Pharmacokinetics, Preliminary Efficacy and Safety of Subcutaneous Melagatran and Oral Ximelagatran
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Objective: The oral direct thrombin inhibitor (oral DTI) ximelagatran and its active form, melagatran, which can be administered subcutaneously, were investigated for the prevention and treatment of thromboembolic complications.
Design and patients: In this randomised, double-blind, double-dummy, parallel-group study in patients (n = 90) undergoing general abdominal and/or pelvic surgery, 8-day and 35-day treatment regimens of postoperatively initiated subcutaneous (sc) melagatran (3mg twice daily) followed by oral ximelagatran (24mg twice daily) were compared with standard-duration sc dalteparin (5000IU) initiated preoperatively. Pharmacodynamic and pharmacokinetic parameters, efficacy (number of patients with distal and/or proximal deep vein thrombosis [DVT] verified by bilateral venography on the final day of treatment) and safety were assessed.
Results: The pharmacokinetics of melagatran were well described by a one-compartment model with first-order absorption after administration of both sc melagatran and oral ximelagatran. Bioavailability of melagatran was 21% after the first oral dose of ximelagatran and was virtually unchanged throughout the study. Activated partial thromboplastin time increased in a non-linear manner with plasma melagatran concentration. The overall rate of DVT was 11.4% (8/70), with events distributed evenly between treatment groups. Bleeding volumes during surgery tended to be higher in the dalteparin group than in the melagatran/ximelagatran groups. Blood transfusion volumes and numbers of patients transfused were similar in all treatment groups.
Conclusions: Good bioavailability of melagatran was achieved following oral administration of ximelagatran. Postoperative sc melagatran followed by oral ximelagatran appeared to be well tolerated, and the efficacy of standard-length or prolonged prophylaxis with sc melagatran and oral ximelagatran may be comparable to that of dalteparin initiated preoperatively.
- 2.Hull RD, Pineo GF, Francis C, et al. Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients: a double-blind, randomised comparison. North American Fragmin Trial Investigators. Arch Intern Med 2000; 160: 2199–207PubMedCrossRefGoogle Scholar
- 5.Hull RD, Pineo GF, Francis C, et al. Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a double-blind, randomised comparison. North American Fragmin Trial Investigators. Arch Intern Med 2000; 160: 2208–15PubMedCrossRefGoogle Scholar
- 17.Eriksson BI, Arfwidsson A-C, Frison L, et al. A dose-ranging study of the oral direct thrombin inhibitor, ximelagatran, and its subcutaneous form, melagatran, compared with dalteparin in the prophylaxis of venous thromboembolism after total hip or total knee replacement: METHRO I. Thromb Haemost 2002; 87(2): 231–7PubMedGoogle Scholar
- 19.Eriksson BI, Agnelli G, Cohen AT, et al. Postoperative direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with perioperative enoxaparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO III study. Thromb Haemost 2003; 89: 288–96PubMedGoogle Scholar
- 21.Eriksson BI, Agnelli G, Cohen AT, et al. The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxaparin for prophylaxis of venous thromboembolism in total hip or total knee replacement: the EXPRESS study. J Thromb Haemost 2003; 1(12): 2490–6PubMedCrossRefGoogle Scholar
- 23.Francis CW, Ginsberg JS, Berkowitz SD, et al. Efficacy and safety of the oral direct thrombin inhibitor ximelagatran compared with current standard therapy for acute, symptomatic deep vein thrombosis, with or without pulmonary embolism: the THRIVE Treatment Study [abstract no. 7]. Blood 2003; 102: 6aGoogle Scholar
- 24.The Executive Steering Committee on behalf of the SPORTIF Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003; 362: 1691–8CrossRefGoogle Scholar
- 26.Biello DR, Mattar AG, McKnight RC, et al. Ventilationperfusion studies in suspected pulmonary embolism. Am J Roentgenol 1979; 133: 1033–7Google Scholar
- 28.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