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Population pharmacokinetics and pharmacodynamics of onceand twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
DOI: https://doi.org/10.1160/TH07-12-0714
Issue: 2008: 100/3 (Sep) pp. 365-516
Pages: 453-461

Population pharmacokinetics and pharmacodynamics of onceand twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement

Wolfgang Mueck 1, Lars C. Borris 2, Ola E. Dahl 3, Sylvia Haas 4, Menno V. Huisman 5, Ajay K. Kakkar 6, Peter Kälebo 7, Eva Muelhofer 1, Frank Misselwitz 1, Bengt I. Eriksson7
1 Bayer HealthCare AG, Wuppertal, Germany; 2 Aarhus University Hospital, Aarhus, Denmark; 3 Thrombosis Research Institute/International Surgical Thrombosis Forum, London, UK; 4 Institute for Experimental Oncology and Therapy Research, Munich, Germany; 5 Leiden University Medical Centre, Leiden, The Netherlands; 6 Thrombosis Research Institute and Barts and London School of Medicine, London, UK; 7 Sahlgrenska University Hospital/Östra, Gothenburg, Sweden

Keywords

total hip replacement, pharmacodynamics, factor Xa, rivaroxaban, population pharmacokinetics

Summary

Rivaroxaban (Xarelto) is an oral, direct factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. The aim was to compare the population pharmacokinetics (PK) and pharmacodynamics (PD) of twice-daily (bid) and once-daily (od) rivaroxaban in patients undergoing total hip replacement (THR). Blood samples were collected from patients enrolled in two phase IIb, dose-ranging studies undertaken to investigate rivaroxaban for thromboprophylaxis after THR. A sparse sampling technique was used and the samples were pooled for PK and PD analysis, which used non-linear mixed effect modelling. Rivaroxaban PK (samples from 758 patients) were well described by an oral,one-compartment model; age and renal function influenced clearance, and body surface area affected volume of distribution.When comparing the same total daily doses, maximum plasma concentrations of rivaroxaban were higher and minimum plasma concentrations were lower with od dosing, compared with bid dosing; however, the 90% intervals overlapped.The area under the plasma concentration–time curve was 18–30% higher in the od than in the bid study. Prothrombin time in seconds (samples from 1181 patients) correlated with rivaroxaban plasma concentrations in a linear fashion in both studies. In conclusion, the PK and PD of rivaroxaban were predictable when given either bid or od.These findings, along with the suggested efficacy and safety of rivaroxaban in the phase II studies, relative to enoxaparin, supported the selection of a convenient, once-daily 10 mg rivaroxaban dose for investigation in phase III studies.

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