A randomized study in healthy volunteers to investigate the safety, tolerability & pharmacokinetics of idarucizumab, a specific antidote to dabigatran


Idarucizumab, a specific antidote to reverse dabigatran activity

Currently no specific reversal agents for any of the non-Vitamin K antagonist oral anticoagulants (NOACs) are available. To fill this gap, Stephan Glund, PhD, Senior Clinical Pharmacokineticist, Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany, and his team have worked on the development of idarucizumab, a specific reversal agent for dabigatran. Their study data provide good clinical evidence that idarucizumab may provide a valuable treatment option for use in emergency situations in patients treated with dabigatran.

In a volunteer study in healthy male volunteers, the novel agent idarucizumab was tested in doses of up to 8 g, and was well-tolerated with no clinically relevant side effects. The specific reversal agent for dabigatran was safe in healthy volunteers and may be given as a very short infusion of five minutes.  Their data indicated that idarucizumab - due to its fast availability - would rapidly neutralize the effect of dabigatran. Idarucizumab is also eliminated quickly.

"Therefore, effective anticoagulation treatment can potentially be resumed quickly as well," Glund said: "In addition, we found that idarucizumab itself did not influence normal coagulation of volunteers as determined by a panel of coagulation assays, and particularly that it had no measurable procoagulant effects." Idarucizumab is mainly excreted via the kidneys, an important elimination route for dabigatran too.

Glund's findings reveal that idarucizumab meets the criteria for an ideal specific reversal agent as it is rapidly present in plasma and thus readily available to bind to dabigatran. It also did not have any effects on thrombin generation and physiological coagulation. Thus it may neutralize dabigatran anticoagulant activity without a procoagulant effect.

The innovative agent is now being evaluated in the ongoing global RE-VERSE AD study in patients treated with dabigatran who require emergency surgical interventions or who present with an uncontrolled or life-threatening bleeding event. The study is running in more than 30 countries worldwide.

At the moment, the clinical development of idarucizumab is still in progress and the agent has not yet been approved. Idarucizumab, however, has been submitted for approval to the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA) and Health Canada. Further submissions are planned.
For now, things look very promising – we have a specific antidote to a NOAC, dabigatran.

Werner Zwick, M.A., Munich, Germany


Reference:
Glund Stephan et al.: Opens external link in new windowA randomized study in healthy volunteers to investigate the safety, tolerability & pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost 2015: 113/5 (May) pp. 911–1157


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