PHARMACOGENETIC ASPECTS OF NEW ORAL ANTICOAGULANTS APPLICATION

The aim of this review is to assess the effect of genetic factors on the pharmacokinetic parameters of new oral anticoagulants. The review presents data from studies investigating the effect of gene polymorphisms that encode biotransformation enzymes and transporter proteins of new oral anticoagulants on the pharmacokinetics of these drugs. RE-LY study showed a 15% decrease in trough dabigatran concentration and 27% lower risk of bleeding in carriers of CES1 gene rs2244613 polymorphism, there was also a tendency to reduce the risk of major bleeding. Further study of CES1 gene rs8192935 polymorphism showed a 3% decrease in trough dabigatran concentration in heterozygotes and 11% in homozygotes. There was found a 2% and 3% decrease in trough concentrations in hetero- and homozygotes for the minor allele of CES1 gene rs2244613 polymorphism, respectively. There was no significant effect of ABCB1 gene rs2032582 and rs1045642 polymorphisms on dabigatran pharmacokinetics. It is known the case of gastrointestinal bleeding in the carrier of allelic variants of ABCB1 gene rs2032582 and rs1045642 polymorphisms. However, there was no significant effect of genotype on rivaroxaban pharmacokinetics in the study involving the carriers of ABCB1 gene rs2032582 and rs1045642 polymorphisms. ABCB1 gene rs4148738 polymorphism was associated with higher apixaban peak concentration. But groups of patients with acute cardioembolic stroke showed no statistically significant difference of apixaban peak concentration depending on ABCB1 gene rs1045642 polymorphism genotype. ABCB1 gene rs1045642 and SLCO1B1 gene rs4149056 polymorphisms have no effect on edoxaban pharmacokinetics. Elevation of edoxaban metabolite concentration in carriers of SLCO1B1 gene allelic variants was not clinically significant because the proportion of metabolite is about 10% of the concentration of the main substance. It is necessary to provide large population studies with control of treatment efficacy and safety to prove clinical significance of genotyping for new oral anticoagulants use.

1. Paré G., Eriksson N., Lehr T., et al. Genetic determinants of dabigatran plasma levels and their relation to bleeding. Circulation. 2013;127(13):1404-12.

2. Dimatteo C., D'Andrea G., Vecchione G., et al. Pharmacogenetics of dabigatran etexilate interindividual variability. Thromb Res. 2016;144:1-5.

3. 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(2):273-283.

4. Ing Lorenzini K., Daali Y., Fontana P., et al. Rivaroxaban-Induced Hemorrhage Associated with ABCB1 Genetic Defect. Front Pharmacol. 2016;7:494.

5. Dimatteo C., D'Andrea G., Vecchione G., et al. ABCB1 SNP rs4148738 modulation of apixaban interindividual variability. Thromb Res. 2016;145:24-6.

6. Kryukov A.V., Sychev D.A., Andreev D.A., et al. The association of ATP binding cassette gene B1 (ABCB1) C3435T polymorphism with apixaban peak concentration in patients with acute cardioembolic stroke and atrial fibrillation. 8th Santorini conference. 03-05 October 2016 Thira-Santorini/Greece. Systems medicine and personalised health and therapy, 2016. P. 20-21.

7. Vandell A.G., Lee J., Shi M., et al. An integrated pharmacokinetic/pharmacogenomic analysis of ABCB1 and SLCO1B1 polymorphisms on edoxaban exposure. Pharmacogenomics J. 2016 Nov 29. doi: 10.1038/tpj.2016.82. [Epub ahead of print]