Population Pharmacokinetics and Pharmacodynamics of Rivaroxaban — an Oral, Direct Factor Xa Inhibitor — in Patients Undergoing Major Orthopaedic Surgery
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Background: There is a clinical need for novel oral anticoagulants with predictable pharmacokinetics and pharmacodynamics. Rivaroxaban is an oral direct Factor Xa (FXa) inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. This analysis was performed to characterize the population pharmacokinetics and pharmacodynamics of rivaroxaban in patients participating in two phase II, double-blind, randomized, active-comparator-controlled studies of twice-daily rivaroxaban for the prevention of venous thromboembolism after total hip- or knee-replacement surgery.
Methods: Sparse blood samples were taken from all patients participating in the studies (n = 1009). In addition, a subset of patients in the hip study (n = 36) underwent full profiling. Rivaroxaban plasma concentrations, FXa activity and the prothrombin time were determined. Nonlinear mixed-effects modelling was used to model the population pharmacokinetics and pharmacodynamics of rivaroxaban.
Results: An oral one-compartment model described the population pharmacokinetics of rivaroxaban well. On the first postoperative day only, categorization of patients as slow or fast absorbers as a tool to address variability in absorption improved the fit of the model. Clearance of rivaroxaban was lower and more variable on the first postoperative day, and so time was factored into the model. Overall, the only major difference between the models for the hip study and the knee study was that clearance was 26% lower in the knee study, resulting in approximately 30% higher exposure. Residual variability in the models was moderate (37% and 34% in the hip and knee studies, respectively). Plasma concentrations of rivaroxaban increased dose dependently. Pharmacokinetic parameters that were estimated using the models agreed closely with results from full-profile patients in the hip study, demonstrating that rivaroxaban pharmacokinetics are predictable. The pharmacokinetics of rivaroxaban were affected by expected covariates: age affected clearance in the hip study only, haematocrit (on the first postoperative day only) and gender affected clearance in the knee study only, and renal function affected clearance in both studies. Bodyweight affected the volume of distribution in both studies. However, the effects of covariates on the pharmacokinetics of rivaroxaban were generally small, and predictions of ‘extreme’ case scenarios suggested that fixed dosing of rivaroxaban was likely to be possible. FXa activity and the prothrombin time were both affected by surgery, probably because of perioperative bleeding and intravenous administration of fluids; therefore, time was included in the pharmacodynamic models. In both studies, FXa activity correlated with rivaroxaban plasma concentrations following a maximum effect model, whereas prothrombin time prolongation correlated following a linear model with intercept. The slope of the prothrombin time prolongation correlation was 3.2 seconds/(100 μg/L) in the hip study and 4.2 seconds/(100 μg/L) in the knee study. Both pharmacodynamic models in both studies demonstrated low residual variability of approximately 10%.
Conclusion: This population analysis in patients undergoing major orthopaedic surgery demonstrated that rivaroxaban has predictable, dose-dependent pharmacokinetics that were well described by an oral one-compartment model and affected by expected covariates. Rivaroxaban exposure could be assessed using the prothrombin time, if necessary, but not the international normalized ratio. The findings suggested that fixed dosing of rivaroxaban may be possible in patients undergoing major orthopaedic surgery.
KeywordsEnoxaparin Rivaroxaban Objective Function Value Predictable Pharmacokinetic International Sensitivity Index
This analysis was supported by Bayer HealthCare AG, who held the data from the original studies and performed the analyses. Bayer HealthCare AG and Scios Inc. had the opportunity to review the manuscript. The steering committees had the final responsibility for the protocol of the original studies, the analyses, and the manuscript. The committee had full and free access to all primary data and had full independence in deciding what to publish. W. Mueck and F. Misselwitz are employees of Bayer HealthCare AG. W.D. Fisher, L.M. Kwong and B.I. Eriksson were investigators in the studies and received grants for enrolling patients. P. Kälebo received honoraria for adjudication of the venograms during the studies. All steering committee members (A.G.G. Turpie, B.I. Eriksson, K.A. Bauer, L. Borris, O.E. Dahl, M. Gent, S. Haas, M.V. Huisman, A.K. Kakkar, L.M. Kwong and W.D. Fisher) received honoraria for their participation. The authors would like to thank Mrs D. Klein, Mrs U. Krueger and Mr M. Frede for their excellent technical assistance, and Dr T. Allinson for medical writing assistance in the preparation of the manuscript, with funding from Bayer HealthCare AG.
- 5.Kubitza D, Beck M, Mueck W, et al. The effect of extreme age, and gender, on the pharmacology and tolerability of rivaroxaban [abstract no. 905]. Blood (ASH Annual Meeting Abstracts) 2006; 108 (11) [online]. Available from URL: http://abstracts.hematologylibrary.org/content/voll08/issue11/ [Accessed 2008 Jan 23]
- 6.Halabi A, Maatouk H, Klause N, et al. Effect of renal impairment on the pharmacology of rivaroxaban (BAY 59-7939) — an oral, direct Factor Xa inhibitor [abstract no. 913]. Blood (ASH Annual Meeting Abstracts) 2006; 108 (11) [online]. Available from URL: http://abstracts.hematologylibrary.org/content/voll08/issue11/ [Accessed 2008 Jan 31]
- 7.Kubitza D, Becka M, Voith B, et al. Effect of enoxaparin on the safety, tolerability, pharmacodynamics and pharmacokinetics of BAY 59-7939 — an oral, direct Factor Xa inhibitor [abstract no. P1704]. J Thromb Haemost 2005; 3 Suppl. 1 [online]. Available from URL: http://www.blackwellpublishing.com/isth2005/abstract.asp?id=47212 [Accessed 2008 Jan 31]
- 10.Kubitza D, Becka M, Zuehlsdorf M, et al. No interaction between the novel, oral direct Factor Xa inhibitor BAY 59-7939 and digoxin [abstract no. 11]. J Clin Pharmacol 2006; 46: 702Google Scholar
- 18.Eriksson UG, Mandema JW, Karlsson MO, et al. Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran: a population model analysis. Clin Pharmacokinet 2003; 42: 687–701PubMedCrossRefGoogle Scholar
- 21.Weinz C, Schwartz T, Pleiss U, et al. Metabolism and distribution of [14C]BAY 59-7939 — an oral, direct Factor Xa inhibitor — in rat, dog and human [abstract no. 196]. Drug Metab Rev 2004; 36 Suppl. 1: 98Google Scholar