Ximelagatran

Ximelagatran (Exanta or Exarta, H 376/95) is an anticoagulant that has been investigated extensively as a replacement for warfarin[1] that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy. In 2006, its manufacturer AstraZeneca announced that it would withdraw pending applications for marketing approval after reports of hepatotoxicity (liver damage) during trials, and discontinue its distribution in countries where the drug had been approved (Germany, Portugal, Sweden, Finland, Norway, Iceland, Austria, Denmark, France, Switzerland, Argentina and Brazil).[2]

Ximelagatran
Clinical data
Trade namesExanta
Pregnancy
category
  • Uncategorized
Routes of
administration		Oral (tablets)
ATC code
Legal status
Legal status
  • Withdrawn from market
Pharmacokinetic data
Bioavailability20%
Metabolismto melagatran
Elimination half-life3–5 hours
ExcretionRenal (80%)
Identifiers
IUPAC name
  • ethyl 2-[[(1R)-1-cyclohexyl-2-
    [(2S)-2-[[4-(N'-hydroxycarbamimidoyl)
    phenyl]methylcarbamoyl]azetidin-1-yl]-
    2-oxo-ethyl]amino]acetate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC24H35N5O5
Molar mass473.574 g·mol−1 (429 g/mol after conversion)
3D model (JSmol)
SMILES
  • O=C(NCc1ccc(C(=N\O)\N)cc1)[C@H]3N(C(=O)[C@H](NCC(=O)OCC)C2CCCCC2)CC3
InChI
  • InChI=1S/C24H35N5O5/c1-2-34-20(30)15-26-21(17-6-4-3-5-7-17)24(32)29-13-12-19(29)23(31)27-14-16-8-10-18(11-9-16)22(25)28-33/h8-11,17,19,21,26,33H,2-7,12-15H2,1H3,(H2,25,28)(H,27,31)/t19-,21+/m0/s1 Y
  • Key:ZXIBCJHYVWYIKI-PZJWPPBQSA-N Y
 NY (what is this?)  (verify)

Method of action

Ximelagatran, a direct thrombin inhibitor,[3] was the first member of this class 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 hydrolysis and dehydroxylation (replacing the ethyl and hydroxyl groups with hydrogen).

The conversion of ximelagatran to melagatran. This conversion includes dealkylation and dehydroxylation.

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,[4][5][6] except for non valvular atrial fibrillation.

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 prothrombin complex concentrate and/or 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 following reports of hepatotoxicity. Subsequent analysis of Phase 2 clinical study data using extreme value modelling showed that the elevated liver enzyme levels observed in Phase 3 clinical studies could have been predicted; if this had been known at the time, it might have affected decisions on future development of the compound.[7]

A chemically different but pharmacologically similar substance, AZD-0837, was developed by Aztrazeneca for similar indications.[2] It is a prodrug of a potent, competitive, reversible inhibitor of free and fibrin-bound thrombin called ARH0637.[8] The development of AZD-0837 has been discontinued. Due to a limitation identified in long-term stability of the extended-release AZD-0837 drug product, a follow-up study from ASSURE on stroke prevention in patients with non-valvular atrial fibrillation, was prematurely closed in 2010 after 2 years. There was also a numerically higher mortality against warfarin.[9][10][11] In a Phase 2 trial for AF the mean serum creatinine concentration increased by about 10% from baseline in patients treated with AZD-0837, which returned to baseline after cessation of therapy.[12]

References
  1. Hirsh J, O'Donnell M, Eikelboom JW (July 2007). "Beyond unfractionated heparin and warfarin: current and future advances". Circulation. 116 (5): 552–560. doi:10.1161/CIRCULATIONAHA.106.685974. PMID 17664384.
  2. "AstraZeneca Decides to Withdraw Exanta" (Press release). AstraZeneca. February 14, 2006. Retrieved 2012-07-16.
  3. Ho SJ, Brighton TA (2006). "Ximelagatran: direct thrombin inhibitor". Vasc Health Risk Manag. 2 (1): 49–58. doi:10.2147/vhrm.2006.2.1.49. PMC 1993972. PMID 17319469.
  4. 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 (1): 41–47. doi:10.1046/j.1538-7836.2003.00034.x. PMID 12871538. S2CID 20556829.
  5. 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. doi:10.1056/NEJMoa035162. PMID 14585938. S2CID 26026547.
  6. 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. doi:10.1056/NEJMoa030104. PMID 14585939.
  7. Southworth, Harry (30 Jul 2014). "Predicting potential liver toxicity from phase 2 data: a case study with ximelagatran". Statistics in Medicine. 33 (17): 2914–2923. doi:10.1002/sim.6142. PMID 24623062. S2CID 36324117.
  8. Ahrens, Ingo; Karlheinz Peter; Gregory Y.H. Lip; Christoph Bode (2012). "Development and Clinical Applications of Novel Oral Anticoagulants. Part II. Drugs Under Clinical Investigation". Discovery Medicine. 13 (73): 445–450. PMID 22742650.
  9. "AZD0837". Astrazenecaclinicaltrials.com. Retrieved 2012-10-16.
  10. AstraZeneca Long-term treatment with the oral direct thrombin inhibitor AZD0837, compared to Vitamin-K antagonists, as stroke prevention in patients with non-valvular atrial fibrillation and one or more risk factors for stroke and systemic embolic events. A 5-year follow-up study study code D1250C0004221 January 2010 Trial D1250C00042 Archived November 10, 2013, at the Wayback Machine
  11. Eikelboom JW, Weitz JI (2010). "Update on Antithrombotic Therapy: New Anticoagulants". Circulation. 121 (13): 1523–32. doi:10.1161/CIRCULATIONAHA.109.853119. PMID 20368532.
  12. Lip GY, Rasmussen LH, Olsson SB, Jensen EC, Persson AL, Eriksson U, Wåhlander KF (December 2009). "Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: a randomized dose-guiding, safety, and tolerability study of four doses of AZD0837 vs. vitamin K antagonists". Eur. Heart J. 30 (23): 2897–907. doi:10.1093/eurheartj/ehp318. PMC 2785945. PMID 19690349.
  • "Ximelagatran". Drug Information Portal. U.S. National Library of Medicine.
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