 | |
| Clinical data | |
|---|---|
| Trade names | Exanta |
| Pregnancy category |
|
| Routes of administration | Oral (tablets) |
| ATC code | |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Bioavailability | 20% |
| Metabolism | tomelagatran |
| Eliminationhalf-life | 3–5 hours |
| Excretion | Renal (80%) |
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| IUPHAR/BPS | |
| DrugBank |
|
| ChemSpider |
|
| UNII | |
| KEGG |
|
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| Chemical and physical data | |
| Formula | C24H35N5O5 |
| Molar mass | 473.574 g·mol−1 (429 g/mol after conversion) |
| 3D model (JSmol) | |
| |
| |
 N Y (what is this?) (verify) | |
Ximelagatran (Exanta orExarta, H 376/95) is ananticoagulant that has been investigated extensively as a replacement forwarfarin[1] that would overcome the problematicdietary,drug interaction, andmonitoring issues associated with warfarin therapy. In 2006, its manufacturerAstraZeneca announced that it would withdraw pending applications for marketing approval after reports ofhepatotoxicity (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, adirect thrombin inhibitor,[3] was the first member of this class that can be taken orally. It acts solely by inhibiting the actions ofthrombin. It is taken orally twice daily, and rapidly absorbed by thesmall intestine. Ximelagatran is aprodrug, being convertedin vivo to the active agent melagatran. This conversion takes place in the liver and many other tissues throughhydrolysis anddehydroxylation (replacing theethyl andhydroxyl groups withhydrogen).
Ximelagatran was expected to replacewarfarin and sometimesaspirin andheparin in many therapeutic settings, includingdeep venous thrombosis, prevention of secondary venousthromboembolism and complications ofatrial 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 fromwarfarin andheparin, which require monitoring of theinternational normalized ratio (INR) and thepartial thromboplastin time (PTT), respectively. A disadvantage recognised early was the absence of anantidote in case acute bleeding develops, while warfarin can be antagonised byprothrombin complex concentrate and/orvitamin K and heparin byprotamine sulfate.
Ximelagatran was generally well tolerated in the trial populations, but a small proportion (5–6%) developed elevatedliver enzyme levels, which prompted theFDA 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 usingextreme value modelling showed that the elevatedliver 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 AstraZeneca for similar indications.[2] It is a prodrug of a potent, competitive, reversible inhibitor of free and fibrin-bound thrombin calledARH0637.[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]
