Population Pharmacokinetics, Pharmacodynamics, and Exploratory Exposure-Response Analyses of Apixaban in Subjects...

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.