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A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatranFinancial support: This study was funded by Boehringer Ingelheim Pharma GmbH & Co. KG.
23 December 2014
Accepted after major revision: 20 February 2015
24 November 2017 (online)
Idarucizumab, a monoclonal antibody fragment that binds dabigatran with high affinity, is in development as a specific antidote for dabigatran. In this first-in-human, single-rising-dose study, we investigated the pharmacokinetics, safety and tolerability of idarucizumab. Healthy male volunteers aged 18–45 years received between 20 mg and 8 g idarucizumab as a 1-hour intravenous infusion in 10 sequential dose groups, or 1, 2 or 4 g idarucizumab as a 5-minute infusion. Subjects within each dose group were randomised 3:1 to idarucizumab or placebo. A total of 110 randomised subjects received study drug (27 placebo, 83 idarucizumab). Peak and total exposure to idarucizumab increased proportionally with dose. Maximum plasma concentrations were achieved near the end of infusion, followed by a rapid decline, with an initial idarucizumab half-life of ∼45 minutes. For the 5-minute infusions, this resulted in a reduction of plasma concentrations to less than 5 % of peak within 4 hours. Idarucizumab (in the absence of dabigatran) had no effect on coagulation parameters or endogenous thrombin potential. Overall adverse event (AE) frequency was similar for idarucizumab and placebo, and no relationship with idarucizumab dose was observed. Drug-related AEs (primary endpoint) were rare (occurring in 2 placebo and 3 idarucizumab subjects) and were mostly of mild intensity; none of them resulted in study discontinuation. In conclusion, the pharmacokinetic profile of idarucizumab meets the requirement for rapid peak exposure and rapid elimination, with no effect on pharmacodynamic parameters. Idarucizumab was safe and well tolerated in healthy males.
Clinical trial registration: http://clinicaltrials.gov/ct2/show/NCT01688830?term=NCT01688830&rank=1 (NCT01688830).
* These authors contributed equally.
- 1 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
- 2 Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342-2352.
- 3 Schulman S, Kakkar AK, Goldhaber SZ. et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129: 764-772.
- 4 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363: 1875-1876.
- 5 Friedman RJ, Dahl OE, Rosencher N. et al. Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials. Thromb Res 2010; 126: 175-182.
- 6 Majeed A, Hwang HG, Connolly SJ. et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation 2013; 128: 2325-2332.
- 7 Heidbuchel H, Verhamme P, Alings M. et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013; 34: 2094-2106.
- 8 Bauer KA. Reversal of antithrombotic agents. Am J Hematol 2012; 87 (Suppl. 01) S119-S126.
- 9 van Ryn J, Stangier J, Haertter S. et al. Dabigatran etexilate - a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116-1127.
- 10 Schiele F, van Ryn J, Canada K. et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013; 121: 3554-3562.
- 11 van Ryn J, Litzenburger T, Schurer J. Reversal of anticoagulant activity of dabigatran and dabigatran-induced bleeding in rats by a specific antidote (antibody fragment). Circulation 2012; 126: A9928.
- 12 Grottke O, Honickel M, van Ryn J. et al. A specific antidote to dabigatran reduces blood loss in dabigatran- and trauma-induced bleeding in pigs. J Am Coll Cardiol 2014; 63: (12_S).
- 13 Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47: 285-295.
- 14 Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012; 23: 138-143.
- 15 Meibohm B, Zhou H. Characterizing the impact of renal impairment on the clinical pharmacology of biologics. J Clin Pharmacol 2012; 52: 54S-62S.
- 16 Christensen EI, Birn H, Storm T. et al. Endocytic receptors in the renal proximal tubule. Physiology 2012; 27: 223-236.
- 17 Behr TM, Sharkey RM, Juweid ME. et al. Reduction of the renal uptake of radiolabeled monoclonal antibody fragments by cationic amino acids and their derivatives. Cancer Res 1995; 55: 3825-3834.
- 18 Behr TM, Becker WS, Sharkey RM. et al. Reduction of renal uptake of monoclonal antibody fragments by amino acid infusion. J Nucl Med 1996; 37: 829-833.
- 19 Reilly PA, Lehr T, Haertter S. et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63: 321-328.