Dabigatran etexilate is a small molecule, non-pharmacological activity of the active form dabigatran predecessor. After oral administration of dabigatran etexilate is rapidly absorbed in the gastrointestinal tract (GIT) and by hydrolysis catalysed by omnadren jelfa esterases, in the liver and is converted into plasma dabigatran. Dabigatran is a potent competitive reversible direct thrombin inhibitor and the main active substance in the blood plasma.
Since thrombin (a serine protease) in the coagulation process converts fibrinogen to fibrin, thrombin inhibition activity prevents the formation of thrombus. Dabigatran has an inhibiting effect on the free thrombin, thrombin bound to fibrin clot, and thrombin-induced platelet aggregation.
In experimental studies on various thrombosis models in vivo and ex vivo confirmed antithrombotic effect and anticoagulant activity of dabigatran after intravenous administration and of dabigatran etexilate – after ingestion.
A direct correlation between dabigatran concentration in plasma and the severity of the anticoagulant effect. Dabigatran prolongs the activated partial thromboplastin time (aPTT), ekarinovoe clotting time (EMU), and thrombin time (PT).
Prevention of venous thromboembolism (VTE) after total large joints
Results from clinical studies in patients undergoing orthopedic surgery – arthroplasty of the knee and hip joints – confirmed the preservation of hemostasis parameters and application of equivalence of 75 mg or 110 mg dabigatran etexilate 1-4 hours after the operation and subsequent maintenance dose of 150 or 220 mg once a day for 6-10 days (knee surgery), and 28-35 days (on the hip joint) as compared with enoxaparin 40 mg 1 time per day, which is applied before and after surgery.
It is an equivalent of dabigatran etexilate antithrombotic effect in the application of 150 mg or 220 mg compared to enoxaparin 40 mg per day in the evaluation of the primary endpoint, which includes all cases of venous thromboembolism and all-cause mortality.
Prevention of stroke and systemic thromboembolism in patients with atrial fibrillation
With long-term, an average of about 20 months, the use in patients with atrial fibrillation, and a moderate to high risk of stroke or systemic thromboembolism have shown that dabigatran etexilate in a dose of 110 mg, designated 2 times a day, was not inferior to warfarin in effectiveness in preventing stroke and systemic thromboembolism in patients with atrial fibrillation; as in the dabigatran group was marked reduction in the risk of intracranial bleeding and total bleeding rate. Application of a higher dose (150 mg 2 times daily) significantly reduced the risk of ischemic and hemorrhagic stroke, cardiovascular death, intracranial bleeding, and total bleeding rate, compared to warfarin. A smaller dose of dabigatran was characterized by a significantly lower risk of major bleeding compared to warfarin.
Net clinical benefit was evaluated omnadren jelfa by determining the combined end point of stroke frequency, systemic thromboembolism, pulmonary thromboembolism, myocardial infarction, cardiovascular death and major bleeding.
The annual incidence of these events in patients treated with dabigatran etexilate was lower than in patients treated with warfarin.
Changes in laboratory parameters of liver function in patients receiving dabigatran etexilate, marked with a comparable or lower incidence when compared with patients treated with warfarin.
Following oral administration of dabigatran etexilate has been a rapid dose-dependent increase of its concentration in plasma and area under the curve “concentration-time» (AUC). Dabigatran etexilate maximum concentration (C max ) is reached within 0.5-2 hours.
After reaching C max plasma concentrations of dabigatran reduced biexponential manner with a terminal half-life (T1 / 2) an average of about 11 hours (the elderly). The final T1 / 2 after repeated use of the drug was about 12-14 h. T1 / 2 is independent of dose. However, in the case of renal function T1 / 2 longer.
The absolute bioavailability of dabigatran etexilate after administration of dabigatran inside capsules, coated from hypromellose, is about 6.5%.
Food intake does not affect the bioavailability of dabigatran etexilate but the time to reach C max is increased by 2 hours.
When using dabigatran etexilate without special capsule shell made of hypromellose, oral bioavailability can be increased about 1.8 times (75%) compared to the dosage form in capsules. Therefore it is necessary to preserve the integrity of the capsules made from hypromellose, given the risk of increasing the bioavailability of dabigatran etexilate, and is not recommended to open the capsule and apply the contents in a pure form (for example, adding to the food or drink) (see. “Dosage and Administration” section).
In the application of dabigatran etexilate after 1-3 hours in patients after surgical treatment of a decline rate of absorption of the drug compared with healthy volunteers. AUC is characterized by gradual increase in amplitude without the occurrence of high peak omnadren jelfa plasma concentrations. C max in the blood plasma observed after 6 hours after administration of dabigatran etexilate or 7-9 hours after surgery. It should be noted that factors such as anesthesia, paresis and gastrointestinal surgery may be important to slow absorption, regardless of dosage form preparation. Reducing the rate of absorption of the drug is usually observed only on the day of surgery. On subsequent days absorption of dabigatran is rapid, reaching a C max at 2 hours after ingestion.
After oral administration in the hydrolysis process under the influence of esterase dabigatran etexilate is rapidly and completely converted to dabigatran, which is the main active metabolite in the blood plasma. When the conjugation is formed dabigatran 4 atsilglyukuronidov pharmacologically active isomer of 1-O, 2-O, 3-O, 4-O, each of which is less than 10% of the total plasma dabigatran. Traces of other metabolites can be detected only by using highly sensitive analytical methods.
The volume of distribution of dabigatran of 60-70 L and greater than the volume of total body water, indicating a moderate distribution of dabigatran omnadren jelfa in the tissues.