human thrombin (Ki = 4.5 nM)

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 etexilate mesylate (BIBR 1048MS; oral; 10, 20 and 50 mg/kg for rats and 1, 2.5 and 5 mg/kg for monkeys) has anticoagulant effects that are dose- and time-dependent, peaking 30 to 120 minutes after administration[1]. Dabigatran etexilate mesylate maximally and significantly increases partial thromboplastin time (aPTT) following oral doses of 10, 20, and 50 mg/kg to 25.2, 38.4, and 78.3 s in 30 min, respectively[1]. Dabigatran etexilate mesylate maximally extends the aPTT to 34.3 s, 44.0 s, and 63.0 s, in that order, two hours after giving the monkey doses of 1, 2.5, or 5 mg/kg[1].

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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)[1]
\n10, 20 and 50 mg/kg for rats and 1, 2.5 and 5 mg/kg for monkeys
\nOral \n

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\n\nThirty 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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\n\nDosing study [4]
\nDabigatran 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.
\n\nTo 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\n

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\n\nIn vivo thromboprophylaxis of mechanical valves [4]
\nSpecific 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.\n

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\n\n\nCoagulation profile [4]
\nWe 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.\n\n

Absorption, Distribution and Excretion
Following oral administration of dabigatran etexilate, the absolute bioavailability of dabigatran is approximately 3% to 7%. Dabigatran etexilate is a substrate of the efflux transporter P-gp. In healthy volunteers, after oral administration of dabigatran etexilate on an empty stomach, peak plasma concentration (Cmax) occurs 1 hour after administration. Concomitant administration with a high-fat meal delays the time to reach Cmax by approximately 2 hours but does not affect the bioavailability of dabigatran; dabigatran can be taken on an empty stomach or with food. Compared to whole capsule formulations, oral bioavailability of dabigatran etexilate granules is increased by 75% by removing the capsule shell. Therefore, dabigatran capsules should not be broken, chewed, or opened before administration. The binding rate of dabigatran to human plasma proteins is approximately 35%. The erythrocyte/plasma partition coefficient of dabigatran, measured by total radioactivity, is less than 0.3. The volume of distribution of dabigatran is 50 to 70 liters. Following a single dose of 10 to 400 mg, the pharmacokinetics of dabigatran are dose-dependent. With twice-daily dosing, the accumulation factor of dabigatran is approximately 2. For more complete data on absorption, distribution, and excretion of dabigatran (of 10 parameters), please visit the HSDB record page.

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Metabolism/Metabolites
After oral administration, dabigatran ester is converted to dabigatran. The major metabolic reaction is the esterase-catalyzed hydrolysis of dabigatran ester to the active ingredient dabigatran. Dabigatran is not a substrate, inhibitor, or inducer of CYP450 enzymes. Dabigatran can undergo a conjugation reaction to form a pharmacologically active acylglucuronide. Dabigatran ester exists in four positional isomers: 1-O, 2-O, 3-O, and 4-O-acylglucuronide, each of which accounts for less than 10% of total dabigatran ester in plasma. This study investigated the pharmacokinetics and metabolism of the direct thrombin inhibitor dabigatran etexilate (BIBR 953 ZW, β-alanine, N-((2-((((4-(aminoiminomethyl)phenyl)amino)methyl)-1-methyl-1H-benzimidazol-5-yl)carbonyl)-N-2-pyridyl) in 10 healthy male subjects. Subjects received 200 mg (14)C-dabigatran etexilate orally (BIBR 1048 MS, an oral prodrug of dabigatran etexilate) or 5 mg (14)C-dabigatran etexilate intravenously. Radioactivity was measured in plasma, urine, and feces over one week. Metabolite profiles were analyzed using high-performance liquid chromatography-online radiometric detection, and metabolite structures were identified by mass spectrometry. Dabigatran etexilate is rapidly converted to dabigatran, with peak plasma dabigatran concentrations reached approximately 1.5 hours after administration. The primary metabolic reaction is the esterase-mediated hydrolysis of dabigatran etexilate to dabigatran. After oral administration, the phase I metabolite accounts for ≤0.6% of the administered dose in urine and 5.8% in feces; after intravenous administration, the phase I metabolite accounts for ≤1.5% of the administered dose in urine and 0.2% in feces. After oral and intravenous administration, dabigatran acylglucuronide accounts for 0.4% and 4% of the administered dose in urine, respectively. In vitro studies have confirmed that dabigatran etexilate is primarily metabolized by esterases, with cytochrome P450 enzymes playing no significant role. These results indicate that pharmacologically active concentrations of dabigatran are readily achieved after oral administration of dabigatran etexilate, and the likelihood of clinically relevant interactions between dabigatran and drugs metabolized by cytochrome P450 is low.

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Biological half-life
The half-life of dabigatran in healthy subjects is 12 to 17 hours.

Hepatotoxicity
In patients using dabigatran long-term, 1.5% to 3% experience moderate ALT elevations (more than 3 times the upper limit of normal), with an overall incidence slightly lower than low molecular weight heparin and similar to warfarin. While no clinically significant liver injury caused by dabigatran has been reported, several cases of ALT elevation with jaundice have occurred in large premarketing clinical trials of dabigatran. These cases were mild and self-limiting, resolving completely upon discontinuation of the drug. However, other causes of liver injury were not identifiable in all cases, and the relationship between liver injury and dabigatran treatment remains unclear. The clinical characteristics of these cases have not been described. In a large clinical trial, approximately 1 in 2000 treated patients experienced unexplained liver injury with elevated bilirubin. In a subsequent case report, a patient developed liver injury within 4 weeks of starting dabigatran etexilate, accompanied by jaundice and mixed serum enzyme elevations, with symptoms rapidly resolving upon discontinuation of the drug. This patient did not exhibit immune hypersensitivity or autoimmune features. Multiple reports of spontaneous liver injury, some of which were fatal, have been received in the surveillance databases of the World Health Organization and the U.S. Food and Drug Administration, but the association between these cases remains unclear. Therefore, clinically significant liver injury with jaundice caused by dabigatran, while rare, is usually mild and resolves spontaneously. Probability Score: D (Possibly a rare cause of clinically significant liver injury). One reason dabigatran has received close attention for its hepatotoxicity evidence is that ximelagatran was the first oral direct thrombin inhibitor developed and evaluated in clinical trials. This drug was subsequently found to be associated with rare but potentially serious cases of liver injury, typically appearing 1 to 6 months after treatment, manifesting as elevated hepatocellular serum enzymes, and the condition could be severe or even fatal. Due to concerns about hepatotoxicity, ximelagatran was not approved for use in the United States. It was also withdrawn from the market in Europe after more cases of clinically significant liver injury were found in patients taking ximelagatran. Subsequent studies have shown a risk of elevated serum ALT during ximelagatran treatment. Related to HLA-DRB107 and DQA1-02.

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Effects during pregnancy and lactation
◉ Overview of use during lactation
In adults, dabigatran etexilate is absorbed orally in less than 7% of its prodrug form; dabigatran etexilate itself is not absorbed orally. Preliminary data from 2 subjects suggest that dabigatran etexilate is rarely excreted into breast milk and is unlikely to affect breastfed infants. If the mother needs to take dabigatran etexilate, this is not a reason to discontinue breastfeeding. Due to limited data, signs of bleeding in preterm infants or newborns should be monitored.
◉ Effects on breastfed infants
Dabigatran etexilate was added to blood samples from newborns and preterm infants at concentrations equivalent to those found in breast milk after administration of 220 mg dabigatran etexilate. Etaxel etexilate has been shown to have no effect on coagulation.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Interactions
The co-administration of CYP3A4 isoenzyme substrates (atorvastatin) and dabigatran etexilate had no clinically relevant effects on the pharmacokinetics of either drug. Similarly, the co-administration of CYP2C9 substrates (diclofenac) and dabigatran etexilate also had no clinically relevant effects on the pharmacokinetics of either drug.
After 7 days of rifampin administration, a single dose of dabigatran etexilate resulted in a 66% decrease in the area under the plasma concentration-time curve (AUC) and a 67% decrease in peak plasma concentration, respectively. Within 7 days of discontinuing rifampin, dabigatran etexilate exposure was close to normal. No adverse reactions are expected if rifampin is not used concurrently. Concomitant use should be avoided.
Concomitant use of dabigatran with P-glycoprotein inhibitors may increase systemic exposure to dabigatran. Although clinical data and pharmacokinetic studies suggest that no dose adjustment is required when dabigatran is used in combination with certain P-glycoprotein inhibitors (e.g., amiodarone, clarithromycin, ketoconazole, quinidine, verapamil), the manufacturer states that these results should not be generalized 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 to either drug alone. For patients with moderate renal impairment (creatinine clearance 30-50 mL/min) who are also receiving dronedarone or systemic rifampin, dose reduction of dabigatran should be considered. For patients with severe renal impairment (creatinine clearance 15-30 mL/min), concomitant use of dabigatran and P-glycoprotein transport inhibitors should be avoided. More (complete) interaction data (20 items in total) for dabigatran can be found on the HSDB record page.

[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.

[5]. Dabigatran Etexilate: A Review in Nonvalvular Atrial Fibrillation. Drugs. 2017;77(3):331-344.

Dabigatran ester mesylate is the mesylate form of the dabigatran ester prodrug. Dabigatran ester is a benzimidazole direct thrombin inhibitor with anticoagulant activity. After administration, dabigatran ester is hydrolyzed by esterases to dabigatran. Dabigatran reversibly binds to thrombin (a serine protease that converts fibrinogen to fibrin) and inhibits its activity. This disrupts the coagulation cascade and inhibits thrombus formation. Dabigatran is a thrombin inhibitor whose mechanism of action is to prevent thrombosis by binding to and blocking thrombus-forming activity. It is used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. See also: Dabigatran (with active fraction). Dabigatran ester (containing active ingredient).

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Drug Indications
Prevention and treatment of thromboembolic events.
Dabigatran is an aromatic amide formed by the condensation of the carboxyl group of 2-{[(4-carbamoylphenyl)amino]methyl}-1-methyl-1H-benzimidazole-5-carboxylic acid with the secondary amino group of N-pyridin-2-yl-β-alanine. It is the active metabolite of the prodrug dabigatran ester and has anticoagulant activity, used for the prevention of stroke and systemic embolism. It is an anticoagulant and also an EC 3.4.21.5 (thrombin) inhibitor and an EC 1.10.99.2 [riboside dihydronicotinamide dehydrogenase (quinone)] inhibitor. It is an aromatic amide belonging to the benzimidazole, carboxymididine, pyridine, and β-alanine derivative classes. Dabigatran is the active form of the orally bioavailable prodrug [dabigatran ester]. Dabigatran is a direct thrombin inhibitor. The mechanism of action of dabigatran is as a thrombin inhibitor. Dabigatran is a direct thrombin inhibitor and anticoagulant used to prevent stroke and venous thrombosis in patients with chronic atrial fibrillation. Dabigatran treatment is associated with a low incidence of elevated serum enzymes, and extremely low incidence of elevated liver enzymes and jaundice. Dabigatran is a benzimidazole direct thrombin inhibitor with anticoagulant activity. After administration, dabigatran reversibly binds to thrombin (a serine protease that converts fibrinogen to fibrin) and inhibits its activity. This disrupts the coagulation cascade and inhibits thrombus formation. Dabigatran is a thrombin inhibitor whose mechanism of action is to prevent thrombosis by binding to and blocking thrombus-forming activity. It is used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. See also: dabigatran ester (its active portion); dabigatran mesylate (its active portion); dabigatran ethyl ester (its active portion).

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Mechanism of Action
Dabigatran and its acylglucuronide are competitive direct thrombin inhibitors. Since thrombin (a serine protease) converts fibrinogen to fibrin in the coagulation cascade, inhibiting thrombin can prevent thrombus formation. The active moiety inhibits both free and thrombus-bound thrombin, as well as thrombin-induced platelet aggregation.
…To evaluate the fibrinolytic effect of the novel direct thrombin inhibitor dabigatran, we used different in vitro models. Dabigatran reduced the resistance of tissue factor-induced plasma clots to fibrinolysis by external tissue plasminogen activator (t-PA) in a concentration-dependent manner (turbidimetric assay), shortening dissolution time by ≥50% at clinically relevant concentrations (1–2 μM). Similar effects were observed in the presence of low concentrations (0.1 and 1 nM) of thrombomodulin, but not in the presence of high concentrations (10 nM) of thrombomodulin. Dabigatran accelerates thrombolysis and is associated with reduced TAFI activation and thrombin production, an effect that can be significantly (but not entirely) counteracted by dabigatran, an inhibitor of TAFI activation—a potato tuber carboxypeptidase inhibitor. Assessment of thrombus viscoelastic properties showed that thrombi formed in the presence of dabigatran were more permeable, less rigid, and coarser in fibers. The effects of these physical changes on fibrinolysis were investigated using a flow-condition model, revealing that dabigatran significantly enhances thrombus sensitivity to t-PA through a primarily TAFI-independent mechanism. At clinically relevant concentrations, dabigatran enhances the sensitivity of plasma thrombi to t-PA-induced dissolution by reducing TAFI activation and altering thrombus structure. These mechanisms may contribute to the drug's antithrombotic activity.

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Therapeutic Use
Benzimazoles; β-alanine/analogs and derivatives
Dabigatran is indicated for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. /US Product Label Contains/

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Drug Warning
/Black Box Warning/ Warning: Premature discontinuation of dabigatran increases the risk of thrombotic events. Premature discontinuation of any oral anticoagulant, including dabigatran, increases the risk of thrombotic events. If you discontinue dabigatran etexilate (Pradaxa) for anticoagulation therapy for reasons other than pathological bleeding or completion of treatment, consider using an alternative anticoagulant.
/Black Box Warning/ Spinal/Epidural Hematoma. Epidural or spinal hematomas may occur in patients receiving dabigatran etexilate treatment and undergoing spinal anesthesia or spinal cord puncture. These hematomas may lead to long-term or permanent paralysis. These risks should be considered when scheduling patients for spinal surgery. Factors that may increase the risk of epidural or spinal hematoma in these patients include: use of indwelling epidural catheters; concurrent use of other medications that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, and other anticoagulants; a history of invasive or recurrent epidural or spinal punctures; a history of spinal deformities or spinal surgery; and the optimal timing between dabigatran etexilate (Pradaxa) administration and spinal intervention is unclear. Patients should be closely monitored for signs and symptoms of neurological dysfunction. If neurological impairment is detected, treatment must be initiated immediately. For patients currently receiving or about to receive anticoagulation therapy, the risks and benefits should be weighed before initiating spinal intervention. The U.S. Food and Drug Administration (FDA) is evaluating post-marketing reports of serious bleeding events related to dabigatran etexilate mesylate (Pradaxa). Bleeding can have serious and even fatal consequences and is a common complication of all anticoagulation therapies. The dabigatran package insert contains warnings about serious and even fatal bleeding. In a large clinical trial comparing dabigatran and warfarin (18,000 patients), the incidence of major bleeding events was similar for both drugs. The FDA is working to determine whether bleeding events were reported more frequently than expected in patients taking dabigatran, based on observations from the large clinical trial supporting its approval. Dabigatran is a blood thinner (anticoagulant) used to reduce the risk of stroke in patients with nonvalvular atrial fibrillation (AF), the most common type of heart rhythm disorder. Currently, the FDA still considers dabigatran to have significant health benefits when used as directed and recommends that healthcare professionals prescribing dabigatran follow the advice on the approved drug label. Patients with AF should not discontinue dabigatran without consulting a healthcare professional. Discontinuing blood thinners increases the risk of stroke. Stroke can lead to permanent disability or even death. Dabigatran is contraindicated in patients with: active pathological bleeding; or a history of severe allergic reactions to dabigatran (e.g., anaphylactic reaction or anaphylactic shock).
For more complete (14) drug warnings for dabigatran, please visit the HSDB record page.

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The clinical syndrome of thromboembolism is caused by the overactivation of the coagulation cascade. Serine protease thrombin plays a crucial role in this process. Therefore, considerable effort has been devoted to discovering safe and effective oral thrombin inhibitors. Based on the X-ray crystal structure of the peptide thrombin inhibitor NAPAP in a bovine thrombin complex, we designed a novel class of non-peptide inhibitors with a 1,2,5-trisubstituted benzimidazole central backbone. Supported by a series of X-ray structural analyses, we optimized the activity of these compounds. Thrombin inhibition was achieved at low nanomolar concentrations, although the binding energy primarily stemmed from nonpolar hydrophobic interactions. To improve in vivo efficacy, we increased the overall hydrophilicity of the molecule by introducing a carboxylic acid group. The highly polar compound 24 (BIBR 953/dabigatran ester) exhibited the best activity in vivo. The zwitterionic molecule was converted into a dual prodrug 31 (BIBR 1048), which showed potent oral activity in different animal species. Based on these results, we selected compound 31 for clinical development. [1] Dabigatran etexilate is a novel oral direct thrombin inhibitor that can safely and effectively reduce the risk of stroke in patients with atrial fibrillation. There are currently no relevant data after mechanical heart valve replacement. We tested the hypothesis that dabigatran etexilate is comparable to heparin in the prevention of thrombosis in mechanical valves using a porcine ectopic aortic valve model. [4] The novel direct thrombin inhibitor dabigatran etexilate was effective in the short-term prevention of thrombosis in mechanical heart valves in our established porcine model. These animal data provide further support for evaluating dabigatran etexilate as a warfarin replacement therapy in clinical trials for appropriately selected patients with bileaflet mechanical aortic valves. [4]

C35H45N7O8S

723.846

723.305

C, 58.08; H, 6.27; N, 13.55; O, 17.68; S, 4.43

872728-81-9

Dabigatran;211914-51-1;Dabigatran-d4 hydrochloride;Dabigatran etexilate;211915-06-9;Dabigatran (ethyl ester);429658-95-7

135566083

White to yellow solid powder

6.96

4

12

18

51

1080

0

O=C(NC(C1C=CC(NCC2N(C)C3C(=CC(C(N(CCC(OCC)=O)C4C=CC=CN=4)=O)=CC=3)N=2)=CC=1)=N)OCCCCCC.O=S(C)(O)=O

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

Dabigatran etexilate mesylate; BIBR-1048MS; Dabigatran etexilate mesylate; Dabigatran etexilate mesilate; 872728-81-9; BIBR 1048 MS; SC7NUW5IIT; BIBR-1048-MS; UNII-SC7NUW5IIT; BIBR 1048MS; BIBR-1048MS; BIBR1048MS; BIBR-1048; BIBR1048; BIBR 1048; band name: Pradaxa

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO: 25~100 mg/mL (34.5~138.2 mM)
Ethanol: ~20 mg/mL (~27.6 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.45 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 (3.45 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (3.45 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.)