Background and objective: Rivaroxaban is an oral, direct Factor Xa inhibitor, which is at an advanced stage of clinical development for prevention and treatment of thromboembolic disorders. Two phase II studies, ODIXa-DVT and EINSTEIN DVT, assessed the efficacy and safety of oral rivaroxaban (once daily or twice daily) for treatment of acute deep-vein thrombosis (DVT). Population pharmacokinetic and pharmacodynamic analyses of rivaroxaban in patients in these two phase II studies were conducted to characterize the pharmacokinetics/pharmacodynamics of rivaroxaban and the relationship between important patient covariates and model parameters. Exposure simulations in patients with atrial fibrillation (AF) were also performed in order to predict the exposure of rivaroxaban, using modified demographic data reflecting the characteristics of a typical AF population.
Methods: A population pharmacokinetic model was developed using plasma samples from these patients. Various simulations were conducted to explore the pharmacokinetics of rivaroxaban in patients with DVT and to predict exposure in those with AF. Correlations between plasma rivaroxaban concentrations and the prothrombin time, Factor Xa activity, HepTest® and activated partial thromboplastin time were also described.
Results: The pharmacokinetics of rivaroxaban in patients with DVT were found to be consistent and predictable across all doses studied. The area under the plasma concentration-time curve (AUC) increased dose dependently. The same total daily doses given once daily achieved higher maximum plasma concentration (C(max)) values (∼20%) and lower trough (minimum) plasma concentration (C(trough)) values (∼60%) than when given twice daily; however, the 5th-95th percentile ranges for these parameters overlapped. Rivaroxaban clearance was moderately influenced by age and renal function, and the volume of distribution was influenced by age, body weight and sex; the effects were within the observed interindividual variability. Simulations in virtual patient populations with AF showed that a rivaroxaban dose of 15 mg once daily in patients with creatinine clearance of 30-49 mL/min would achieve AUC and C(max) values similar to those observed with 20 mg once daily in patients with normal renal function. The prothrombin time correlated almost linearly with plasma rivaroxaban concentrations (≤500 μg/L).
Conclusion: Population analyses of phase II clinical data indicated that the pharmacokinetics and pharmacodynamics of all rivaroxaban doses were predictable and were affected by expected demographic factors in patients with acute DVT.