Dabigatran

Dabigatran etexilate

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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
Clinical data
[[Regulation of therapeutic goods |Template:Engvar data]]	EU EMA: Pradaxa
Routes of administration	oral
Legal status
Legal status	CA: Schedule VI UK: POM (Prescription only)
Identifiers
CAS Number	211915-06-9 211914-51-1 (without etexilate)
ATC code	B01AE07 (WHO)
PubChem	CID 6445226
ChemSpider	4948999
Chemical data
Formula	C34H41N7O5
Molar mass	627.734 g/mol (471.511 without etexilate)[[]]

File:Dabigatran structure.svg

Dabigatran: the active drug (without etexilate)

Dabigatran is an anticoagulant from the class of the direct thrombin inhibitors. It is being studied for various clinical indications and may replace warfarin as the preferred anticoagulant in many cases. It is orally administered as the prodrug dabigatran etexilate (marketed as Pradaxa since April 2008 in European countries and Pradax in Canada). It was developed by the pharmaceutical company Boehringer Ingelheim.

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).

Phase 3 clinical trials are ongoing in the treatment and prevention of secondary venous thromboembolism (VTE) in post-operative orthopedic patients; also long-term prophylaxis in acute coronary syndrome, and in stroke patients with atrial fibrillation and symptomatic VTE because of various causes (FDA advistory meeting regarding BI's NDA is scheduled for September, 2010). For people with atrial fibrillation, it is the first competitor to warfarin that is likely to be marketed for stroke prevention, although caution is still urged by reviewers.

Dosing

A 2004 study showed a good safety profile at doses between 12.5 and 300 mg twice daily.

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. 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.

Absorption is unrelated to food but may be decreased if taken with a proton pump inhibitor. Metabolism is slowed in people taking quinidine, verapamil, or amiodarone.

Approval and usage

On March 18, 2008, the European Medicines Agency granted marketing authorisation for dabigatran.

The National Health Service in Britain has 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 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, but more than ten times the cost of warfarin. Furthermore, 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.

Major trials

RE-LY

A 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.

RE-COVER

A recent 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.

External links

• Official site
• Warfarinfo page on dabigatran
• [1]

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