Direct Oral Anticoagulants (DOAC): Newly Identified Genes and Genetic Variants

January 26, 2019 – Pharmacogenomic approaches are increasingly revealing newly identified genes and genetic variants that are at the base of remarkable inter-individual pharmacokinetic and pharmacodynamic variation of novel direct oral anticoagulants (DOAC).

Lately, DOACs have shown an upward prescribing trend due to seemingly favourable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring, be it in the clinic or by means of INR self-monitoring. Recent studies, however, have documented inter-individual variability in plasma drug levels of DOACs.

It is surprising, that until now, this inter-individual variability in the disposition of DOACs has not been taken more into serious consideration when prescribing DOAC’s, particularly under the heavily promoted premise that regular (and, yes, sometimes annoying for the patient) INR-monitoring would no longer be needed. In the clear, we are talking a very dangerous medical constellation, possibly life-threatening or fatal for an affected patient.

There exists an urgent need to thoroughly understand the pharmacogenomic background for the inter-individual variability of the disposition of DOACs in general and the four most commonly prescribed DOACs such as Dabigatran (Pradaxa), Rivaroxaban (Xarelto), Apixaban (Eliquis), and Edoxaban (Savaysa) in particular. In a recent and very important study,  published in the Journal of Personalised Medicine (JPM), an extensive search was performed on recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of individual patient’s disposition of DOACs. Additionally, commonly associated drug-drug interactions of DOACs were taken into account.

The study found that SNP’s in the CES1 gene and ABCB1 gene are the most common documented genetic variants that contribute to alteration in peak and trough levels of Dabigatran (Pradaxa) with demonstrated clinical impact. Furthermore, SNP’s in the ABCB1 gene are implicated in alteration of plasma drug levels of not only Rivaroxaban (Pradaxa) and Apixaban (Eliquis). Studies conducted with genetic variants in Factor Xa-, ABCB1-, SLCOB1-, CYP2C9-, and VKORC1-genes didn’t, in contrast, not reveal any significant association with plasma drug levels of Edoxaban (Savaysa). Pharmacokinetic drug-drug interactions of Dabigatran (Pradaxa) are mainly mediated by P-glycoprotein. Moreover, strong inhibitors and inducers of CYP3A4 and P-glycoprotein should be avoided in patients treated with Rivaroxaban (Pradaxa), Apixaban (Eliquis), and Edoxaban (Sawaysa). Among strong inhibitors of CYP3A4, you will find many co-medications, but also dietary ingredients such as grapefruit juice (see an extended table on possibly confounding factors here).

In conclusion, some of the inter-individual variability in the disposition of DOACs in the population is attributable to genetic variants of gene loci, also resulting in drug-drug interactions, which may be influenced by confounding factors such a dietary habits of patients under anticoagulant therapy. Under these conditions, the serious question arises if DOACs should in fact be prescribed and used by patients without obligation for a regular INR-monitoring. The possible risk associated seem somewhat high, under the conditions that they may be fatal. And, if something goes wrong, it may be of particular interest (and, by the way, most of the time ignored or selectively forgotten by prescribers and patients alike) that currently, a DOAC reversal agent is only approved by FDA for Dabigatran (Pradaxa), namely Idarucizumab (Praxbind).

See some further information on anticoagulation: