Key result
PXR*1B/*1B and low creatinine clearance predict higher apixaban trough levels, whereas POR*28 predicts lower levels.
Why the study?
The study was conducted to examine the impact of polymorphisms in CYP3A5, ABCB1, ABCG2, POR, and NR1I2 on steady-state trough concentrations of apixaban.
Do genetic polymorphisms in PXR and POR affect steady-state trough concentrations of apixaban in patients with non-valvular atrial fibrillation?
Observational (n=86)
No
Do genetic polymorphisms in PXR and POR affect steady-state trough concentrations of apixaban in patients with non-valvular atrial fibrillation?
Effect estimate: partial R2 = 0.057 (PXR*1B/*1B) and 0.046 (POR*28)
p-value: p=<0.05
Genetic polymorphisms in PXR and POR, along with creatinine clearance, significantly influence the steady-state trough concentrations of apixaban in patients with non-valvular atrial fibrillation.
Genetic variants may affect apixaban levels in NVAF; hypothesis-generating and requires prospective validation before any clinical application.
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 steady-state trough concentrations (C0h) of apixaban. Methods: The analyses included 86 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: Stepwise selection multiple linear regression analyses demonstrated that decreased creatinine clearance and the PXR*1B/*1B genotype correlated with increased apixaban C0h, while the presence of the POR*28 allele correlated with decreased C0h (partial R2 = 0.196, 0.057, and 0.046, all P < 0.05). The C0h of apixaban showed a moderate correlation with prothrombin time (r = 0.594 P < 0.001). 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 affect the C0h of apixaban.
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Nakagawa et al. (2022) conducted an observational in Non-valvular atrial fibrillation (n=86). PXR*1B haplotype and POR*28 genotype vs. Wild-type/other genotypes was evaluated on Steady-state trough concentration (C0h) of apixaban (partial R2 = 0.057 (PXR*1B/*1B) and 0.046 (POR*28), p=<0.05). The PXR*1B/*1B genotype and decreased creatinine clearance correlated with increased apixaban trough concentrations, while the POR*28 allele correlated with decreased concentrations.
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