Impacts of pregnane X receptor and cytochrome P450 oxidoreductase gene polymorphisms on trough concentrations of apixaban in patients with non-valvular atrial fibrillation

Abstract

Purpose We examined the impact of polymorphisms in genes encoding cytochrome P450 (CYP) 3A5 (gene code CYP3A5), P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), cytochrome P450 oxidoreductase (POR), and pregnane X receptor (PXR; NR1I2) on the daily dose-adjusted steady-state trough concentrations (C_0h/D) of apixaban. Methods The analyses included 104 patients with non-valvular atrial fibrillation (NVAF) undergoing AF catheter ablation. The CYP3A5*3; ABCG2 421C > A; ABCB1 1236C > T, 2677G > A/T, 3435C > T, and 2482-2236G > A; NR1I2 11156A > C, 11193T > C, and 8055C > T; and POR*28 genotypes were determined. The combination of the noted NR1I2 genotypes determined the PXR*1B haplotype. Results Multiple linear regression analyses demonstrated that decreased creatinine clearance (Ccr) and the PXR*1B/*1B haplotype correlated with increased C_0h/D of apixaban, while the presence of the POR*28 allele correlated with decreased C_0h/D of apixaban (partial R² = 0.168, 0.029, and 0.044, all P < 0.05). The mean (95% CI) of estimated marginal means of apixaban C_0h/D calculated using Ccr as a covariate was the highest in POR*28 noncarriers with PXR*1B/*1B (23.5 [21.0–25.9] ng/mL/[mg/day]) and lowest in POR*28 carriers with other haplotypes (16.6 [15.5–17.7] ng/mL/[mg/day]). Conclusion The PXR*1B haplotype and POR*28 genotype statuses, which involve genes that impact the expression of multiple drug-metabolizing enzymes and drug-transporters, may have modest effects on the C_0h/D of apixaban, but these effects were found to be small.