Thrombin (Ki = 4.5 nM)

Dabigatran selectively and reversibly inhibits the thrombin-induced platelet aggregation (IC50: 10 nM) and human thrombin (Ki: 4.5 nM), but it has no inhibitory effect on other agents that stimulate platelets. Dabigatran selectively and reversibly inhibits the thrombin-induced platelet aggregation (IC50: 10 nM) and human thrombin (Ki: 4.5 nM), but it has no inhibitory effect on other agents that stimulate platelets. With an IC50 of 0.56 μM, dabigatran inhibits the production of thrombin in platelet-poor plasma (PPP), as determined by the endogenous thrombin potential (ETP). At 0.23, 0.83, and 0.18 μM, respectively, dabigatran doubles the activated partial thromboplastin time (aPTT), prothrombin time (PT), and ecarin clotting time (ECT) in human PPP. Dabigatran exhibits concentration-dependent anticoagulant effects in a variety of species in vitro.[1]

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Dabigatran (BIBR 953) doubles the activated partial thromboplastin time (aPTT), prothrombin time (PT), and ecarin clotting time (ECT) in human platelet-poor plasma at concentrations of 0.23, 0.83, and 0.18 μM, respectively. It also exhibits concentration-dependent anticoagulant effects in a variety of species in vitro[1].

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Dabigatran is a reversible and selective, direct thrombin inhibitor (DTI) undergoing advanced clinical development as its orally active prodrug, dabigatran etexilate. This study set out to determine the molecular potency and anticoagulant efficacy of dabigatran and its prodrug dabigatran etexilate. This was achieved through enzyme inhibition and selectivity analyses, surface plasmon resonance studies, platelet aggregation, thrombin generation and clotting assays in vitro and ex vivo. These studies demonstrated that dabigatran selectively and reversibly inhibited human thrombin (Ki: 4.5 nM) as well as thrombin-induced platelet aggregation (IC(50): 10 nM), while showing no inhibitory effect on other platelet-stimulating agents. Thrombin generation in platelet-poor plasma (PPP), measured as the endogenous thrombin potential (ETP) was inhibited concentration-dependently (IC(50): 0.56 microM). Dabigatran demonstrated concentration-dependent anticoagulant effects in various species in vitro, doubling the activated partial thromboplastin time (aPTT), prothrombin time (PT) and ecarin clotting time (ECT) in human PPP at concentrations of 0.23, 0.83 and 0.18 microM, respectively. [1]

Dabigatran extends the aPTT in rats (0.3, 1 and 3 mg/kg) and rhesus monkeys (0.15, 0.3 and 0.6 mg/kg) in a dose-dependent manner following intravenous administration. (Source: ) In comparison to enoxaparin, dabigatran etexilate (20 mg/kg) causes less prolongation of the K value, as well as less decreases in angle and maximum amplitude in swine. [/2] The dose-dependent reduction of thrombus formation by dabigatran (0.01-0.1 mg/kg) has an ED50 (50% of the effective dose) of 0.033 mg/kg and complete inhibition at 0.1 mg/kg. The dose- and time-dependent inhibition of thrombus formation by dabigatran etexilate (5-30 mg/kg) reaches its maximum within 30 minutes of pretreatment, indicating a quick onset of action. [3]

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Dabigatran (0.01-0.1 mg/kg; i.v.) inhibits the formation of clots with an ED50 of 0.033 mg/kg in Wessler model[3].

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In vivo, Dabigatran prolonged the aPTT dose-dependently after intravenous administration in rats (0.3, 1 and 3 mg/kg) and rhesus monkeys (0.15, 0.3 and 0.6 mg/kg). Dose- and time-dependent anticoagulant effects were observed with dabigatran etexilate administered orally to conscious rats (10, 20 and 50 mg/kg) or rhesus monkeys (1, 2.5 or 5 mg/kg), with maximum effects observed between 30 and 120 min after administration, respectively. These data suggest that dabigatran is a potent, selective thrombin inhibitor and an orally active anticoagulant as the prodrug, Dabigatran etexilate. [1]

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Dabigatran is a reversible direct, selective thrombin inhibitor, undergoing clinical development as its orally active prodrug, dabigatran etexilate. The objective of this trial was to assess the antithrombotic and anticoagulant effects of dabigatran and dabigatran etexilate in a rat model of venous thrombosis. In order to do this a modified Wessler model was used to assess the antithrombotic and anticoagulant effects of intravenous (i.v.) dabigatran and oral Dabigatran etexilate administration. In addition, a rat tail bleeding time model was used to investigate the antihemostatic effect of Dabigatran. The study demonstrated that bolus administration of dabigatran (0.01-0.1 mg/kg) reduced thrombus formation dose-dependently, with an ED50 (50% of the effective dose) of 0.033 mg/kg and complete inhibition at 0.1 mg/kg. By comparison, ED50 values for heparin (0.03-0.3 mg/kg), hirudin (0.01-0.5 mg/kg) and melagatran (0.1-0.5 mg/kg) were 0.07, 0.15 and 0.12 mg/kg, respectively. Oral administration of dabigatran etexilate (5-30 mg/kg) inhibited thrombus formation in a dose- and time-dependent manner, with maximum inhibition within 30 min of pretreatment, suggesting a rapid onset of action. Following i.v. administration of Dabigatran (0.1-1.0 mg/kg), a statistically significant prolongation of bleeding time was observed at doses at least 15- and 5-fold greater than ED50 and ED100 (100% of the effective dose) doses, respectively; there was no significant increase in bleeding tendency at the maximum therapeutically effective dose (0.1 mg/kg). It can be concluded that dabigatran and its oral prodrug, dabigatran etexilate, show promise in the management of thromboembolic disease [3].

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Because of its strong in vitro activity and its favorable selectivity profile vs related serine proteases (Table 3), Dabigatran/24 was investigated biologically in depth and turned out to be a very potent anticoagulant in vivo. Among all of the inhibitors of this structural class, it exhibited the strongest activity and the longest duration of action in anaesthetized rats after i.v. administration. Unlike compound 2, it was well-tolerated in these animals up to the highest given dose of 10 mg/kg. It was, however, not orally active, which is not surprising considering that it is a very polar, permanently charged molecule with a logP of −2.4 (n-octanol/buffer, pH 7.4) [2].

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At 30 days, we observed 638 ± 895 mg thrombus in no anticoagulation group, 121 ± 128 mg in enoxaparin group, and 19 ± 31 mg in Dabigatran etexilate group (P = .01 enoxaparin vs dabigatran etexilate). Fewer platelets were deposited on valves in dabigatran etexilate group (2.7 × 108) than in enoxaparin group (1.8 × 109, P = .03). No major or occult hemorrhagic or embolic events were observed. By thromboelastographic analysis, dabigatran etexilate produced less prolongation of K value (P = .01) and less decreases in angle (P = .01) and maximum amplitude (P = .001) than enoxaparin.
Dabigatran etexilate is as effective as enoxaparin for short-term thromboprophylaxis of mechanical valves. It prevents valve thrombus and platelet deposition at 30 days without increased adverse events. These promising results serve as a foundation for prospective clinical trials with dabigatran etexilate as an alternative to warfarin in patients with bileaflet mechanical aortic valves. [4]

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Dosing Study [4]
Administration of Dabigatran etexilate at 20 mg/kg orally twice daily reproducibly increased the APTT to 2 to 2.5 times normal (Figure 2, A). Administration of enoxaparin at 2.0 mg/kg subcutaneously twice daily reproducibly increased anti-Xa levels to at least 0.6 (Figure 2, B). These doses were used for the remainder of the study.

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Measurement of Anticoagulation [4]
Serial hematologic assays confirmed appropriate dose and drug effects for both treatment arms. The APTT increased in animals treated with Dabigatran etexilate, and there was also a significant increase in the prothrombin time. (Figure 3, A and B). As expected, we observed increased anti-Xa levels at all time points for animals receiving enoxaparin relative to the no anticoagulation and dabigatran etexilate groups (Figure 3, C). We observed significantly less circulating fibrinogen in the dabigatran etexilate group at all 3 time points of the study (Figure 3, D).

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Valve Thrombus [4]
There was 1 premature death in the no anticoagulation group as a result of overwhelming sepsis on postoperative day 6. When the animals were killed, mean thrombus weight was statistically different between the groups. We observed 638 ± 895 mg of thrombus with no anticoagulation, 121 ± 128 mg with enoxaparin, and 19 ± 31 mg with Dabigatran etexilate (P = .04; Figure 4, A). This represented a 30-fold decrease in mean valve thrombus for the dabigatran etexilate group relative to the no anticoagulation group. Comparing the 2 treatment groups, we found significantly less thrombus on valves among animals receiving dabigatran etexilate (P = .02; Figure 4, B). Similarly, the mean number of platelets deposited on the valve prosthesis was lower in the dabigatran etexilate group (2.7 × 108) than in the enoxaparin group (1.8 × 109, (P = .03; Figure 4, C). Representative postmortem photographs of explanted valves from the no anticoagulation, enoxaparin, and dabigatran etexilate groups are shown in Figure 5.

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Thromboelastography [4]
Native and kaolin thromboelastographic assays were performed at baseline and during anticoagulation. We observed that at least in vivo the thromboelastographic coagulation profile (R and K times, angle, and maximum amplitude) in animals receiving Dabigatran etexilate looked more like the profiles obtained from animals with no anticoagulation than like those of animals receiving enoxaparin (Figure 6). This was true for both kaolin and native thromboelastographic assays (native data not shown), suggesting adequate anticoagulation despite a normal-appearing thromboelastographic profile.

Measurement of Thrombin Inhibition. [2]
The thrombin inhibitory effects (IC50) of the compounds were determined with a commercially available chromogenic assay. Human thrombin (0.042 U/mL) was preincubated for 10 min at 37 °C with 10 different dilutions (concentration range of 0.003−100 μM) of the test compounds dissolved in DMSO or with DMSO as control. Upon addition of the preincubation mixture to the chromogenic substrate, tosyl-glycyl-prolyl-arginine-4-nitranilide acetate, nitraniline is cleaved by thrombin and the increase in absorbance at 405 nm, related to the free nitraniline, is measured in a spectrophotometer. By plotting the absorbance at 405 nm vs the concentration of the test compound, the concentration that induced a 50% thrombin inhibition (IC50) was calculated. All measurements were performed in duplicate, and the mean values of both determinations are represented.

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Measurement of the aPTT. [2]
aPTT was measured in a coagulometer as a measure for the anticoagulant effect of the respective compound. Bloodsamples were collected in sodium citrate solution (final concentration 0.313%). Each native blood sample (0.1 mL) was pipetted into a test tube prewarmed to 37 °C. The PTT reagent (0.1 mL) was added, mixed, and incubated for exactly 3 min. Calcium chloride solution (0.1 mL), prewarmed to 37 °C, was added in order to activate the coagulation cascade, and the time (aPTT; in seconds) was determined that elapsed from the addition of calcium chloride to the onset of clotting.

Male rats (280-350 g) and rhesus monkeys of either sex (3-8 kg)
10, 20 and 50 mg/kg for rats and 1, 2.5 and 5 mg/kg for monkeys
Oral

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Thirty swine underwent implantation of modified bileaflet mechanical valved conduit bypassing the ligated, native descending thoracic aorta. Animals randomly received no anticoagulation (n = 10), enoxaparin 2 mg/kg subcutaneously twice daily (n = 10), or Dabigatran etexilate 20 mg/kg orally twice daily. Primary end point was amount of valve thrombus at 30 days. Secondary end points included quantitative measurement of platelet deposition on valve prosthesis, thromboelastography, and hemorrhagic and embolic events. [4]

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Dosing study [4]
Dabigatran etexilate is a novel, orally administered prodrug of the direct thrombin inhibitor Dabigatran. Unlike warfarin, it has a rapid clinical onset with a predictable dose response. Additionally, there are no known food or drug interactions, and it does not require frequent monitoring for therapeutic effect. Its half-life is approximately 12 hours, and it has no other active metabolites. Dabigatran is predominantly eliminated by renal excretion.
To identify the most effective doses of Dabigatran etexilate and enoxaparin in swine, we first performed a dosing study. Animals were dosed with either Dabigatran etexilate or enoxaparin, and appropriate hematologic assay samples were drawn at 0, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, and 72 hours.11 Our aim was to find the doses of Dabigatran etexilate and enoxaparin that corresponded to therapeutic levels in our strain of animals. For Dabigatran etexilate, we aimed to increase the activated partial thromboplastin time (APTT) 2 to 2.5 times normal. For enoxaparin, we sought an anti-Xa level of at least 0.6 at 4 hours.12

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In vivo thromboprophylaxis of mechanical valves [4]
Specific details regarding this model of heterotopic aortic valve prostheses have been reported elsewhere.9, 13 Briefly, 30 swine were randomly sorted into 3 treatment arms of postoperative anticoagulation. These treatments consisted of no anticoagulation (n = 10), enoxaparin at 2.0 mg/kg administered subcutaneously twice daily (n = 10), and Dabigatran etexilate at 20 mg/kg by mouth twice daily (n = 10). The clinical formulation of Dabigatran etexilate (small tartaric acid pellets coated with drug in capsules) was used in the study. The low–molecular weight heparin enoxaparin was used as the standard for anticoagulation because of the difficulty in maintaining a therapeutic window with warfarin in swine.14 Additionally, low–molecular weight heparins are used to bridge patients to warfarin anticoagulation and as an alternative to warfarin for some patients unable to take warfarin.15, 16 These doses were determined from the results of our dosing studies. Animals received their assigned treatment medication beginning on postoperative day 1.

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Coagulation profile [4]
We used several hematologic and anticoagulation assays to assess the effects of Dabigatran etexilate on the coagulation system. At baseline (before valve implantation), on days 10 and 20, and when the animal was killed (30 days), we performed a complete blood cell count; measured prothrombin time, APTT, fibrinogen, and anti-Xa levels; and performed thromboelastography. We used the TEG 5000 device with native and kaolin cups and pins (Haemoscope Corporation, Niles, Ill). Measurements obtained included R time (minutes), K time (minutes), angle (degrees), and maximal amplitude (mm). R time measures time to initial fibrin formation, K time measures time to strong clot formation and cross-linking, angle measures the speed of clot strengthening, and maximum amplitude measures final clot strength. We included thromboelastography because it evaluates the entire coagulation system and is becoming more widely used in managing cardiovascular surgical patients.

Absorption, Distribution and Excretion
Oral dabigatran has a bioavailability of 3-7%, although the relative bioavailability of dabigatran pellets is 37% higher than that for capsules and the bioavailability increases to 75% when the capsule shell is removed; dabigatran capsules should not be tampered with in any way prior to administration. The Cmax is achieved by one hour following oral dosing, which is extended to two hours if accompanied by a high-fat meal. Dabigatran can be taken with or without food. Dabigatran pharmacokinetics are approximately linear over a range of 10-400 mg in healthy adults and adult patients and it has an accumulation factor of two in adult and pediatric patients.
Dabigatran is primarily eliminated in the urine. Following oral administration of radiolabeled dabigatran, 7% of the radioactivity is recovered in urine and 86% is recovered in feces.
Dabigatran has a volume of distribution of 50-70L.
Following intravenous administration, renal clearance constitutes ~80% of total dabigatran clearance.

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Metabolism / Metabolites
Dabigatran is administered as the orally available prodrug dabigatran etexilate that is subsequently metabolized to the active form. _In vitro_ studies and observations regarding the oral bioavailability and levels of plasma prodrug suggest extensive first-pass metabolism by carboxylesterases, first by intestinal CES2 to form BIBR0951 (also known as M2) and then subsequently by hepatic CES1 to form [dabigatran]. Dabigatran etexilate can also first undergo CES1-mediated hydrolysis to BIBR1087 (M1) followed by CES2-mediated hydrolysis to [dabigatran], though it is hypothesized that the former pathway accounts for most of the active form in plasma. Dabigatran can undergo 1-_O_-acyl glucuronidation by UGT1A9, UGT2B7, and UGT2B15 followed by acyl migration to form the corresponding 2-_O_-, 3-_O_-, and 4-_O_-acyl glucuronides; all of these acyl glucuronides exhibit activity similar to [dabigatran] but account for a small fraction of recovered metabolites. In addition to these better characterized metabolic pathways, detailed LC/MS characterization suggests a wide variety of possible metabolites following oral or intravenous administration, most of which are present in only trace amounts in plasma, urine, or feces. These include a variety of oxidation, hydrolysis, and conjugation products, including through the addition of mannitol.

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Biological Half-Life
Dabigatran has a half-life of 12-17 hours in adult patients and 12-14 hours in pediatric patients.

Hepatotoxicity
Chronic therapy with dabigatran is associated with moderate ALT elevations (greater than 3 times the upper limit of normal) in 1.5% to 3% of patients, an overall rate which is slightly lower than with low molecular weight heparin and similar to the rates with warfarin. While case reports of clinically apparent liver injury due to dabigatran have not been published, several instances of ALT elevations with jaundice occurred during the large, prelicensure clinical trials of dabigatran. These cases were mild and self-limited, resolving completely once therapy was stopped. However, other causes of liver injury could not always be identified and the relationship of the injury to dabigatran therapy remains unclear. The clinical features of these cases were not described. In one large clinical trial, these unexplained cases of liver injury with bilirubin elevations occurred in approximately 1 in 2000 patients treated. In a subsequent case report, liver injury with jaundice and a mixed pattern of serum enzyme elevations arose within 4 weeks of starting dabigatran and resolved rapidly with its discontinuation. Immunoallergic and autoimmune features were not present. There have been multiple spontaneous reports of liver injury, some of which were fatal, made to WHO and FDA surveillance databases, but the relatedness of the episodes has not been clearly defined. Thus, clinically apparent liver injury with jaundice due to dabigatran occurs but is rare and typically mild and self-limited.
Likelihood score: D (possible rare cause of clinically apparent liver injury).
One reason why dabigatran was subjected to close scrutiny for evidence of hepatotoxicity was that the initial oral, direct thrombin inhibitor developed and evaluated in clinical trials was ximelagatran (zye" mel a gat' ran), which subsequently was found to be associated with rare but potentially severe cases of liver injury, typically arising after 1 to 6 months of treatment with a hepatocellular pattern of serum enzyme elevations and potentially severe and fatal course. Ximelagatran did not receive approval for use in the United States because of concerns about hepatotoxicity. After several further cases of clinically apparent hepatic injury were found in patients taking ximelagatran, it was also withdrawn from use in Europe. Risk of serum ALT elevations during ximelagatran therapy were later shown to be linked to HLA-DRB1*07 and DQA1*-02.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
In adults, less than 7% of dabigatran is absorbed orally in its prodrug form of dabigatran etexilate mesylate; dabigatran itself is not absorbed orally. Preliminary data from 2 individuals indicate that dabigatran is poorly excreted into breastmilk and unlikely to affect the breastfed infant. If the mother requires dabigatran, it is not a reason to discontinue breastfeeding. Because data are limited, monitor preterm or newborn infants for signs of bleeding.
◉ Effects in Breastfed Infants
Samples of newborn and preterm infant blood spiked with of dabigatran in the concentrations found in breastmilk after a 220 mg dose of dabigatran etexilate indicate that no effect on coagulation would occur.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Interactions
The concomitant use of a CYP3A4 isoenzyme substrate (atorvastatin) and dabigatran did not have clinically relevant effects on the pharmacokinetics of either drug. Also, the concomitant use of a CYP2C9 substrate (diclofenac) and dabigatran did not have clinically relevant effects on the pharmacokinetics of either drug.
Administration of rifampin for 7 days followed by a single dose of dabigatran resulted in decreases of 66 and 67% in dabigatran area under the plasma concentration-time curve (AUC) and peak plasma concentration, respectively. Within 7 days of rifampin discontinuance, dabigatran exposure approached levels expected without concurrent use of rifampin. Concomitant use should be avoided.
Concomitant use of dabigatran with P-glycoprotein inhibitors may increase systemic exposure to dabigatran. While clinical data and pharmacokinetic studies indicate that concomitant use of dabigatran with certain P-glycoprotein inhibitors (i.e., amiodarone, clarithromycin, ketoconazole, quinidine, verapamil) does not necessitate dosage adjustments, the manufacturer states that these results should not be extrapolated to all P-glycoprotein inhibitors.
Concomitant use of P-glycoprotein transport inhibitors and dabigatran in patients with renal impairment is expected to increase systemic exposure to dabigatran compared with that resulting from either factor alone. Reduction of dabigatran dosage should be considered in patients with moderate renal impairment (creatinine clearance of 30-50 mL/minute) who are receiving concomitant dronedarone or systemic ketoconazole. Concomitant use of dabigatran and P-glycoprotein transport inhibitors in patients with severe renal impairment (creatinine clearance of 15-30 mL/minute) should be avoided.
For more Interactions (Complete) data for Dabigatran (20 total), please visit the HSDB record page.

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Protein Binding
Dabigatran is ~35% bound to plasma proteins, including human serum albumin.

[1]. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally activeprodrug, dabigatran etexilate. Thromb Haemost. 2007 Jul;98(1):155-62.

[2]. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem. 2002 Apr 25;45(9):1757-66.

[3]. Effects of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate, on thrombus formation and bleeding time in rats. Thromb Haemost. 2007 Aug;98(2):333-8.

[4]. Effectiveness of dabigatran etexilate for thromboprophylaxis of mechanical heart valves. J Thorac Cardiovasc Surg. 2011 Jun;141(6):1410-6.

Dabigatran etexilate is an oral prodrug that is hydrolyzed to the competitive and reversible direct thrombin inhibitor [dabigatran]. 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.
A THROMBIN inhibitor which acts by binding and blocking thrombogenic activity and the prevention of thrombus formation. It is used to reduce the risk of stroke and systemic EMBOLISM in patients with nonvalvular atrial fibrillation.
See also: Dabigatran (has active moiety); Dabigatran Etexilate Mesylate (has salt form).

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Drug 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. Dabigatran etexilate is also approved by the EMA to prevent VTE in adult patients. For pediatric patients, Dabigatran etexilate is used to treat TVE and prevent recurrent TVE for patients from birth to less than 18 years of age.
FDA Label

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Mechanism of Action
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_i 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.

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Pharmacodynamics
Dabigatran etexilate is a double prodrug that is hydrolyzed to the active [dabigatran] 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 [warfarin] 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, [idarucizumab] is available for use in adult patients; the safety and efficacy of [idarucizumab] 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.

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Dabigatran is an aromatic amide obtained by formal condensation of the carboxy group of 2-{[(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1H-benzimidazole-5-carboxylic acid with the secondary amoino group of N-pyridin-2-yl-beta-alanine. The active metabolite of the prodrug dabigatran etexilate, it acts as an anticoagulant which is used for the prevention of stroke and systemic embolism. It has a role as an anticoagulant, an EC 3.4.21.5 (thrombin) inhibitor and an EC 1.10.99.2 [ribosyldihydronicotinamide dehydrogenase (quinone)] inhibitor. It is an aromatic amide, a member of benzimidazoles, a carboxamidine, a member of pyridines and a beta-alanine derivative.
Dabigatran is the active form of the orally bioavailable prodrug [dabigatran etexilate].
Dabigatran is a Direct Thrombin Inhibitor. The mechanism of action of dabigatran is as a Thrombin Inhibitor.
Dabigatran is a direct inhibitor of thrombin and anticoagulant which is used for prevention of stroke and venous embolism in patients with chronic atrial fibrillation. Dabigatran therapy has been associated with a low rate of serum enzyme elevations and rare instances of liver enzyme elevations and jaundice.
Dabigatran is a benzimidazole and direct thrombin inhibitor, with anticoagulant activity. Upon administration, dabigatran reversibly binds to and inhibits the activity of thrombin, a serine protease that converts fibrinogen into fibrin. This disrupts the coagulation cascade and inhibits the formation of blood clots.
A THROMBIN inhibitor which acts by binding and blocking thrombogenic activity and the prevention of thrombus formation. It is used to reduce the risk of stroke and systemic EMBOLISM in patients with nonvalvular atrial fibrillation.
See also: Dabigatran Etexilate (is active moiety of); Dabigatran Etexilate Mesylate (active moiety of); Dabigatran Ethyl Ester (is active moiety of).

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Mechanism of Action
Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.
... To evaluate the profibrinolytic effect of dabigatran, a new, direct thrombin inhibitor, using different in vitro models. The resistance of tissue factor-induced plasma clots to fibrinolysis by exogenous tissue-type plasminogen activator (t-PA) (turbidimetric method) was reduced by dabigatran in a concentration-dependent manner, with > or = 50% shortening of lysis time at clinically relevant concentrations (1-2 um). A similar effect was observed in the presence of low (0.1 and 1 nm) but not high (10 nm) concentrations of thrombomodulin. Acceleration of clot lysis by dabigatran was associated with a reduction in TAFI activation and thrombin generation, and was largely, although not completely, negated by an inhibitor of activated TAFI, potato tuber carboxypeptidase inhibitor. The assessment of the viscoelastic properties of clots showed that those generated in the presence of dabigatran were more permeable, were less rigid, and consisted of thicker fibers. The impact of these physical changes on fibrinolysis was investigated using a model under flow conditions, which demonstrated that dabigatran made the clots markedly more susceptible to flowing t-PA, by a mechanism that was largely TAFI-independent. Dabigatran, at clinically relevant concentrations, enhances the susceptibility of plasma clots to t-PA-induced lysis by reducing TAFI activation and by altering the clot structure. These mechanisms might contribute to the antithrombotic activity of the drug.

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Therapeutic Uses
Benzimidazoles; beta-Alanine/analogs & derivatives
Dabigatran is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. /Included in US product label/

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Drug Warnings
/BOXED WARNING/ WARNING: PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS. Premature discontinuation of any oral anticoagulant, including Pradaxa, increases the risk of thrombotic events. If anticoagulation with Pradaxa is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.
/BOXED WARNING/ SPINAL/EPIDURAL HEMATOMA. Epidural or spinal hematomas may occur in patients treated with Pradaxa who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: use of indwelling epidural catheters; concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants; a history of traumatic or repeated epidural or spinal punctures; a history of spinal deformity or spinal surgery; optimal timing between the administration of Pradaxa and neuraxial procedures is not known. Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated.
The FDA is evaluating post-marketing reports of serious bleeding events in patients taking dabigatran etexilate mesylate (Pradaxa). Bleeding that may lead to serious or even fatal outcomes is a well-recognized complication of all anticoagulant therapies. The dabigatran drug label contains a warning about significant and sometimes fatal bleeds. In a large clinical trial (18,000 patients) comparing dabigatran and warfarin, major bleeding events occurred at similar rates with the two drugs. FDA is working to determine whether the reports of bleeding in patients taking dabigatran are occurring more commonly than would be expected, based on observations in the large clinical trial that supported the approval of dabigatran. Dabigatran is a blood thinning (anticoagulant) medication used to reduce the risk of stroke in patients with non-valvular atrial fibrillation (AF), the most common type of heart rhythm abnormality. At this time, FDA continues to believe that dabigatran provides an important health benefit when used as directed and recommends that healthcare professionals who prescribe dabigatran follow the recommendations in the approved drug label. Patients with AF should not stop taking dabigatran without talking to their healthcare professional. Stopping use of blood thinning medications can increase their risk of stroke. Strokes can lead to permanent disability and death.
Dabigatran is contraindicated in patients with: active pathological bleeding; history of a serious hypersensitivity reaction to dabigatran (e.g., anaphylactic reaction or anaphylactic shock).
For more Drug Warnings (Complete) data for Dabigatran (14 total), please visit the HSDB record page.

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The clinical syndromes of thromboembolism are evoked by an excessive stimulation of the coagulation cascade. In this context, the serine protease thrombin plays a key role. Considerable efforts have therefore been devoted to the discovery of safe, orally active inhibitors of this enzyme. On the basis of the X-ray crystal structure of the peptide-like thrombin inhibitor NAPAP complexed with bovine thrombin, we have designed a new structural class of nonpeptidic inhibitors employing a 1,2,5-trisubstituted benzimidazole as the central scaffold. Supported by a series of X-ray structure analyses, we optimized the activity of these compounds. Thrombin inhibition in the lower nanomolar range could be achieved although the binding energy mainly results from nonpolar, hydrophobic interactions. To improve in vivo potency, we increased the overall hydrophilicity of the molecules by introducing carboxylate groups. The very polar compound 24 (BIBR 953/Dabigatran) exhibited the most favorable activity profile in vivo. This zwitterionic molecule was converted into the double-prodrug 31 (BIBR 1048), which showed strong oral activity in different animal species. On the basis of these results, 31 was chosen for clinical development.[1]

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Dabigatran etexilate, a new oral direct thrombin inhibitor, is safe and effective in reducing risk of stroke among patients with atrial fibrillation. No data exist in the setting of mechanical heart valves. We tested the hypothesis that dabigatran etexilate is as effective as heparin for thromboprophylaxis of mechanical valves in a porcine heterotopic aortic valve model. [4]

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The novel direct thrombin inhibitor dabigatran etexilate was effective for short-term thromboprophylaxis of mechanical heart valves in our porcine model. These animal data provide additional support for clinical trials evaluating dabigatran etexilate as an alternative to warfarin for appropriately selected patients with bileaflet mechanical valve aortic valves. [4]

C34H41N7O5

627.73

627.316

C, 65.05; H, 6.58; N, 15.62; O, 12.74)

211915-06-9

Dabigatran;211914-51-1;Dabigatran-d4 hydrochloride;Dabigatran etexilate mesylate;872728-81-9;Dabigatran etexilate-d13;Dabigatran (ethyl ester);429658-95-7;BIBR 1087 SE;212321-78-3

135565674

White to off-white solid powder

1.2±0.1 g/cm3

827.9±75.0 °C at 760 mmHg

128-129°

454.5±37.1 °C

0.0±3.0 mmHg at 25°C

1.615

5.13

3

9

18

46

991

0

O(C(/N=C(\C1C([H])=C([H])C(=C([H])C=1[H])N([H])C([H])([H])C1=NC2C([H])=C(C(N(C3=C([H])C([H])=C([H])C([H])=N3)C([H])([H])C([H])([H])C(=O)OC([H])([H])C([H])([H])[H])=O)C([H])=C([H])C=2N1C([H])([H])[H])/N([H])[H])=O)C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H]

XETBXHPXHHOLOE-UHFFFAOYSA-N

InChI=1S/C34H41N7O5.CH4O3S/c1-4-6-7-10-21-46-34(44)39-32(35)24-12-15-26(16-13-24)37-23-30-38-27-22-25(14-17-28(27)40(30)3)33(43)41(20-18-31(42)45-5-2)29-11-8-9-19-36-29;1-5(2,3)4/h8-9,11-17,19,22,37H,4-7,10,18,20-21,23H2,1-3H3,(H2,35,39,44);1H3,(H,2,3,4)

ethyl 3-[[2-[[4-(N-hexoxycarbonylcarbamimidoyl)anilino]methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoate;methanesulfonic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.98 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (3.98 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)