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

Abstract:

AIMS:This 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. METHODS:Data 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. RESULTS:The 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 70 ml min-1 ) with the CYP3A5*1/*1 and ABCG2 421C/C or C/A genotypes was estimated to be 3.06 l h-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 24.7 l. CONCLUSION:The 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.

journal_name

Br J Clin Pharmacol

authors

Ueshima S,Hira D,Kimura Y,Fujii R,Tomitsuka C,Yamane T,Tabuchi Y,Ozawa T,Itoh H,Ohno S,Horie M,Terada T,Katsura T

doi

10.1111/bcp.13561

subject

Has Abstract

pub_date

2018-06-01 00:00:00

pages

1301-1312

issue

6

eissn

0306-5251

issn

1365-2125

journal_volume

84

pub_type

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