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.

Keywords: cytochrome P450; drug transporters; genetic polymorphism; pharmacogenomics; population analysis.

© 2018 The British Pharmacological Society.

Figures

Figure 1

Correlation between the population mean estimates of both oral apixaban and creatinine clearance in the final model. In panel A, the thick and thin lines indicate the population mean estimates for a typical patient with the CYP3A5*1/*1 and ABCG2 421C/C or C/A genotype, and for a typical patient with the CYP3A5*1/*1 and ABCG2 421A/A genotypes, respectively. In panel B, the thick dotted and thin dotted lines indicate the population mean estimates for a typical patient with the CYP3A5*1/*3 or *3/*3 and ABCG2 421C/C or C/A genotype, and for a typical patient with the CYP3A5*1/*3 or *3/*3 and ABCG2 421A/A genotypes, respectively

Figure 2

Goodness‐of‐fit plots for the final model of apixaban. The relationship between the observed concentrations (OBS) and population predictions (PRED), and individual predictions (IPRED), are shown in panels A and B, respectively. The relationship between conditional weighted residuals (CWRES) and the time after last dose, and PRED are shown in panels C and D, respectively. Open circles indicate the observed values. Each dotted line shows a line of identity

Figure 3

Visual predictive checks of apixaban concentrations with data obtained from the final model. Open circles show the observed concentrations in all patients (A), patients administered twice daily a dose of 5 mg day−1 (B), 10 mg day−1 (C) and 20 mg day−1 (D). The top dotted, middle solid, and bottom dotted lines are shown as the 95th, 50th, and 5th percentiles, respectively, as calculated from 1000 simulated data sets

Figure 4

Simulations of AUC from time 0 to 12 h (AUC0−12) for apixaban in the 200 replication data sets in a patient administered a typical dose of 5 mg twice daily. These simulations are conducted using the final model. The box‐and‐whisker plots are presented according to the Tukey style. Open circles show the outliers. Four groups consist of patients with the CYP3A5*1/*1 and ABCG2 421C/C or C/A genotype (group A), patients with the CYP3A5*1/*1 and ABCG2 421A/A genotypes (group B), patients with the CYP3A5*1/*3 or *3/*3 and ABCG2 421C/C or C/A genotype (group C), and patients with the CYP3A5*1/*3 or *3/*3 and ABCG2 421A/A genotypes (group D). ***P < 0.001 by the Kruskal–Wallis test, followed by Dunn's multiple comparison test