Pharmacokinetics, Preliminary Efficacy and Safety of Subcutaneous Melagatran and Oral Ximelagatran
- David BergqvistAffiliated withDepartment of Surgery, Uppsala University Hospital Email author
- , Jan-Helge SolhaugAffiliated withDiakonhjemmets Hospital
- , Lena HolmdahlAffiliated withSahlgrenska University Hospital/Östra
- , Ulf G. ErikssonAffiliated withAstraZeneca R&D Mölndal
- , Magnus AnderssonAffiliated withAstraZeneca R&D Mölndal
- , Barbro BobergAffiliated withAstraZeneca R&D Mölndal
- , Mats ÖgrenAffiliated withAstraZeneca R&D Mölndal
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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.
- Pharmacokinetics, Preliminary Efficacy and Safety of Subcutaneous Melagatran and Oral Ximelagatran
Clinical Drug Investigation
Volume 24, Issue 3 , pp 127-136
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- 1. Department of Surgery, Uppsala University Hospital, Uppsala, S-751 85, Sweden
- 2. Diakonhjemmets Hospital, Oslo, Norway
- 3. Sahlgrenska University Hospital/Östra, Göteborg, Sweden
- 4. AstraZeneca R&D Mölndal, Mölndal, Sweden