Population Pharmacokinetics of Apixaban in Subjects With Nonvalvular Atrial Fibrillation

• Published in: CPT: pharmacometrics and systems pharmacology Vol. 7; no. 11; pp. 728 - 738
• Main Authors: Cirincione, Brenda, Kowalski, Kenneth, Nielsen, Jace, Roy, Amit, Thanneer, Neelima, Byon, Wonkyung, Boyd, Rebecca, Wang, Xiaoli, Leil, Tarek, LaCreta, Frank, Ueno, Takayo, Oishi, Masayo, Frost, Charles
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.11.2018; John Wiley and Sons Inc
• Subjects: Age; Anticoagulants; Cardiac arrhythmia; Clinical trials; Embolisms; Employees; Pharmacokinetics; Studies; Thrombosis; Japan
• ISSN: 2163-8306; 2163-8306
• DOI: 10.1002/psp4.12347

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 < 25% change in apixaban exposure vs. the reference NVAF subject (non‐Asian, male, aged 65 years, weighing 70 kg without concomitant CYP3A4/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 < 15% and not considered clinically significant.