Ximelagatran

Ximelagatran
Systematic (IUPAC) name
ethyl 2-[[(1R)-1-cyclohexyl-2- [(2S)-2-[[4-(N'-hydroxycarbamimidoyl) phenyl]methylcarbamoyl]azetidin-1-yl]- 2-oxo-ethyl]amino]acetate
Identifiers
CAS number	192939-46-1
ATC code	B01AE05
PubChem	5478933
Chemical data
Formula	C24H35N5O5
Mol. mass	474 (429 after conversion)
Pharmacokinetic data
Bioavailability	20%
Metabolism	None
Half life	3-5h
Excretion	Renal (80%)
Therapeutic considerations
Pregnancy cat.	uncategorised
Legal status	Rx only/POM
Routes	Oral

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

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.

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

• AstraZeneca (February 14, 2006). AstraZeneca Decides to Withdraw Exanta. Press release.
• Eriksson, H; Wahlander K, Gustafsson D, Welin LT, Frison L, Schulman S, THRIVE Investigators (January 2003). "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". Journal of Thrombosis and Haemostasis 1: 41–47. 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 (October 2003). "Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement". New England Journal of Medicine 349 (18): 1703–1712. PMID 14585938.
• Schulman, S; Wåhlander K, Lundström T, Clason SB, Eriksson H, THRIVE III investigators (October 2003). "Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran". New England Journal of Medicine 349 (18): 1713–1721. PMID 14585939.
• Weitz, JI (August 2004). "New anticoagulants for treatment of venous thromboembolism". Circulation 110 (Suppl 1): 19–26. PMID 15339877.