Systematic (IUPAC) name | |
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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 | 211915-06-9 211914-51-1 (without etexilate) |
ATC code | B01AE07 |
PubChem | CID 6445226 |
ChemSpider | 4948999 |
ChEMBL | CHEMBL539697 |
Chemical data | |
Formula | C34H41N7O5 |
Mol. mass | 627.734 g/mol (471.511 without etexilate) |
SMILES | eMolecules & PubChem |
InChI=1S/C34H41N7O5/c1-4-6-7-10-21-46-34(44)39-32(35)24-12-15-26(16-13-24)37-23-30-38-27-22-25(14-17-28(27)40(30)3)33(43)41(20-18-31(42)45-5-2)29-11-8-9-19-36-29/h8-9,11-17,19,22,37H,4-7,10,18,20-21,23H2,1-3H3,(H2,35,39,44)
Key: KSGXQBZTULBEEQ-UHFFFAOYSA-N |
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Pharmacokinetic data | |
Bioavailability | 3–7%[1] |
Protein binding | 35%[1] |
Half-life | 12–17 hours[1] |
Therapeutic considerations | |
Licence data | EMA:Link, US FDA:link |
Pregnancy cat. | C(US) |
Legal status | Schedule VI (CA) POM (UK) ℞-only (US) |
Routes | oral |
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Dabigatran (Pradaxa in Europe and USA, Pradax in Canada) is an anticoagulant from the class of the direct thrombin inhibitors. It is being studied for various clinical indications and in many cases it offers an alternative to warfarin as the preferred orally administered anticoagulant ("blood thinner") since it does not require prothrombin time monitoring while offering similar results in terms of efficacy. It was developed by the pharmaceutical company Boehringer Ingelheim.
Contents |
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).[2]
Dosing
A 2004 study showed a good safety profile at doses between 12.5 and 300 mg twice daily.[3]
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.[4] A phase III study, comparing dabigatran doses of 150 mg and 220 mg once daily with the standard 40 mg dose of enoxaparin once daily, confirmed that dabigatran performed as well as enoxaparin in preventing thrombosis, with a similar risk profile.[5]
Absorption is unrelated to food but may be decreased if taken with a proton pump inhibitor.[6] Metabolism is slowed in people taking quinidine, verapamil, or amiodarone.[citation needed]
Approval and usage
On March 18, 2008, the European Medicines Agency granted marketing authorisation for Pradaxa for the treatment and prevention of thromboembolic disease.[7]
The National Health Service in Britain authorised the use of dabigatran for use in preventing blood clots in hip and knee surgery patients. The British Heart Foundation is campaigning for the drug to be widely prescribed in place of warfarin, which has the disadvantage of requiring administration up to a week before a target INR level is reached, 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 several other anticoagulants,[8] but more than ten times the cost of warfarin. However, the total cost of warfarin use includes the time and cost of INR monitoring which is not required with dabigatran.
In Canada, approval came on June 13, 2008, for the prevention of blood clots in patients who have undergone total hip or total knee replacement surgery. Approval for atrial fibrillation patients at risk of stroke came in October 2010.[9]
The U.S. Food and Drug Administration (FDA) approved Pradaxa on October 19, 2010, for prevention of stroke in patients with non-valvular atrial fibrillation.[10][11][12][13] The approval came after an advisory committee recommended the drug for approval on September 20, 2010[14] although caution is still urged by reviewers.[15]
Major trials
RE-LY study
A manufacturer-sponsored phase III study, RE-LY, evaluated the efficacy and safety of two different doses of dabigatran relative to warfarin in over 18,000 patients with atrial fibrillation. 18,113 patients with atrial fibrillation were randomized to one of three arms: (1) adjusted dose warfarin, (2) dabigatran 110 mg twice daily, or (3) dabigatran 150 mg twice daily. The warfarin arm was open label, but adverse events were adjudicated by reviewers blinded to treatment. Dabigatran 110 mg was non-inferior to warfarin for the primary efficacy endpoint of stroke or systemic embolization, while dabigatran 150 mg was significantly more effective than warfarin or dabigatran 110 mg. Major bleeding occurred significantly less often with dabigatran 110 mg than warfarin; dabigatran 150 mg showed similar bleeding to warfarin.[11]
RE-COVER
A 2009 large (2539 patients), randomized, double-blind trial by the RE-COVER study group demonstrated non-inferiority of dabigatran when compared to warfarin in the treatment of acute venous thromboembolism, with a similar rate of major bleeding and a lower rate of combined major plus non-major bleeding. Patients randomized to dabigatran had fewer minor bleeds but more dyspepsia and more drug discontinuation. Dabigatran-treated patients did not require coagulation testing.[16]
References
- ^ a b c Pradaxa Full Prescribing Information. Boehringer Ingelheim. October 2010.
- ^ 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:10.1021/jm0109513. PMID 11960487. Lay summary.
- ^ 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:10.1111/j.1538-7836.2004.00890.x. PMID 15333033. http://www.blackwell-synergy.com/doi/full/10.1111/j.1538-7836.2004.00890.x.
- ^ 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:10.1111/j.1538-7836.2004.01100.x. PMID 15634273. http://www.blackwell-synergy.com/doi/full/10.1111/j.1538-7836.2004.01100.x.
- ^ 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:10.1016/S0140-6736(07)61445-7. 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:10.1177/0091270005274550. PMID 15831779.
- ^ "Pradaxa EPAR". European Medicines Agency. http://www.emea.europa.eu/ema/humandocs/Humans/EPAR/pradaxa/pradaxa.htm. Retrieved 2011-01-30.
- ^ "Clot drug 'cold save thousands'". BBC News Online. 2008-04-20. http://news.bbc.co.uk/1/hi/health/7354818.stm. Retrieved 2008-04-21.
- ^ Kirkey, Sharon (29 October 2010). "Approval of new drug heralds 'momentous' advance in stroke prevention". Montreal Gazette. http://www.montrealgazette.com/health/Approval+drug+heralds+momentous+advance+stroke+prevention/3739714/story.html. Retrieved 29 October 2010.
- ^ Turpie AG (January 2008). "New oral anticoagulants in atrial fibrillation". Eur Heart J 29 (2): 155–65. doi:10.1093/eurheartj/ehm575. PMID 18096568.
- ^ a b Connolly, SJ; Ezekowitz, MD; Yusuf, S et al. (September 2009). "Dabigatran versus warfarin in patients with atrial fibrillation" (PDF). N Engl J Med 361 (12): 1139–51. doi:10.1056/NEJMoa0905561. PMID 19717844. http://www.nejm.org/doi/pdf/10.1056/NEJMoa0905561.
- ^ "Boehringer wins first US OK in blood-thinner race". Thomson Reuters. 2010-10-19. http://www.reuters.com/article/2010/10/19/boehringer-pradaxa-idUSN1916563620101019. Retrieved 2010-10-20.
- ^ "FDA approves Pradaxa to prevent stroke in people with atrial fibrillation". U.S. Food and Drug Administration (FDA). 2010-10-19. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230241.htm.
- ^ Shirley S. Wang (2010-09-20). "New Blood-Thinner Recommended by FDA Panel". The Wall Street Journal. http://blogs.wsj.com/health/2010/09/20/new-blood-thinner-recommended-by-fda-panel/. Retrieved 2010-10-20.
- ^ Merli G, Spyropoulos AC, Caprini JA (August 2009). "Use of emerging oral anticoagulants in clinical practice: translating results from clinical trials to orthopedic and general surgical patient populations". Ann Surg 250 (2): 219–28. doi:10.1097/SLA.0b013e3181ae6dbe. PMID 19638915.
- ^ Schulman S, Kearon C, Kakkar AK, et al. (December 2009). "Dabigatran versus warfarin in the treatment of acute venous thromboembolism" (PDF). N Engl J Med 361 (24): 2342–52. doi:10.1056/NEJMoa0906598. PMID 19966341. http://www.nejm.org/doi/pdf/10.1056/NEJMoa0906598.
External links
- Pradaxa.com. Boehringer Ingelheim.
- Pradaxa Prescribing Information. Boehringer Ingelheim.
- Dabigatran. MedlinePlus. United States National Library of Medicine (NLM).
- Dabigatran. Drug Information Portal. United States National Library of Medicine (NLM).
- Dabigatran. Drugs.com.
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