indication

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.

pharmacology

Dabigatran etexilate is an inactive pro-drug that gets converted to dabigatran, the active form, by esterase-catalyzed hydrolysis in the plasma and liver. Dabigatran, the main active principle in plasma, is a rapid-acting competitive and reversible direct inhibitor of thrombin. Thrombin, a serine protease, is responsible for the conversion of fibrinogen to fibrin during the coagulation cascade. Inhibition of thrombin consequently prevents thrombus development. Dabigatran inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.

mechanism of action

Esterase-catalysed hydrolysis of dabigatran etexilate in the plasma and liver yields the active form, dabigatran. Dabigatran competitively and reversibly binds to thrombin thereby inhibiting its ability to convert fibrinogen to fibrin during the coagulation cascade.

toxicity

The most common adverse reactions include dyspepsia or gastritis-like symptoms. The approximate lethal dose 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.

biotransformation

Dabigatran is typically metabolised by esterases and microsomal carboxylesterases. CYP450 enzymes do not seem to be involved. Pharmacologically active acylglucoronides are formed via conjugation. Four positional isomers, 1-O, 2-O, 3-O, and 4-O, acylglucuronides exist, each accounting for less than 10% of total plasma dabagatran.

absorption

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.

half life

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

route of elimination

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.

drug interactions

Amiodarone: Amiodarone may increase the serum concentration of dabigatran etexilate, resulting in increased risk of bleeding. Consider modifying therapy.

Carbamazepine: P-Glycoprotein inducers such as carbamazepine may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.

Dexamethasone: P-Glycoprotein inducers such as dexamethasone may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.

Doxorubicin: P-Glycoprotein inducers such as doxorubicin may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.

Ginkgo biloba: Additive anticoagulant/antiplatelet effects of gingko may increase bleed risk for patients on dabigatran. Concomitant therapy should be avoided.

Nefazodone: P-Glycoprotein inducers such as nefazodone may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.

Prazosin: P-Glycoprotein inducers such as prazosin may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.

Quinidine: Quinidine may increase the serum concentration of dabigatran etexilate, resulting in increased bleeding. Consider modification of therapy.

Rifampin: P-Glycoprotein inducers such as rifampin may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.

Rivaroxaban: Using additional anticoagulants such as dabigatran can increase the anticoagulant effect of rivaroxaban. Avoid concurrent use of rivaroxaban with other anticoagulants whenever possible, other than during transition periods, due to the possible increased for bleeding.

Tipranavir: P-Glycoprotein inducers such as tipranavir may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.

Trazodone: P-Glycoprotein inducers such as trazodone may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.

Verapamil: Verapamil may increase serum concentrations of the active metabolite(s) of dabigatran etexilate, resulting in an increased risk of bleeding. Therapy modification should be considered.

Vinblastine: P-Glycoprotein inducers such as vinblastine may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.