Pharmacogenetic Aspects of Rivaroxaban Therapy in Patients Over 80 Years Old with Atrial Fibrillation

Relevance. It is a widely recognized fact that variations in the genes responsible for drug transportation and metabolism can impact their pharmacokinetic properties. ABCB1 gene polymorphisms, in particular, have been linked to alterations in drug distribution and the onset of negative side effects. The results of studies regarding the effect of ABCB1 genetic variations on the drug response to rivaroxaban are contradictory, which was the subject of our study.

Aim. This study is aimed to evaluate the effect of ABCB1 gene polymorphism (rs1045642 and rs4148738) on the pharmacokinetics of rivaroxaban in patients 80 years of age and older with non-valvular AF.

Materials and methods. We examined 128 patients over 80 (mean age 87.5 years [83–90 years]) with non-valvular atrial fibrillation (AF). Every patient underwent genotyping of the rs1045642 and rs4148738 polymorphisms of the ABCB1 gene, determination of the minimum equilibrium concentration of rivaroxaban (Cmin, ss), prothrombin time (PT) in blood plasma and analysis of medical documentation for the presence of minimal clinically significant bleeding (clinically relevant nonmajor (CRNM) bleeding). Additionally, the results were assessed taking into account the range of the therapeutic window for rivaroxaban Cmin,ss (6–87 ng/ml), and standardization of the minimum equilibrium concentration of rivaroxaban per daily drug dose (Cmin,ss / D) was carried out.

Results. In SS carriers compared with patients carrying CT and TT for rs1045642 and rs4148738 of the ABCB1 gene, there were no significant differences in the values of Cmin,ss of rivaroxaban, Cmin,ss/D of rivaroxaban and the number of patients in whom Cmin,ss exceeded the range of 87 ng/ml (p > 0.05). The PT level in CC carriers compared to patients carrying the CT genotype rs1045642 (ABCB1) did not differ significantly, while in TT carriers the PT level was higher compared to carriers of the CC genotype rs1045642 (ABCB1): Me 14.2 [13.0– 16.1] sec versus Me 13.3 [12.4–14.5] sec (p = 0.049). The level of PT in carriers of CC compared with carriers of ST and TT for rs4148738 of the ABCB1 gene did not differ significantly. In TT carriers, CRNM bleeding was significantly more common compared to CC carriers for rs1045642 of the ABCB1 gene (29.3% versus 4.5%, p = 0.021). In carriers of TT, CRNM bleeding was significantly more common compared to carriers of CC (39.3% vs. 8.1%, p = 0.008) and CT of the ABCB1 gene mutated at rs4148738 (39.3% vs. 14.3%, p = 0.002).

Conclusions. Our data did not show the effect of ABCB1 gene polymorphism (rs1045642 and rs4148738) on the pharmacokinetics of rivarxaban in patients 80 years and over with non-valvular AF in routine clinical practice. However, in TT carriers, CRNM bleeding was significantly more common in comparison with CC at rs1045642 of the ABCB1 gene and in comparison with CT and CC at rs4148738 of the ABCB1 gene, which requires a more profound study of genetics contribution to the pharmacological response of rivaroxaban.