Dabigatran etexilate is an oral prodrug that is metabolized by a serum esterase to dabigatran. It is a synthetic, competitive and reversible direct thrombin inhibitor. Inhibition of thrombin disrupts the coagulation cascade and inhibits the formation of clots. Dabigatran etexilate may be used to decrease the risk of venous thromboembolic events in patients who have undergone total hip or knee replacement surgery, or to prevent stroke and systemic embolism in patients with atrial fibrillation, in whom anticoagulation therapy is indicated. In contrast to warfarin, because its anticoagulant effects are predictable, lab monitoring is not necessary. FDA approved on October 19, 2010.

• Anticoagulants
• Antithrombins
• Benzimidazoles
• Blood and Blood Forming Organs
• Enzyme Inhibitors
• Fibrinolytic Agents
• Hematologic Agents
• P-glycoprotein/ABCB1 Substrates
• Protease Inhibitors
• Pyridines
• Serine Proteinase Inhibitors

Dabigatran is indicated for the prevention of venous thromboembolic events in patients who have undergone elective hip or knee replacement surgery (based on RE-NOVATE, RE-MODEL, and RE-MOBILIZE trials). In 2010, it was approved in the US and Canada for prevention of stroke and systemic embolism in patients with atrial fibrillation (approval based on the RE-LY trial). Contraindications: severe renal impairment (CrCL < 30 ml/min); haemorrhagic manifestations, bleeding diathesis or spontaneous or pharmacologic impairment of haemostasis; lesions at risk of clinically significant bleeding (e.g. extensive cerebral infarction (haemorrhagic or ischemic) in the last 6 months, active peptic ulcer disease); concomitant treatment with P-glycoprotein inhibitors (e.g. oral ketoconazole, verapamil); and those with known hypersensitivity to dabigatran, dabigatran etexilate or any ingredient used in the formulation or component of the container. As of December 2012, dabigatran is contraindicated in patients with mechanical prosthetic heart valves.

• Deep Venous Thrombosis
• Deep vein thrombosis recurrent
• Recurrent pulmonary embolism
• Strokes
• Systemic Embolism
• Prophylaxis of Pulmonary embolism

Dabigatran directly inhibits thrombin in a concentration-dependent, reversible, specific, and competitive manner which results in a prolongation of aPTT (partial thromboplastin time), ECT (Ecarin clotting time), and TT (thrombin time). It may increase INR but this laboratory parameter is relatively insensitive to the activity of dabigatran.

Peak plasma concentrations were achieved in 6 hours in post surgical patients. In healthy patients, maximum concentrations were achieved in 0.5 to 2 hours. The absolute bioavailability of dabigatran in the body after administration of dabigatran etexilate was 6.5%. Food does not affect the bioavailability of dabigatran etexilate, but it delays the time to peak plasma concentrations by 2 hours. Oral bioavailability may increase by up to 75% when pellets are taken out of the hydroxypropylmethylcellulose (HPMC) capsule. Therefore, capsules should not be opened and pellets taken alone. Furthermore, although absorption of dabigatran etexilate is independent of gastrointestinal acidity, coadministration of pantoprazole (proton pump inhibitor) may reduce the bioavailability of dabigatran. Despite this finding, dose adjustment is not required.

Moderate tissue distribution with a Vd of 60-70L. Accumulation factor, twice daily dosing = 2

Relatively low binding (34-35%) to plasma proteins.

Mainly excreted in urine (85%). Fecal excretion accounts for 6% of the orally administered dose. Dabigatran is primarily eliminated unchanged via the kidneys at a rate of 100 ml/min corresponding to the glomerular filtration rate.

12-14 hours in healthy volunteers. 14-17 hours in patients treated for prevention of venous thromboembolism following hip- or knee-replacement surgery.

The most common adverse reactions include dyspepsia or gastritis-like symptoms. The approximate lethal dose (LD50) in rats and mice was observed at single oral doses of > 2000 mg/kg. Oral doses of 600 mg/kg did not induce any toxicologically meaningful changes in dogs and Rhesus monkeys. Dabigatran was well-tolerated in rats and Rhesus monkeys during repeat-dose toxicity studies. No evidence of mutagenic potential.

• Humans and other mammals

• St. John's Wort

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• B01AE — Direct thrombin inhibitors
• B01A — ANTITHROMBOTIC AGENTS
• B01 — ANTITHROMBOTIC AGENTS
• B — BLOOD AND BLOOD FORMING ORGANS

• 20:12.04.12