Population Pharmacokinetics and Pharmacodynamics of Apixaban Linking Its Plasma Concentration to Intrinsic Activated Coagulation Factor X Activity in Japanese Patients with Atrial Fibrillation.

Apixaban is used in the prevention and treatment of patients with deep vein thrombosis or pulmonary embolism, and in the prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (AF). In this study, we aimed to elucidate intrinsic factors affecting efficacy of apixaban by conducting population pharmacokinetic and pharmacodynamic analysis using data from 81 Japanese AF patients. The intrinsic FXa activity was determined to assess the pharmacodynamic effect of apixaban. The pharmacokinetic and pharmacodynamic profiles were described based on a one-compartment model with first-order absorption and a maximum inhibitory model, respectively. Pharmacokinetic and pharmacodynamic analysis was conducted using a nonlinear mixed effect modeling program. The population pharmacokinetic parameters of apixaban were fixed at the reported values in our recent study. The population mean of half-maximal inhibitory concentration (IC50) of apixaban was estimated to be 45.3 ng/mL. The population mean IC50 decreased 27.7% for patients with heart failure, but increased 55% for patients with a medical history of cerebral infarction. In contrast, no covariates affected the population mean of baseline of intrinsic FXa activity (BASE) and maximum effect (Imax) value of apixaban. The population mean of BASE and Imax value were estimated to be 40.2 and 38.4 nmol/min/mg protein, respectively. The present study demonstrates for the first time that the co-morbidity of heart failure as well as the medical history of cerebral infarction are an intrinsic factor affecting the pharmacodynamics of apixaban.