Pharmacogenetics of Direct Oral Anticoagulants: A Systematic Review

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.

Implementation of Pharmacogenomics and Artificial Intelligence Tools for Chronic Disease Management in Primary Care Setting

“…At that time, clinical outcomes associated with testing use cases and interventions (i.e., CYP2C19 for clopidogrel) with respect to that variant must be studied in randomized controlled trials before a recommendation for clinical testing is adopted. This approach has proven to be challenging, even for one of the most advanced areas of pharmacogenomic testing, anticoagulant therapy [ 40 ]. It takes time for the justification (pilot studies of ancillary studies piggybacked on drug registration trials) to reach a critical threshold calling for a randomized controlled trial that might ultimately demonstrate the clinical utility of testing for a given drug–gene pair.…”

Effect of polymorphisms in CYP3A4*22 (rs35599367) C>T, CYP3A5*3 (rs776746) A>G, ABCB1 (rs4148738) C>T and ABCB1 (rs1045642) C>T genes on apixaban anticoagulation: pilot study results

“…Персонализация терапии ПОАК, в т. ч. апиксабана, является ведущей задачей для обеспечения эффективности и безопасности применения этих препаратов. Важную роль в вариабельности фармакокинетики играют полиморфизмы генов ферментов биотрансформации (СУР3А4/5), а также белков-переносчиков (P-gp) [17]. На данный момент исследований в этом поле не так много.…”

Treatment of direct oral anticoagulants in patients with liver cirrhosis and portal vein thrombosis

“…86 Its terminal half-life is 9-10 hours in healthy individuals. 87 Peak levels and drug exposure of a single edoxaban dose were elevated in patients with Child-Pugh classes A and B compared to healthy individuals. 92 Andexanet-α is a recombinant modified Factor Xa protein approved by the FDA for the reversal of apixaban and rivaroxaban (not yet FDA-approved for edoxaban).…”

“…86 Its terminal half-life is 14-17 hours in healthy individuals. 87 Dabigatran peak levels (Cmax) and exposure (area under the curve [AUC]) were slightly lower in patients with Child-Pugh class B than in healthy individuals. 88 The current guidelines do not include recommendations for dabigatran usage or dosing in patients with hepatic dysfunction.…”

“…Its terminal half-life is 9-13 hours in healthy individuals. 87 Peak drug levels (Cmax) and drug exposure (AUC) of a single rivaroxaban dose are slightly elevated in patients with Child-Pugh class A and moderately elevated in patients with Child-Pugh class B. 90 Rivaroxaban was shown to prolong the PT in patients with Child-Pugh classes A and B.…”