Personalization of Anticoagulant Therapy with Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Chronic Kidney Disease Based on Pharmacogenetic Testing

Abstract

Background. Polymorphic variants of the genes encoding these isoenzymes and carrier proteins involved in the pharmacokinetics of direct oral anticoagulants (DOAC) may alter their function and, therefore, hypothetically may increase the risk of bleeding associated with the use of DOAC. Aims to study the possible relationship between the presence of polymorphic variants of ABCB1 (rs2032582, rs1045642, rs1128503), CYP3A5 (rs776746) and CYP3A4 (rs35599367) genes on the residual equilibrium concentration (Cmin,ss /D) of apixaban, CYP3A isoenzyme activity and bleeding development in patients with AF and CKD C3C4 stages. Methods. The study included 142 patients with AF combined with chronic CKD stages C3 and C4, receiving apixaban therapy, aged 58 to 99 years (median age 84 years). Pharmacogenetic, pharmacokinetic testing and assessment of CYP3A isoenzyme group activity were performed. Results. Plasma concentration of apixaban depended on the stage of CKD: a higher level of Cmin,ss /D was observed in patients with CKD stage C4 compared to patients with CKD stage C3a and with CKD stage C3b. When studying the effect of rs1045642 (C3435T) polymorphism of ABCB1 gene on apixaban pharmacokinetics, it was found that carriers of homozygous TT genotype had lower median apixaban concentration in blood compared to carriers of CC and TC genotypes (p = 0.027 and 0.034 respectively). For rs2032582 polymorphism of ABCB1 gene, we recorded that patients with GG genotype had higher Cmin,ss /D level of apixaban compared to GT genotype carriers (p = 0.037). CYP3A metabolic activity was statistically significantly lower (p = 0.036) in the group with a history of bleeding compared with that in patients in the group without a history of bleeding (0.8 (0.5; 1.3) and 1.2 (0.7; 2.1); p = 0.036). CYP3A metabolic activity did not differ between patients with different CYP3A5 (rs776746) and CYP3A4 (rs35599367) polymorphism genotypes. For the rs1045642 polymorphic variant, there were fewer carriers of the heterozygous TC genotype (16 (45.7%) patients) among patients with bleeding during the follow-up period compared to patients with no bleeding (43 (53.1%) patients; p = 0.024). Conclusions. The results of the study indicate the presence of an association between genome-wide changes (polymorphic variants of the ABCB1 (rs1045642) and CYP3A5 (rs776746) gene and the presence of apixaban-associated bleeding in patients with AF and CKD stages 34. Mechanisms of such an association require further study.