Dabigatran
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Dabigatran
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| Systematic (IUPAC) name | |
| Ethyl 3-{[(2-{[(4-{N'-[(hexyloxy)carbonyl] carbamimidoyl}phenyl)amino]methyl}-1-
methyl-1H-benzimidazol-5-yl)carbonyl] (2-pyridinyl)amino}propanoate |
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| Identifiers | |
| CAS number | 211914-51-1 |
| ATC code | B01 |
| PubChem | |
| Chemical data | |
| Formula | C34H41N7O5 |
| Mol. mass | 627.734 (471.511 without etexilate) |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | ? |
| Half life | ? |
| Excretion | ? |
| Therapeutic considerations | |
| Licence data |
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| Pregnancy cat. |
? |
| Legal status | |
| Dependence Liability | unknown |
| Routes | oral |
Dabigatran is an anticoagulant from the class of the direct thrombin inhibitors. It is being studied for various clinical indications, for some of which it may replace warfarin as the preferred anticoagulant. It is orally administered as the prodrug dabigatran etexilate (marketed as Pradaxa since April in first European countries). It was developed by pharmaceutical company Boehringer-Ingelheim.
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[edit] Development
Dabigatran (then compound BIBR 953) was discovered from a panel of chemicals with similar structure to benzamidine-based thrombin inhibitor α-NAPAP (N-alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide), which had been known since the 1980s as a powerful inhibitor of various serine proteases, specifically thrombin but also trypsin. Addition of a hydrophobic side chain led to the orally absorbed prodrug BIBR 1048 (dabigatran etexilate).[1]
Phase 3 clinical trials are ongoing in treatment and prevention of secondary venous thromboembolism (VTE) in post-operative orthopedic patients; long-term prophylaxis in acute coronary syndrome and stroke patients with atrial fibrillation and symptomatic VTE because of various causes (expected results by 2009-2010).[2] In stroke prevention in patients with atrial fibrillation, it is the first drug likely to be marketed.[3]
[edit] Dosing
A 2004 study showed a good safety profile at doses between 12.5 and 300 mg twice daily.[4]
In a phase II study comparing dabigatran with enoxaparin showed increased efficacy in preventing thrombosis in patients undergoing orthopedic surgery, but a possible increased bleeding risk in patients receiving higher doses of dabigatran.[5] Finally, a phase III study, comparing doses of 150 and 220 once daily with the standard dose of enoxaparin 40 mg once daily, confirmed that dabigatran performed equally well as enoxaparin inpreventing thrombosis, with a similar risk profile.[6]
Absorption is unrelated to food but may be decreased with co-administration of proton pump inhibitors.[7]
[edit] Approval and usage
On March 18, 2008, the European Medicines Agency granted marketing authorisation for dabigatran.[8]
The National Health Service in Britain have authorised the use of dabigatran for use in preventing blood clots in hip and knee surgery patients. Charities, including the British Heart Foundation are campaigning for the drug to be widely prescribed in place of Warfarin, which has the down side of having to be taken for at least one month, and heparin, which is administered intravenously or subcutaneously in its low molecular weight form. Dabigatran will cost the NHS £4.20 per day, which is equivalent to other anticoagulants.[9]
[edit] References
- ^ Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W (April 2002). "Structure-based design of novel potent nonpeptide thrombin inhibitors". J. Med. Chem. 45 (9): 1757–66. doi:. PMID 11960487.
- ^ Currently active clinical trials of Dabigatran at ClinicalTrials.gov http://www.clinicaltrials.gov/ct/search?term=Dabigatran&submit=Search
- ^ Turpie AG (January 2008). "New oral anticoagulants in atrial fibrillation". Eur. Heart J. 29 (2): 155–65. doi:. PMID 18096568.
- ^ Eriksson BI, Dahl OE, Ahnfelt L, et al (September 2004). "Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I". J. Thromb. Haemost. 2 (9): 1573–80. doi:. PMID 15333033.
- ^ Eriksson BI, Dahl OE, Büller HR, et al (January 2005). "A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial". J. Thromb. Haemost. 3 (1): 103–11. doi:. PMID 15634273.
- ^ Eriksson BI, Dahl OE, Rosencher N, et al (September 2007). "Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial". Lancet 370 (9591): 949–56. doi:. PMID 17869635.
- ^ Stangier J, Eriksson BI, Dahl OE, et al (May 2005). "Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement". J Clin Pharmacol 45 (5): 555–63. doi:. PMID 15831779.
- ^ European Medicines Agency. Public assessment report for Pradaxa (PDF). Retrieved on 2008-04-23.
- ^ "Clot drug 'cold save thousands'", BBC News Online, BBC, 2008-04-20. Retrieved on 2008-04-21.
[edit] External links
- Official site
- Warfarinfo page on dabigatran
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