Population Pharmacokinetics, Pharmacodynamics, and Exploratory Exposure–Response Analyses of Apixaban in Subjects Treated for Venous Thromboembolism

• Published in: CPT: pharmacometrics and systems pharmacology Vol. 6; no. 5; pp. 340 - 349
• Main Authors: Byon, W, Sweeney, K, Frost, C, Boyd, RA
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.05.2017; John Wiley and Sons Inc
• Subjects: Adolescent; Adult; Age; Aged; Aged, 80 and over; Anticoagulants; Dose-Response Relationship, Drug; Factor Xa Inhibitors - adverse effects; Factor Xa Inhibitors - pharmacokinetics; Factor Xa Inhibitors - pharmacology; Factor Xa Inhibitors - therapeutic use; Female; Hemorrhage - chemically induced; Humans; Male; Middle Aged; Models, Biological; Original; Pharmacodynamics; Pharmacokinetics; Pyrazoles - adverse effects; Pyrazoles - pharmacokinetics; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Pyridones - adverse effects; Pyridones - pharmacokinetics; Pyridones - pharmacology; Pyridones - therapeutic use; Stock options; Studies; Thromboembolism; Treatment Outcome; Venous Thromboembolism - drug therapy; Venous Thromboembolism - metabolism; Young Adult
• ISSN: 2163-8306; 2163-8306
• DOI: 10.1002/psp4.12184

Apixaban is approved for treatment of venous thromboembolism (VTE) and prevention of recurrence. Population pharmacokinetics, pharmacokinetics–pharmacodynamics (anti‐FXa activity), and exposure–response (binary bleeding and thromboembolic endpoints) of apixaban in VTE treatment subjects were characterized using data from phase I–III studies. Apixaban pharmacokinetics were adequately characterized by a two‐compartment model with first‐order absorption and elimination. Age, sex, and Asian race had less than 25% impact on exposure, while subjects with severe renal impairment were predicted to have 56% higher exposure than the reference subject (60‐year‐old non‐Asian male weighing 85 kg with creatinine clearance of 100 mL/min). The relationship between apixaban concentration and anti‐FXa activity was described by a linear model with a slope estimate of 0.0159 IU/ng. The number of subjects with either a bleeding or thromboembolic event was small, and no statistically significant relationship between apixaban exposure and clinical endpoints could be discerned with a logistic regression analysis.