Population pharmacokinetics and pharmacogenomics of apixaban in Japanese adult patients with atrial fibrillation

作者:Ueshima Satoshi; Hira Daiki; Kimura Yuuma; Fujii Ryo; Tomitsuka Chiho; Yamane Takuya; Tabuchi Yohei; Ozawa Tomoya; Itoh Hideki; Ohno Seiko; Horie Minoru; Terada Tomohiro; Katsura Toshiya*
来源:British Journal of Clinical Pharmacology, 2018, 84(6): 1301-1312.
DOI:10.1111/bcp.13561

摘要

AimsThis study aimed to analyse the effects of genetic polymorphisms in drug transporters and metabolizing enzymes, and clinical laboratory data on the pharmacokinetic parameters of apixaban.
MethodsData were collected from 81 Japanese patients with atrial fibrillation. Pharmacogenomic data were stratified by ABCB1, ABCG2 and CYP3A5 polymorphisms. The pharmacokinetic profile of apixaban was described by a one-compartment model with first-order absorption. Population pharmacokinetic analysis was conducted using a nonlinear mixed effect modelling (NONMEM) program.
ResultsThe nonlinear relationship between oral clearance (CL/F) of apixaban and creatinine clearance (Ccr) was observed. The population mean of CL/F for a typical patient (Ccr value of 70mlmin(-1)) with the CYP3A5*1/*1 and ABCG2 421C/C or C/A genotypes was estimated to be 3.06lh(-1). When Ccr values were set to the typical value, the population mean of CL/F was 1.52 times higher in patients with the CYP3A5*1/*1 genotype compared with patients with the CYP3A5*1/*3 or *3/*3 genotype, while the population mean of CL/F was 1.49 times higher in patients with the ABCG2 421C/C or C/A genotype compared with patients with the ABCG2 421A/A genotype. However, no covariates affected the population mean of the apparent volume of distribution (Vd/F) of apixaban. The population mean of Vd/F was estimated to be 24.7l.
ConclusionThe present study suggests that the ABCG2 421A/A and CYP3A5*3 genotypes and renal function are intrinsic factors affecting apixaban pharmacokinetics. These findings may provide useful information for precision medicine using apixaban, to avoid the risk of adverse reactions.

  • 出版日期2018-6