Specifics of drug-drug interactions between rivaroxaban and a P-glycoprotein inhibitor depending on the CYP3A4/A5 gene polymorphism in patients aged 80 years and older with non-valvular atrial fibrillation

BACKGROUND: An increased risk of bleeding during rivaroxaban administration is associated with polymorphism of genes involved in its biotransformation, as well as with the use of drugs inhibiting shared metabolic pathways. However, the data are inconsistent.

AIM: To study specifics of drug-drug interactions between rivaroxaban and a P-glycoprotein inhibitor (using verapamil as an example) depending on the polymorphism of the CYP3A4 (rs35599367) and CYP3A5 (rs776746) genes in patients aged 80 years and older with non-valvular atrial fibrillation.

MATERIALS AND METHODS: A total of 128 patients (median age 87.5 years [83; 90], 75% women) were examined. All patients underwent genotyping for the studied gene variants, determination of the minimum steady-state concentration of rivaroxaban (C_{min, ss}), standardization of the minimum steady-state concentration of rivaroxaban per daily dose (C_{min, ss}/D), determination of prothrombin time in plasma, and analysis of medical documentation for the occurrence of clinically significant minor bleeding.

RESULTS: Compared to patients receiving rivaroxaban without calcium channel blockers, co-administration of rivaroxaban and verapamil in carriers of the CC variant of the CYP3A4 gene resulted in higher values of C_{min, ss} (73.8 [49; 113.5] vs. 40.5 [25.6; 73.3] ng/mL), C_{min, ss}/D (2.5 [1.7; 4.0] vs. 4.7 [2.9; 7.7] ng/mL/mg), prothrombin time (14.8 [13.3; 17.3] vs. 14.0 [12.6; 14.5] s) and clinically significant minor bleeding [10/30 (33.3%) vs. 6/45 (13.3%) cases], p < 0.05. In carriers of the GG variant of the CYP3A5 gene, the same regimen resulted in higher values of C_{min, ss} (74.7 [50.6; 108.8] vs. 40.2 [25.7; 72.3] ng/mL), C_{min, ss}/D (4.6 [3.0; 7.3] vs. 2.5 [1.7; 4.0] ng/mL×mg), prothrombin time (14.6 [12.8; 15.2] vs. 14.0 [12.6; 14.5] s) and clinically significant minor bleeding [10/27 (37%) vs. 5/40 (12.5%) cases], p < 0.05. Furthermore, in carriers of the GA+AA variant of the CYP3A5 gene, this regimen resulted in higher values of C_{min, ss} (88.1 [5.5; 88.1] vs. 52.8 [25.0; 77.2] ng/mL), C_{min, ss}/D (5.7 [0.4; 5.7] vs. 3.5 [1.7; 5.2] ng/mL×mg), p < 0.05. The combined use of rivaroxaban with verapamil in carriers of the CT variant of the CYP3A4 gene was not observed in our sample.

CONCLUSIONS: Carriers of the homozygous wild-type CYP3A4/A5 genotype showed high pharmacokinetic variability to the administration of verapamil (a strong P-glycoprotein inhibitor and a moderate CYP3A4 inhibitor).