-
Dabigatran etexilate
- indication:Dabigatran is indicated for the prevention of venous thromboembolic events in patients who have undergone elective hip or knee replacement surgery (based on RENOVATE, REMODEL, and REMOBILIZE 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 RELY 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.
- pharmacologypharmacology:
- mechanism: 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.
- absorprion: Post surgical patients took 6 hours to reach peak plasma concentrations. In healthy patients, however, 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 delays the time to peak plasma concentrations by 2 hours. Oral bioavailability may increased by up to 75% when pellets are taken out of the hydroxypropylmethylcellulose (HPMC) capsule. Therefore, capsules should not be opened and pellets taken alone.
- halflife: 12-14 hours in healthy volunteers. 14-17 hours in patients in for major surgeries.
- roouteelimination: 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.
- volumedistribution: Moderate tissue distribution with V<sub>d</sub> of 60-70L
- clearance: