Population Pharmacokinetics of Asundexian in People at Risk for Thromboembolic/Cardiovascular Events

Asundexian is a potent, selective, and reversible inhibitor of activated clotting Factor XI currently under development for secondary prevention of recurrent ischemic stroke in the ongoing Phase III OCEANIC-STROKE study (NCT05686070). Here, we report the development of a population pharmacokinetic (popPK) model for asundexian. Plasma concentration data were available from 2914 participants enrolled in nine Phase I and II studies of asundexian. The pharmacokinetics (PK) of asundexian were well described by the popPK model. Within the investigated dose range of asundexian 10-100 mg once daily, the PK of asundexian was dose-proportional. The systemic apparent clearance (CL/F) of asundexian was estimated to be 2.25 L/h and the central volume of distribution (V_C/F) was 35.3 L. Body weight, age, sex, concomitant administration of cytochrome P450 3A4 (CYP3A4) inhibitors, and renal function were identified as statistically significant covariates influencing the PK of asundexian. After accounting for differences in the distribution of these covariates, the PK of asundexian was comparable in healthy participants and participants at risk for thromboembolic/cardiovascular events. Similarly, no significant differences in PK were noted among participants with atrial fibrillation, ischemic stroke, or acute myocardial infarction. No clinically relevant covariates were identified that would warrant dose adjustments in various special populations of interest, including those defined by body weight, age, sex, and renal function, for the prevention of secondary ischemic strokes.