Dabigatran etexilate

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Structural formula
Structural formula of dabigatran etexilate
General
Non-proprietary name Dabigatran etexilate
other names

Ethyl-3 - {[(2 - {[(4- { N '- [(hexyloxy) -carbonyl] carbamimidoyl} -phenyl) -amino] -methyl} -1-methyl-1 H -benzimidazol-5-yl) carbonyl] (2-pyridinyl) amino} propanoate

Molecular formula
  • C 34 H 41 N 7 O 5 (dabigatran etexilate)
  • C 25 H 25 N 7 O 3 (dabigatran)
External identifiers / databases
CAS number
  • 211915-06-9 (dabigatran etexilate)
  • 211914-51-1 (dabigatran)
EC number 606-722-8
ECHA InfoCard 100.126.485
PubChem 9578572
ChemSpider 4948999
DrugBank DB06695
Wikidata Q20078502
Drug information
ATC code

B01 AE07

Drug class

Direct thrombin inhibitor

properties
Molar mass 627.73 g · mol -1
Melting point
  • 128-129 ° C (dabigatran etexilate)
  • 276–277 ° C (dabigatran)
pK s value
  • pK S 1 = 4.0
  • pK S 2 = 6.7
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS hazard labeling
no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Dabigatran etexilate is a drug from the group of anticoagulants ( anticoagulants ); more precisely the non-peptide thrombin inhibitors. The substance is a prodrug which, after being converted into the pharmacologically active dabigatran, directly inhibits blood coagulation factor IIa ( thrombin ). After ingestion, the substance is filtered from the blood in the kidneys and eliminated in the urine, which is why dabigatran etexilate is not suitable as an anticoagulant for patients with renal insufficiency.

Dabigatran etexilate is suitable for oral administration and in this form (trade name Pradaxa ; manufacturer Boehringer Ingelheim ) approved in the EU for the prevention of blood clots in the veins after elective surgical knee or hip replacement, and since 2011 also for stroke prevention in patients with atrial fibrillation and risk of stroke.

Pharmacological properties

Dabigatran etexilate itself is pharmacologically inactive. After absorption , the active form dabigatran is produced in the plasma and liver by hydrolysis of the prodrug form catalyzed by esterases . The absolute bioavailability after oral administration is around 6.5%, maximum plasma levels are reached after 0.5 to 2 hours. The terminal half-life of dabigatran was on average 12-14 hours (healthy subjects) and 14-17 hours (patients after major orthopedic surgery).

Dabigatran binds competitively and reversibly directly to thrombin and blocks its effect, so that the conversion of fibrinogen to fibrin and thus the formation of clots does not occur. Dabigatran thus also prevents the thrombin-induced clumping of blood platelets ( thrombocyte aggregation ). The anticoagulant effect of dabigatran correlates with its concentration in the plasma: the therapeutic concentration is 0.05-0.1 mg / l, measurable as 10-20% of the norm in the new F10a / F2a coagulation test EXCA ( extrinsic coagulation activity assay ).

In vitro interaction studies showed that dabigatranneither inhibits nor inducesthe major cytochromes P450 . Dabigatran is mainly excreted unchanged in the urine.

Clinical information

application

Dabigatran etexilate is approved for use in adults. The substance is given twice a day in a fixed daily dose; coagulation monitoring is not necessary.

Elderly patients over 75 years of age should be treated with caution as clinical data are limited in this age group. Patients with mild to moderate renal insufficiency and patients taking amiodarone should be treated with caution and at a reduced dose. Due to the lack of data on safety and efficacy, Pradaxa is not recommended for use in patients under 18 years of age. There are insufficient data from the use of dabigatran etexilate in pregnant women. Women of childbearing potential should therefore avoid pregnancy during treatment with the agent, and dabigatran etexilate should not be used if possible if pregnant. Breastfeeding women should discontinue breastfeeding during treatment with dabigatran etexilate.

Treatment with dabigatran etexilate should be started for anesthesia procedures close to the spinal cord such as spinal anesthesia or epidural anesthesia at the earliest four to six hours after the puncture or after the catheter has been removed and if the neurological findings are normal. At least 34 hours should have elapsed since the last dose of dabigatran etexilate before spinal cord anesthesia.

Contraindications

Treatment with dabigatran etexilate is contraindicated in acute bleeding, severe renal insufficiency ( creatinine clearance below 30 milliliters / minute), impaired liver function, artificial heart valve with anticoagulant therapy. A determination of the creatinine clearance is always necessary before the start of treatment, and kidney function must be adequately monitored during treatment.

Side effects

The most common side effects are bleeding. The RE-LY study showed that the overall risk of severe bleeding is lower with the administration of dabigatran etexilate compared to warfarin . In severe bleeding, those with a fatal outcome treated with dabigatran etexilate at a dose of 150 mg twice daily have a comparable risk (0.23% per year) to treatment with warfarin (0.33% per year), but a lower risk Dose (110 mg dabigatran etexilate twice daily) the risk is lower (0.19% per year) than with warfarin. The relative bleeding risk for dabigatran etexilate versus warfarin increases with age or with impaired renal function , which must be taken into account in the risk-benefit assessment . The number of red blood cells in the blood may decrease.

In September 2013, the manufacturers of the "new oral anticoagulants" ( apixaban , dabigatran etexilate and rivaroxaban ) pointed out in a joint information letter agreed with the responsible pharmaceutical authorities that reports of adverse drug reactions (ADRs) from clinical studies and from practice have shown that Even with the new oral anticoagulants, there is a significant risk of severe bleeding events, including death. In order to minimize the risk of bleeding, the prescribing physicians must individually assess the risk of bleeding of the patient and observe the information on dosage and contraindications as well as warnings and precautionary measures. Common to all new oral anticoagulants are the following contraindications:

  • acute, clinically relevant bleeding
  • Lesions or clinical situations considered to be a significant risk factor for major bleeding
  • simultaneous use of other anticoagulants such as heparins or vitamin K antagonists (with a few exceptions).

Kidney dysfunction can also be a contraindication, but different recommendations apply to the three drugs.

One problem is the treatment of acute bleeding in the context of accidents. However, since Pradaxa is the only one of the "new oral anticoagulants" to have an antidote ( idarucizumab , trade name: Praxbind ) available, which cancels the effect of the drug within a few minutes, this offers an opportunity to minimize acute bleeding. This antidote can also be used in the context of planned operations.

Interactions with other means

The simultaneous use of other blood coagulation inhibitors (e.g. warfarin , heparins ) or non-steroidal anti-inflammatory drugs can lead to a risk of bleeding, as the anticoagulant effects add up.

Dabigatran etexilate competes with some drugs for the efflux transporter P-glycoprotein , which increases serum levels. It is therefore contraindicated if quinidine , ketoconazole , itraconazole , cyclosporine or tacrolimus are taken at the same time ; if verapamil is taken, the dabigatran dose should be reduced. In contrast, rifampicin , carbamazepine and ingredients from St. John's wort induce the P-glycoprotein, so that the dabigatrans serum levels are lowered. Dabigatran and its prodrug dabigatran etexilate showed no in vitro effects on human cytochrome P450 enzymes; Studies have confirmed that there is no degradation via the cytochrome P450 system in vivo either .

Cancellation of the anticoagulant

In a two-arm prospective cohort study in 2015, an almost complete antagonization could be achieved for the first time by the intravenous bolus administration of 5 g idarucizumab. The changed coagulation values ​​under dabigatran normalized within a few minutes in 88% and 98% of the patients, respectively. The antagonist is a monoclonal antibody fragment that binds dabigatran with an affinity 350 times higher than that of thrombin and thus neutralizes it, without a procoagulant effect. Since the mortality in this study with dabigatran-associated acute bleeding events was very high at 20% and there was no placebo control, the clinical significance of this antagonist was initially not clear. Idarucizumab has been approved throughout the EU since November 2015 to cancel the anticoagulant effects of dabigatran, for example in the case of uncontrollable or life-threatening bleeding or before emergency operations.

Studies

The effectiveness of Pradaxa was examined in two randomized, double-blind parallel group studies with a total of almost 5600 patients who underwent knee or hip replacement surgery. Patients received 150 or 220 mg dabigatran etexilate orally or 40 mg enoxaparin subcutaneously once daily . The primary endpoint was the combination of the total number of venous thromboembolism (VTE) and the total mortality ; a secondary endpoint was the combination of severe VTE and VTE-related mortality.

In both studies, dabigatran etexilate was shown to be as effective as enoxaparin in preventing blood clots and preventing death:

  • In the study with patients after knee replacement, almost 38% suffered a blood clot taking enoxaparin, compared to 36% taking 220 mg dabigatran etexilate and 40% taking 150 mg dabigatran etexilate. There was one death in each group.
  • In the study with patients after hip replacement, almost 7% suffered a blood clot taking enoxaparin, compared to 6% taking 220 mg dabigatran etexilate and 8.7% taking 150 mg dabigatran etexilate.

In both studies, the 220 mg dose tended to be more effective than the 150 mg dose.

There were no significant differences between dabigatran etexilate and enoxaparin with regard to the occurrence of profuse bleeding, increased liver enzyme levels and acute coronary events.

In the indication of atrial fibrillation, dabigatran was compared with warfarin, which is common in the USA, in the RELY study, which was completed in 2009. A comparative study on phenprocoumon, which is increasingly used in Europe, does not exist.

A study for the use in heart valve patients was canceled and the European Medicines Agency (EMA), like the US drug authority FDA, declared the use in these patients to be contraindicated.

Other Information

Chemical-pharmaceutical information

The mesilate ( methanesulfonic acid salt) of dabigatran etexilate is used pharmaceutically . The solubility of the salt, a yellowish to yellow solid, in an aqueous medium is strongly dependent on the pH value and increases with acidic pH values, the solubility in water is 1.8 mg / ml. Dabigatran etexilate mesilate is easily soluble in methanol , soluble in ethanol , slightly soluble in isopropanol , very slightly soluble in acetone and practically insoluble in ethyl acetate . Dabigatran etexilate mesilate has no chiral centers and is polymorphic ; two modifications are known. In the commercial synthesis the modification I arises in the anhydrous form.

development

Boehringer Ingelheim began the search for a low molecular weight, orally administrable active ingredient in 1992 on the basis of the structure of the peptidic thrombin inhibitor N -α- (2-naphthylsulfonylglycyl) -4-amidinophenylalanine piperidine (α-NAPAP). Starting with a three-substituted benzimidazole as the basic structure, the molecule was gradually approximated to an optimal conformation and affinity for binding to thrombin. The resulting strongly polar and therefore poorly resorbable dabigatran was modified by the introduction of two protective groups (esterified carboxy group and O - n -hexyl carbamate group ) in such a way that it is sufficiently orally bioavailable. "Etexilat" is an artificial word made up of the two reactants ethanol and hexanoic acid . From 1996 the anticoagulant effect of dabigatran was investigated in vitro and in animal models, and clinical studies began in the late 1990s. In March 2008, Pradaxa was approved for the European market by the EU Commission , followed by approval of additional indications in August 2011.

criticism

In the period from March 2008 to November 2011, 260 people worldwide died while taking the drug. Patients with kidney failure in particular died because the active ingredient dabigatran etexilate, which is removed from the blood via the kidneys and then via the urine, could not be filtered out of the blood. A bruise that was otherwise classified as harmless led to internal bleeding and even death, as the bleeding could not be stopped in time. According to a study by the American health authority FDA from May 2014, in which 134,000 patients were examined, the risk of death as well as the risk of stroke and cerebral haemorrhage with Pradaxa is compared to coumarin (in this case the coumarin used in the USA warfarin - in Germany rather Marcumar administered) but less. However, the study also showed that gastrointestinal bleeding was more common with dabigatran. More than 2000 plaintiffs in the USA blamed the pharmaceutical company Boehringer Ingelheim for severe and sometimes fatal bleeding caused by Pradaxa. Instead of the compensation lawsuit scheduled for September 2014, Boehringer has previously concluded a settlement for the sum of 650 million dollars (about 470 million euros) in order to avoid years of litigation and the "imponderables of the US legal system".

Drug Prescription Report

In the drug prescription report for 2008, dabigatran etexilate was given the rating B (= improvement of pharmacodynamic or pharmacokinetic properties ). Of 29 drugs newly approved in 2008, 7 were rated A (= innovative structure with therapeutic relevance ), 6 were rated B (= improvement in pharmacodynamic or pharmacokinetic properties ), 15 were rated C (= analog preparation with no or only minor differences ) and one received the rating D (= insufficiently assured active principle or unclear therapeutic value ).

Web links

Individual evidence

  1. ↑ a b N. H. Hauel, H. Nar, H. Priepke, U. Ries, JM Stassen, W. Wienen: Structure-based design of novel potent nonpeptide thrombin inhibitors. In: J. Med. Chem. 45 (9), 2002, pp. 1757-1766. PMID 11960487 .
  2. ↑ a b c d Assessment report (English; PDF; 281 kB) of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency at Pradaxa, as of March 2008.
  3. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
  4. ↑ a b Stroke prevention: Pradaxa receives EU approval. In: Pharmaceutical newspaper . August 5, 2011.
  5. ↑ New drugs (PDF; 382 kB), information from the drug commission of the German medical profession (AkdÄ), November 18, 2011.
  6. ↑ a b c d Product information from the European Medicines Agency on Pradaxa , as of August 2011.
  7. ↑ Wiebke Gogarten, Hugo K. Van Aken: Perioperative thrombosis prophylaxis - platelet aggregation inhibitors - importance for anesthesia. In: AINS - Anesthesiology · Intensive Care Medicine · Emergency Medicine · Pain Therapy. No. 4, April 2012, pp. 242-254. doi: 10.1055 / s-002-23167 .
  8. ↑ SA Kozek-Langenecker, D. Fries, M. Gütl, N. Hofmann, P. Innerhofer, W. Kneifl, L. Neuner, P. Perger, T. Pernerstorfer, G. Pfanner and others: Locoregional anesthesia with anticoagulant medication. Recommendations of the Perioperative Coagulation Working Group (AGPG) of the Austrian Society for Anaesthesiology and Intensive Care Medicine (ÖGARI). In: The anesthesiologist. Vol. 54, No. 5, 2005, pp. 476-484. doi: 10.1007 / s00101-005-0827-0 .
  9. ↑ Rote-Hand-Brief on Pradaxa of January 7, 2013, accessed on March 19, 2016.
  10. ↑ Red Hand Letter from Boehringer Ingelheim on October 27, 2011. (PDF; 497 kB) Accessed on October 28, 2011 .
  11. ↑ Product information Pradaxa 150 mg hard capsules, as of August 2011.
  12. ↑ Information letter on risk factors for the occurrence of bleeding from September 5, 2013. (PDF; 2.5 MB) Retrieved on September 9, 2013 .
  13. ↑ Blood coagulation: Dabigatran antidote is approved. Retrieved August 28, 2017 .
  14. ^ Charles V. Pollack, Paul A. Reilly, John Eikelboom, Stephan Glund, Peter Verhamme, Richard A. Bernstein, Robert Dubiel, Menno V. Huisman, Elaine M. Hylek, Pieter W. Kamphuisen, Jörg Kreuzer, Jerrold H. Levy , Frank W. Sellke, Joachim Stangier, Thorsten Steiner, Bushi Wang, Chak-Wah Kam, Jeffrey I. Weitz: Idarucizumab for Dabigatran Reversal. In: New England Journal of Medicine . 215, Volume 373, No. 6, August 6, 2015, pp. 511-520, doi: 10.1056 / NEJMoa1502000 .
  15. ↑ Stroke prevention: First specific antidote to cancel the effect of Pradaxa® (dabigatran) approved in the EU on November 26, 2015. Archived from the original on December 8, 2015 ; accessed on November 28, 2015 .
  16. ↑ Summary of Product Characteristics , EMA, accessed May 23, 2017.
  17. ↑ Dabigatran versus Warfarin in Patients with Atrial Fibrillation. NEJM, September 2009, doi: 10.1056 / NEJMoa0905561 .
  18. ↑ Pradaxa: Explicit contraindication for artificial heart valves. In: Deutsches Ärzteblatt. January 9, 2013.
  19. ^ NH Hauel, H. Nar, H. Priepke, U. Ries, JM Stassen, W. Wienen: Structure-based design of novel potent nonpeptide thrombin inhibitors. ] In: J. Med. Chem. 45 (9), 2002, pp. 1757-1766. PMID 11960487 .
  20. ↑ New indications in sight. In: Pharmaceutical newspaper . No. 14, 2009.
  21. ↑ Pradaxa is no more dangerous than other blood thinners. In: time online. November 14, 2011.
  22. ↑ US Department of Health and Human Services: FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa (dabigatran) compared to warfarin. 2014.
  23. ^ Stroke remedy Pradaxa: wave of lawsuits flooded Boehringer. n-tv, February 13, 2014, accessed on July 17, 2014 .
  24. ↑ Boehringer pays $ 650 million. In: WirtschaftsWoche Online. May 28, 2014, accessed October 24, 2014 .
  25. ^ U. Schwabe, D. Paffrath: Drug Ordinance Report 2009. Springer Medizin Verlag, Heidelberg 2009.