Population pharmacokinetic-pharmacodynamic modeling analysis of intrinsic FXa and bleeding from edoxaban treatment.

Edoxaban is an oral, once-daily, direct factor Xa (FXa) inhibitor that has been evaluated for the prevention of stroke in patients with atrial fibrillation (AF) and for the treatment and prevention of venous thromboembolism (VTE) recurrence. Pharmacokinetic (PK) and pharmacodynamic (PD) modeling and logistic regression analyses were used to explore the clinical data from phase 1 and 2 studies to determine the relationship among PK exposure, PD response, and bleeding risk. Population PK/PD modeling was performed using plasma edoxaban concentration data from combined phase 1 and 2 studies and using intrinsic FXa data from a phase 2 AF study. A 2-compartment PK model adequately described the combined PK data, and a dynamic binding model characterized the dynamics of the intrinsic factor X activity (iFXa) data. Logistic regression analysis then identified the relationship between the iFXa and the observed bleeding risk. The more protracted suppression of FXa over the dosing interval for a 30-mg twice-daily dose compared with a 60-mg once-daily dose offers an explanation for the significantly higher bleeding rate at the former dose.