetics (transport and metabolism) is high, and could result from genetic polymorphisms. As recommended by the French Network of Pharmacogenetics (RNPGx), the management of some treatments in cardiovascular diseases (as antiplatelet agents, oral vitamin K antagonists, and statins) can rely on genetic testing in order to improve healthcare by reducing therapeutic resistance or toxicity. This paper is a review of association studies between single nucleotide polymorphisms (SNPs) and systemic exposure variation of DOACs. Most of the results presented here have a lot to do with some SNPs of CES1 (rs2244613, rs8192935, and rs71647871) and ABCB1 (rs1128503, rs2032582, rs1045642, and rs4148738) genes, and dabigatran, rivaroxaban, and apixaban. Regarding edoxaban and betrixaban, as well as SNPs in the CYP3A4 and CYP3A5 genes, literature is scarce, and further studies are needed.

Highlights

French Network of Pharmacogenetics (RNPGx), the management of some treatments in cardiovascular diseases can rely on genetic testing in order to improve healthcare by reducing therapeutic resistance or toxicity
There is no recommendation with a high level of evidence regarding the search for polymorphisms of the CES1, ABCB1, CYP3A4, CYP3A5, and ABCG2 genes as part of therapeutic optimization for patients undergoing direct oral anticoagulants (DOACs) treatment
CES1 polymorphism in patients treated with dabigatran in the same way as the search for CYP2C19 and clopidogrel, or CYP2C9 and warfarin polymorphisms

Summary

Introduction

French Network of Pharmacogenetics (RNPGx), the management of some treatments in cardiovascular diseases (as antiplatelet agents, oral vitamin K antagonists, and statins) can rely on genetic testing in order to improve healthcare by reducing therapeutic resistance or toxicity. Dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban are direct oral anticoagulants (DOACs). The interindividual variability of these treatments is significant, and can lead to hemorrhagic or thromboembolic events This variability could be related to polymorphisms of genes coding for proteins responsible for the activation, transport, or metabolism of DOACs, such as CES1, ABCB1, CYP3A4, and CYP3A5 (Table 1). Their pharmacokinetic and pharmacodynamic variability is impacted by drug interactions when CYP450 or P-glycoprotein inducers or inhibitors are co-administered. DOACs are not subject to pharmacogenetic testing in clinical practice, unlike other cardiovascular drugs

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Conclusion