| Drug ID: | D096 |
| Drug Name: | Dabigatran Etexilate |
| Synonyms: |
Dabigatran etexilate
|
| Type: | Chemical drug |
| DrugBank ID: |
DB06695
|
| DrugBank Description: |
Dabigatran etexilate is an oral prodrug that is hydrolyzed to the competitive and reversible direct thrombin inhibitor . Dabigatran etexilate may be used to decrease the risk of venous thromboembolic events in patients in whom anticoagulation therapy is indicated. In contrast to warfarin, because its anticoagulant effects are predictable, lab monitoring is not necessary. Dabigatran etexilate was approved by the FDA in 2010.
|
| PubChem ID: |
135565674
|
| CasNo: |
211915-06-9
|
| Repositioning for NAFLD: |
Yes
|
| SMILES: |
Cn1c2c(nc1CNc1ccc(cc1)C(=N)NC(=O)OCCCCCC)cc(cc2)C(=O)N(CCC(=O)OCC)c1ccccn1
|
| Structure: |
|
| InChiKey: |
KSGXQBZTULBEEQ-UHFFFAOYSA-N
|
| Molecular Weight: |
227.238
|
| DrugBank Targets: |
Prothrombin inhibitor
|
| DrugBank MoA: |
Hemostasis is a complex process that balances coagulation to prevent excessive thrombus formation or excessive bleeding. Central to the coagulation process is the serine protease thrombin (FIIa), which is synthesized as inactive prothrombin (FII) and subsequently activated by FXa/FVa, leading to a positive feedback loop and the production of large quantities of thrombin; once enough thrombin is formed, it cleaves soluble fibrinogen to form insoluble fibrin fibres that, together with aggregated platelets, form a clot. Although beneficial in wound healing, aberrant thrombus formation can lead to serious health consequences.
Dabigatran is a univalent reversible direct thrombin inhibitor (DTI) that competitively inhibits thrombin with a K<sub>i</sub> of 4.5 ± 0.2 nmol/L. Furthermore, the reversible nature of the inhibition is believed to allow for some normal physiological thrombin function, which may help alleviate some adverse effects associated with anticoagulation therapy. In addition, dabigatran has several glucuronidated metabolites, all of which have been shown to possess _in vitro_ activity similar to the parent compound.
In addition to a direct effect on thrombin activity, dabigatran has also been shown to inhibit platelet aggregation, another step in the coagulation pathway. However, the mechanism remains unclear as dabigatran inhibits platelet aggregation stimulated by thrombin and von Willebrand factor (vWF), but not by other pathways such as ADP- or thromboxane A2-induced aggregation.
|
| DrugBank Pharmacology: |
Dabigatran etexilate is a double prodrug that is hydrolyzed to the active by intestinal and hepatic carboxylesterases. Dabigatran is a reversible competitive thrombin inhibitor that directly inhibits the conversion by thrombin of fibrinogen to fibrin, impairing the clotting process and acting as an anticoagulant. Dabigatran use prolongs coagulation markers such as the activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), thrombin time (TT), and dilute thrombin time (dTT), but not the international normalized ratio (INR), which cannot be used in this context as it can in monitoring.
As with all anticoagulant therapies, dabigatran carries a risk of bleeding, which may increase with concomitant use of antiplatelet agents, fibrinolytic therapy, heparins, or chronic NSAID use, and should be monitored for. Premature discontinuation of dabigatran, in the absence of an alternative anticoagulant, also carries an increased risk of thromboembolic events. Due to the risk of an epidural or spinal hematoma, dabigatran should generally not be used in the context of neuraxial anesthesia or spinal puncture; if such use is unavoidable, careful monitoring should be employed. Dabigatran should not be used in patients with prosthetic heart valves due to an increased occurrence of major bleeding and thromboembolic events. Dabigatran is a substrate of the P-gp transporter and should generally not be administered together with P-gp inhibitors or inducers, especially in patients with impaired renal function. Lastly, dabigatran or any other direct-acting oral anticoagulant should not be administered in patients with triple-positive antiphospholipid syndrome (APS) due to an increased risk of recurrent thrombotic events. In case of the need for emergency reversal, is available for use in adult patients; the safety and efficacy of has not been established in pediatric patients yet, for whom reversal may be achieved through hemodialysis, prothrombin complex concentrates, or recombinant FVIIa. However, none of these have been sufficiently evaluated in clinical trials.
|
| DrugBank Indication: |
Dabigatran etexilate is available in both oral pellet and capsule form. Dabigatran etexilate pellets are indicated for the treatment of venous thromboembolic events (VTE) in pediatric patients between three months and 12 years of age who have been treated with a parenteral anticoagulant for at least 5 days. They are also indicated in the same age group to reduce the risk of recurrence of VTE in patients who have been previously treated.
In capsule form, dabigatran etexilate is indicated in adults to reduce the risk of stroke and systemic embolism associated with non-valvular atrial fibrillation and for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days. It is also indicated in adults to reduce the risk of recurrence of DVT and PE in patients who have been previously treated and for the prophylaxis of DVT and PE in patients who have undergone hip replacement surgery. Lastly, it is indicated in pediatric patients between eight and 18 years of age for the treatment of venous thromboembolic events (VTE) in patients who have been treated with a parenteral anticoagulant for at least 5 days and to reduce the risk of recurrence of VTE in patients who have been previously treated.
|
| Targets: |
thrombin inhibitor
|
| Therapeutic Category: |
--
|
| Clinical Trial Progress: |
Phase 1 completed (NCT03143166: The DE tablet demonstrated BE to the capsule; however, at high gastric pH, BA of the tablet was reduced by approximately 70%, which may lead to reduced efficacy. Data indicate the importance of examining not only BE under standard conditions, but relative BA at elevated gastric pH. Such investigations may avoid the reduced BA at elevated pH that is quite common in the target population (the elderly and/or patients treated with gastric-acid modifying co-medications), and therefore reduce treatment failure with DE.)
|
| Latest Progress: |
Under clinical trials
|
