title: Idarucizumab, a specific reversal agent for dabigatran: mode of action, pharmacokinetics and pharmacodynamics, and safety and efficacy in phase 1 subjects.
abstract: The direct oral anticoagulants (DOACs) provide a number of clinical advantages over vitamin K antagonists for the treatment of thromboembolism, including improved efficacy and safety, as well as no need for regular monitoring of anticoagulant effect. However, as with all anticoagulants, bleeding complications may occur, and anticoagulant reversal may be required in specific clinical situations, such as in patients experiencing spontaneous or traumatic bleeds, or in anticoagulated patients requiring emergency surgery or other invasive procedures. Therefore, several reversal agents for the DOACs are in development. This includes the specific reversal agent idarucizumab, which has been approved by the U.S. Food and Drug Administration and the European Medicines Agency for use in patients treated with dabigatran when urgent reversal of its anticoagulant effects is needed. Idarucizumab is a humanized monoclonal antibody fragment that binds with high affinity to free and thrombin-bound dabigatran, resulting in an almost irreversibly bound idarucizumab-dabigatran complex and thereby neutralizing dabigatran's anticoagulant activity. The reversal of the anticoagulant effects of dabigatran by idarucizumab has been demonstrated in animal bleeding models, in healthy volunteers with a range of ages and renal function, and in anticoagulated patients. In the phase 1 trials, at doses of 2 g or greater, idarucizumab resulted in immediate and complete reversal of the dabigatran anticoagulant effects and was well tolerated. In the absence of dabigatran, idarucizumab showed no effect on coagulation parameters or thrombin formation. These findings provide initial evidence that idarucizumab could provide a safe and effective means of reversing anticoagulant activity in patients treated with dabigatran in need of emergency surgery or in emergency bleeding situations.
authors.affiliation: Clinical Development, Cardiology, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT. Electronic address: paul.reilly@boehringer-ingelheim.com.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Reilly
authors.affiliation: Clinical Development and Medical Affairs, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany.
authors.forename: Joanne
authors.initials: J
authors.lastname: van Ryn
authors.affiliation: Department of Anesthesiology, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Grottke
authors.affiliation: Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Glund
authors.affiliation: Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Stangier
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000991:Antithrombins; D017321:Clinical Trials, Phase I as Topic; D000069604:Dabigatran / Q000037:antagonists & inhibitors*; D006801:Humans; D007668:Kidney / Q000502:physiology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000991:Antithrombins; C000594745:idarucizumab; D000069604:Dabigatran