Population pharmacokinetics and pharmacogenomics of edoxaban in Japanese adults with atrial fibrillation

BACKGROUND: Edoxaban is used as an anti-coagulant to prevent cardioembolic infarction, deep vein thrombosis, and pulmonary embolism. Edoxaban pharmacokinetics have been reported to be affected by several factors such as renal function, age, body weight, and the concomitant use of P-glycoprotein inhibitors. However, the relationship between genetic polymorphisms in drug metabolizing enzymes and transporters and the inter-individual variability of edoxaban pharmacokinetics in patients with atrial fibrillation (AF) remains unclear. Additionally, there is little information concerning PPK analysis using real world data. In this study a population pharmacokinetic and pharmacogenomic analysis was conducted to clarify covariate factors affecting the edoxaban pharmacokinetics in Japanese adult AF patients. METHODS: One hundred and thirty-one blood samples were collected from 131 patients. The edoxaban pharmacokinetic profile was described by a one-compartment model, and pharmacogenomic data were stratified according to CYP3A5 (CYP3A5*3) and ABCB1 (ABCB1 1236 C > T, 2677G > T/A, and 3435 C > T) polymorphisms. A non-linear mixed-effects modeling software (NONMEM™) was used to evaluate the effects of patient characteristics and genetic polymorphisms on the edoxaban pharmacokinetics. RESULTS: The apparent oral clearance (CL/F) of edoxaban was estimated, and the apparent volume of distribution was fixed at the reported value. The CL/F of edoxaban was correlated non-linearly with creatinine clearance (CLcr), wherein the population mean CL/F for a typical patient (CLcr = 61.8 mL/min) was estimated to be 28.2 L/h. Other clinical laboratory data and genetic polymorphisms, excluding CLcr, did not affect the edoxaban pharmacokinetics. CONCLUSIONS: These results suggest that genetic polymorphisms of CYP3A5 and ABCB1 are not considered intrinsic factors affecting edoxaban pharmacokinetics in Japanese adult AF patients. Similarly to previous studies, renal function affects its pharmacokinetics. These findings may provide useful information for individualized anticoagulant therapy with edoxaban to prevent adverse events without reference to genetic polymorphisms of CYP3A5 and ABCB1.