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Ximelagatran bgcolor="#ffffff" align="center" colspan="2" |
Ximelagatran | align="center" colspan="2" | ethyl N-[(R)-cyclohexyl-
[[(2S)-2-[[4-(hydroxycarbamimidoyl)benzyl]
carbamoyl]-1-azetidinyl]carbonyl]methyl] glycinate | CAS number
192939-46-1 | ATC code
B01AE05 | | bgcolor="#eeeeee" | Chemical formula | bgcolor="#ddeeff" | CHNO | | bgcolor="#eeeeee" | Molecular weight | bgcolor="#ddeeff" | 474 (429 after conversion) | | bgcolor="#eeeeee" | Bioavailability | bgcolor="#ddeeff" | 20% | | bgcolor="#eeeeee" | Metabolism | bgcolor="#ddeeff" | None | | bgcolor="#eeeeee" | Elimination half life | bgcolor="#ddeeff" | 3-5h | | bgcolor="#eeeeee" | Excretion | bgcolor="#ddeeff" | Renal (80%) | | bgcolor="#eeeeee" | Delivery | bgcolor="#ddeeff" | Oral | Ximelagatran (Exanta®, H 376/95) is an anticoagulant that has been investigated extensively but is awaiting approval by the Food and Drug Administration (FDA). Its manufacturer, AstraZeneca, is marketing it as a replacement for warfarin that overcomes the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy. Method of action It is the first member of the novel drug class of direct thrombin inhibitors, as it acts solely by inhibiting the actions of thrombin. It is taken orally twice daily, and rapidly absorbed by the small intestine. Ximelagatran is a prodrug, being converted in vivo to the active agent melagatran. This conversion takes place in the liver through dealkylation and dehydroxylation (replacing the ethyl and hydroxyl groups with hydrogen). Uses Ximelagatran is expected to replace warfarin and sometimes aspirin and heparin in many therapeutic settings, including deep venous thrombosis, prevention of secondary venous thromboembolism and atrial fibrillation. The efficacy of ximelagatran for these indications has been well-documented. (Eriksson et al., 2003; Frances et al., 2004; Schulman et al., 2004) An advantage, according to its manufacturer, is that it can be taken orally without any monitoring of its anticoagulant properties. This sets it apart from warfarin and heparin, which require monitoring of the international normalized ratio (INR) and the partial thromboplastin time (PTT), respectively. A disadvantage is the absence of an antidote in case acute bleeding develops, while warfarin can be antagonised by Vitamin K and heparin by protamine sulfate. Side-effects Ximelagatran was generally well tolerated in the trial populations, but a small proportion (5-6%) developed elevated liver enzyme levels. Marketing Several large studies have been conducted to test the efficacy and safety of ximelagatran in patients with deep venous thrombosis and atrial fibrillation. Despite the evidence, the FDA rejected the initial application in March 2004 for potential liver toxicity considerations. References - Eriksson H, Wahlander K, Gustafsson D, Welin LT, Frison L, Schulman S; Thrive Investigators. A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I. J Thromb Haemost 2003;1:41-7. PMID 12871538.
- Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, Peters GR, Roth AW, McElhattan J, Colwell CW Jr; EXULT A Study Group. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2004;349:1703-12. PMID 14585938.
- Schulman S, Whlander K, Lundstrm T, Clason SB, Eriksson H, THRIVE III investigators. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003;349:1713-21. PMID 14585939.
- Weitz JI. New anticoagulants for treatment of venous thromboembolism. Circulation 2004;110(Suppl 1):19-26. PMID 15339877.
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