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 (Cmax) values (∼20%) and lower trough (minimum) plasma concentration (Ctrough) 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 Cmax 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.
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This analysis was supported by Bayer HealthCare, who held the data from the original studies and performed the analyses. Wolfgang Mueck, Anthonie Lensing and Frank Misselwitz are employees of Bayer HealthCare. Both Wolfgang Mueck and Frank Misselwitz own limited stock in Bayer AG. Hervé Decousus is a member of the study management and coordination committee for the EINSTEIN Study Programme and has received grants from Bayer HealthCare. Giancarlo Agnelli and Paolo Prandoni have no conflicts of interest to declare.
The authors would like to thank Dagmar Klein, Ulrike Krueger and Matthias Frede for their excellent technical assistance, and to acknowledge Shahid Salaria, who provided editorial assistance with funding from Bayer HealthCare and Johnson & Johnson Pharmaceutical Research & Development, LLC.
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