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'Ximelagatran' ('Exanta'® or 'Exarta'®, H 376/95) is an anticoagulant that has been investigated extensively as a replacement for warfarin that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy. In 2006, its manufacturer AstraZeneca announced that it would not attempt to market ximelagatran after reports of hepatotoxicity (liver damage) during trials, and to discontinue its distribution in countries where the drug had been approved.

Contents

Method of action

Uses

Side-effects

References

Method of action

Ximelagatran was the first member of the drug class of ''direct thrombin inhibitors'' that can be taken orally. 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 and many other tissues through dealkylation and dehydroxylation (replacing the ethyl and hydroxyl groups with hydrogen).

Uses

Ximelagatran was expected to replace warfarin and sometimes aspirin and heparin in many therapeutic settings, including deep venous thrombosis, prevention of secondary venous thromboembolism and complications of atrial fibrillation such as stroke. The efficacy of ximelagatran for these indications had been well-documented (Eriksson ''et al'' 2003, Frances ''et al'' 2004, Schulman ''et al'' 2004).
An advantage, according to early reports by its manufacturer, was that it could be taken orally without any monitoring of its anticoagulant properties. This would have set it apart from warfarin and heparin, which require monitoring of the international normalized ratio (INR) and the partial thromboplastin time (PTT), respectively. A disadvantage recognised early was 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, which prompted the FDA to reject an initial application for approval in 2004. The further development was discontinued in 2006 after it turned out hepatic damage could develop in the period subsequent to withdrawal of the drug. According to AstraZeneca, a chemically different but pharmacologically similar substance, AZD0837, is undergoing testing for similar indications (AstraZeneca press release 2006).

References

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★ 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, , H, Eriksson, Journal of Thrombosis and Haemostasis, 2003

★ Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement, , CW, Francis, New England Journal of Medicine, 2003

★ Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran, , S, Schulman, New England Journal of Medicine, 2003

★ New anticoagulants for treatment of venous thromboembolism, , JI, Weitz, Circulation, 2004