Population Pharmacokinetics of Apixaban in Subjects With Nonvalvular Atrial Fibrillation

TLDR

The study characterizes apixaban population pharmacokinetics in NVAF patients and quantifies how intrinsic and extrinsic factors affect drug exposure. A two‑compartment PPK model with first‑order absorption and elimination was built from phase I–III data, incorporating covariates such as age, sex, Asian race, renal function, and CYP3A4/P‑gp inhibitor use to predict clearance. Covariate effects on exposure were generally <25%, except severe renal impairment increased exposure by 55%; the dose‑reduction algorithm lowered median exposure by ~27% with substantial overlap between 2.5‑mg and 5‑mg groups, and Asian race had <15% impact, deemed clinically insignificant.

Abstract

This analysis describes the population pharmacokinetics ( PPK ) of apixaban in nonvalvular atrial fibrillation ( NVAF ) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I–III studies. Apixaban exposure was characterized by a two‐compartment PPK model with first‐order absorption and elimination. Predictive covariates on apparent clearance included age, sex, Asian race, renal function, and concomitant strong/moderate cytochrome P450 ( CYP )3A4/P‐glycoprotein (P‐gp) inhibitors. Individual covariate effects generally resulted in &lt; 25% change in apixaban exposure vs. the reference NVAF subject (non‐Asian, male, aged 65 years, weighing 70 kg without concomitant CYP 3A4/P‐gp inhibitors), except for severe renal impairment, which resulted in 55% higher exposure than the reference subject. The dose‐reduction algorithm resulted in a ~27% lower median exposure, with a large overlap between the 2.5‐mg and 5‐mg groups. The impact of Asian race on apixaban exposure was &lt; 15% and not considered clinically significant.