Key result
Carriage of the T allele in ABCB1 gene polymorphic variants rs1045642 and rs2032582 was associated with significantly higher residual equilibrium and dose-adjusted concentrations of rivaroxaban.
Why the study?
To evaluate the relationship between polymorphic variants of ABCB1, CYP3A5, CYP3A4, and CYP2J2 genes and residual equilibrium concentrations of rivaroxaban in patients with non-valvular AF and stage 3 and 4 CKD.
Do polymorphic variants of ABCB1, CYP3A5, CYP3A4, and CYP2J2 genes affect the residual equilibrium concentrations of rivaroxaban in patients with non-valvular atrial fibrillation and stage 3-4 chronic kidney disease?
Observational (n=123)
Do polymorphic variants of ABCB1, CYP3A5, CYP3A4, and CYP2J2 genes affect the residual equilibrium concentrations of rivaroxaban in patients with non-valvular atrial fibrillation and stage 3-4 chronic kidney disease?
Absolute Event Rate: 60.5% vs 54.8%
p-value: p=0.016
The carriage of the T allele in polymorphic variants rs1045642 and rs2032582 of the ABCB1 gene significantly increases the residual equilibrium concentrations of rivaroxaban in patients with atrial fibrillation and chronic kidney disease.
ABCB1 variants may affect rivaroxaban exposure in AF with CKD; hypothesis-generating and should not yet change practice.
Aim. To study the possible relationship between polymorphic variants of ABCB1 (rs2032582, rs1045642, rs1128503), CYP3A5 (rs776746), CYP3A4 (rs35599367) and CYP2J2 (rs890293) genes with residual equilibrium concentrations (Cmin,ss) of rivaroxaban in patients with non-valvular atrial fibrillation (AF) and stage 3 and 4 chronic kidney disease (CKD). Material and methods. A total of 123 patients 52 to 97 years old (median age, 82 years) with AF in combination with stage 3 and 4 CKD were included in the study. Each patient underwent a pharmacogenetic and pharmacokinetic study. Results. Cmin,ss and dose-adjusted concentration (Cmin,ss/D) of rivaroxaban were significantly higher in patients with the TT genotype than with the CT genotype of the polymorphic variant rs1045642 of the ABCB1 gene (Сmin,ss 60,5 [36,7;173] ng/ml and 54,8 [23,1;97,3] ng/ml, respectively, р=0,016; Сmin,ss/D 4,06[2,3;8,1] ng/ml/mg and 2,2 [1,1;4,9] ng/ml/mg, р=0,006). In patients with the T allele (CT and TT genotypes), compared with CC genotype carriers, Cmin,ss and Cmin,ss/D were significantly higher (Cmin,ss 60,5 [36,7;173] ng/ml and 45,8 [20,9;82,3] ng/ml, respectively, p=0,029; Cmin,ss/D 4,06 [2,3;8,1] ng/ml/ mg and 2,6 [1,2;4,8] ng/ml/mg, respectively, p=0,014). Also, Cmin,ss and Cmin,ss/D was significantly higher in patients with the TT genotype according to the polymorphic variant rs2032582 of the ABCB1 gene than in patients with the GG genotype (p=0,02 and р=0,016 respectively). Cmin,ss and Cmin,ss/D in T allele (GT and TT genotypes) carriers were significantly higher than in T allele homozygotes (Cmin,ss 57,1 [27,7;106,0] ng/ml versus 37,6 [18,6;61,7] ng/ml respectively, p=0,024; Cmin,ss/D 3,6 [1,7;7,4] ng/ml/mg versus 2,3 [1,1;4,09] ng/ml/mg respectively, p=0,032). Differences in Сmin,ss and Сmin,ss/D of rivaroxaban were detected when comparing TC, CC and TT genotypes of polymorphism rs1128503 of the ABCB1 gene. When comparing Сmin,ss and Сmin,ss/D of rivaroxaban among carriers of AG and GG genotypes of the rs776746 polymorphism of the CYP3A56986A>G gene, no significance was detected (p>0,05). Also, no difference in Cmin,ss and Cmin,ss/D was found when comparing carriers of the CC and CT genotypes of the rs35599367 polymorphism of the CYP3A4 gene, and carriers of the CC and AC genotypes of the rs890293 polymorphism of the CYP2J2 gene (p>0,05). Conclusion. The carriage of T allele by polymorphic variants rs1045642 and rs2032582 of the ABCB1 gene affects Cmin,ss and Cmin,ss/D of rivaroxaban.
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Shatalova et al. (2023) conducted an observational in Non-valvular atrial fibrillation and stage 3-4 chronic kidney disease (n=123). TT genotype of ABCB1 rs1045642 polymorphism vs. CT genotype of ABCB1 rs1045642 polymorphism was evaluated on Residual equilibrium concentration (Cmin,ss) of rivaroxaban (ng/ml) (p=0.016). Carriage of the T allele in ABCB1 gene polymorphic variants rs1045642 and rs2032582 was associated with significantly higher residual equilibrium and dose-adjusted concentrations of rivaroxaban.
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