Edoxaban Population Pharmacokinetics in Chinese Patients with Nonvalvular Atrial Fibrillation: Model-Informed Dose Adjustment

Abstract Edoxaban is a novel oral anticoagulant that directly inhibits factor Xa. The ENGAGE population pharmacokinetic (PopPK) model was established using data from the ENGAGE AF-TIMI 48 trial, which included over 21,000 participants, predominantly (81%) White/Caucasian individuals. However, its applicability to Chinese patients necessitates further evaluation. This study assessed the suitability of the ENGAGE PopPK model for Chinese patients with nonvalvular atrial fibrillation (NVAF). We analyzed 730 pharmacokinetic (PK) plasma samples from 104 Chinese NVAF patients using nonlinear mixed-effects modeling. A two-compartment model with first-order absorption and linear elimination optimally described the PK data of edoxaban in this cohort. Body weight (WT) and creatinine clearance were identified as significant covariates of apparent clearance (CL/F), and positively correlated with CL/F. Model-based simulations demonstrated that, in the 30 mg once-daily (q.d.) dosing group, patients with moderate renal impairment and low WT experienced higher systemic exposure than those with only one of these attributes. Additionally, patients with moderate renal impairment, whether alone or combined with low WT, displayed elevated steady-state trough concentrations (Cmin,ss) compared to those receiving the 60 mg q.d. dose. Our PopPK model characterizes the PK profile of edoxaban in Chinese NVAF patients, identifies critical covariates influencing drug exposure, and proposes an evidence-based dosing regimen tailored to this population. This trial was registered at www.clinicaltrials.gov as #NCT05320627.