nach oben

Erschienen in:

01.03.2004 | Original Research Article

Pharmacokinetics, Preliminary Efficacy and Safety of Subcutaneous Melagatran and Oral Ximelagatran

A Multicentre Study of Thromboprophylaxis in Elective Abdominal Surgery

verfasst von: Dr David Bergqvist, Jan-Helge Solhaug, Lena Holmdahl, Ulf G. Eriksson, Magnus Andersson, Barbro Boberg, Mats Ögren

Erschienen in: Clinical Drug Investigation | Ausgabe 3/2004

Einloggen, um Zugang zu erhalten

Abstract

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.

The use of trade names is for product identification purposes only and does not imply endorsement.

Geerts WH, Heit JH, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119: 132–75SCrossRef

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: 2199–207PubMedCrossRef

Bergqvist D, Benoni G, Bjorgell O, et al. Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. N Engl J Med 1996; 335: 696–700PubMedCrossRef

Dahl OE, Andreassen G, Aspelin T, et al. Prolonged thromboprophylaxis following hip replacement surgery: results of a double-blind, prospective, randomised, placebo-controlled study with dalteparin (Fragmin). Thromb Haemost 1997; 77: 26–31PubMed

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: 2208–15PubMedCrossRef

Lassen MR, Borris LC, Anderson BS, et al. Efficacy and safety of prolonged thromboprophylaxis with a low molecular weight heparin (dalteparin) after total hip arthroplasty: the Danish Prolonged Prophylaxis (DaPP) Study. Thromb Res 1998; 89: 281–7PubMedCrossRef

Planes A, Vochelle N, Darmon JY, et al. Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: double-blind randomised comparison of enoxaparin versus placebo. Lancet 1996; 348: 224–8PubMedCrossRef

Eriksson BI, Wille-Jorgensen P, Kälebo P, et al. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med 1997; 337: 1329–35PubMedCrossRef

Gustafsson D, Nystrom J, Carlsson S, et al. The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: intestinal absorption properties, biochemical and pharmacodynamic effects. Thromb Res 2001; 101: 171–81PubMedCrossRef

10.

Gustafsson D, Antonsson T, Bylund R, et al. Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes. Thromb Haemost 1998; 79: 110–8PubMed

11.

Elg M, Gustafsson D, Carlsson S. Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat. Thromb Res 1999; 94: 187–97PubMedCrossRef

12.

Eriksson BI, Carlsson S, Halvarsson M, et al. Antithrombotic effect of two low molecular weight thrombin inhibitors and a low-molecular weight heparin in a caval vein thrombosis model in the rat. Thromb Haemost 1997; 78: 1404–7PubMed

13.

Mattsson C, Björkman J-A, Ulving J-C. Melagatran, hirudin and heparin as adjuncts to tissue-type plasminogen activator in a canine model of coronary artery thrombolysis. Fibrinolysis Proteol 1997; 11: 121–8CrossRef

14.

Mehta JL, Chen L, Nichols WW, et al. Melagatran, an oral active-site inhibitor of thrombin, prevents or delays formation of electrically induced occlusive thrombus in the canine coronary artery. J Cardiovasc Pharmacol 1998; 31: 345–51PubMedCrossRef

15.

Eriksson UG, Bredberg U, Hoffmann K-J, et al. Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans. Drug Metab Dispos 2003; 31: 294–305PubMedCrossRef

16.

Eriksson UG, Bredberg U, Gislén K, et al. Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young, healthy male subjects. Eur J Clin Pharmacol 2003; 59: 35–43PubMed

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): 231–7PubMed

18.

Eriksson BI, Bergqvist D, Kälebo P, et al. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet 2002; 360: 1441–7PubMedCrossRef

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: 288–96PubMed

20.

Francis CW, Davidson BL, Berkowitz SD, et al. Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty: a randomised, double-blind trial. Ann Intern Med 2002; 137: 648–55PubMed

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): 2490–6PubMedCrossRef

22.

Schulman S, Wåhlander K, Lundström T, et al. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran: the THRIVE III Investigators. N Engl J Med 2003; 349: 1713–21PubMedCrossRef

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: 6a

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: 1691–8CrossRef

25.

Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg 1972; 104: 134–44PubMedCrossRef

26.

Biello DR, Mattar AG, McKnight RC, et al. Ventilationperfusion studies in suspected pulmonary embolism. Am J Roentgenol 1979; 133: 1033–7

27.

Larsson M, Logren U, Ahnhoff M, et al. Determination of melagatran, a novel, direct thrombin inhibitor, in human plasma and urine by liquid chromatography—mass spectrometry. J Chromatogr B 2001; 766: 47–55CrossRef

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: 687–701PubMedCrossRef

29.

Johansson LC, Frison L, Logren U, et al. Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003; 42: 381–92PubMedCrossRef

30.

Wiig JN, Solhaug JH, Bilberg T, et al. Prophylaxis of venographically diagnosed deep vein thrombosis in gastrointestinal surgery: multicentre trials 20mg and 40mg enoxaparin versus dextran. Eur J Surg 1995; 161(9): 663–8PubMed

Titel: Pharmacokinetics, Preliminary Efficacy and Safety of Subcutaneous Melagatran and Oral Ximelagatran
A Multicentre Study of Thromboprophylaxis in Elective Abdominal Surgery
verfasst von: Dr David Bergqvist
Jan-Helge Solhaug
Lena Holmdahl
Ulf G. Eriksson
Magnus Andersson
Barbro Boberg
Mats Ögren
Publikationsdatum: 01.03.2004
Verlag: Springer International Publishing
Erschienen in: Clinical Drug Investigation / Ausgabe 3/2004
Print ISSN: 1173-2563
Elektronische ISSN: 1179-1918
DOI: https://doi.org/10.2165/00044011-200424030-00001

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Pharmacokinetics, Preliminary Efficacy and Safety of Subcutaneous Melagatran and Oral Ximelagatran

A Multicentre Study of Thromboprophylaxis in Elective Abdominal Surgery

Abstract

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2004

Cotrimoxazole in the Treatment of Acute Uncomplicated Falciparum Malaria in Nigerian Children

Efficacy and Safety of the Platelet-Activating Factor Receptor Antagonist BN 52021 (Ginkgolide B) in Patients with Severe Sepsis

Depression during Pregnancy

Pancreotoxicity of Propofol Sedation during Purulent Meningitis