Population pharmacokinetics and pharmacodynamics of apixaban in Japanese patients with atrial fibrillation

Abstract

Background: Apixaban is a direct inhibitor of coagulation factor Xa (FXa), and is orally administered to prevent stroke or systemic embolism in patients with venous thromboembolism and non-valvular atrial fibrillation (AF). Although its efficacy and safety were reported to be equal or superior to those of warfarin, bleeding is still one of the most serious adverse reactions during anticoagulant therapy. Additionally, the potential factors affecting inter-individual pharmacokinetic/pharmacodynamic (PK/PD) variability of apixaban in AF patients remain unclear. This study aimed to elucidate intrinsic PK/PD factors of apixaban by conducting the population PK/PD analysis in Japanese AF patients.

Methods: Eighty one Japanese AF patients treated with apixaban were enrolled in this study. The PD effect of apixaban was assessed by determining the intrinsic FXa activity. The PK and PD profiles of apixaban were described based on a one-compartment model with first-order absorption and a maximum inhibitory model, respectively. The PK/PD analysis was conducted using non-linear mixed effect modeling (NONMEM^TM) program. In this analysis, age, body weight, renal and hepatic functional indices, and genetic variants of CYP3A5, ABCG2, and ABCB1 were used as candidates for the PK covariate of apixaban. Additionally, medical histories of patients were used as candidates for the PD covariate of apixaban.

Results: The population mean of the apparent oral clearance (CL/F) of apixaban was described as a power function of creatinine clearance. Furthermore, the population mean of CL/F of apixaban was significantly higher in patients with CYP3A5*1/*1 genotype than that in patients with CYP3A5*1/*3 or *3/*3 genotypes, while the population mean of CL/F was significantly lower in patients with ABCG2 421A/A genotype than in patients with ABCG2 421C/C or C/A genotypes. The population mean of a half-maximal inhibitory concentration (IC₅₀) of apixaban was significantly increase when patients who had a history of cerebral infarction.

Conclusions: Our results indicate that ABCG2 421A/A and CYP3A5*3 genotypes and renal function are significant predictors of apixaban PK profile, and that a history of cerebral infarction have a significant impact on apixaban PD profile. These findings provide useful information for pharmacotherapy of apixaban to avoid the risk of adverse events.