Neutralization of EP217609, a new dual-action FIIa/FXa anticoagulant, by its specific antidote avidin: a phase I study

• Published in: European journal of clinical pharmacology 2017, Vol.73 (1), p.15-28
• Main Authors: Gueret, P., Combe, S., Krezel, C., Fuseau, E., van Giersbergen, P. L. M., Petitou, M., Neuhart, E.
• Format: Article
• Language: English
• Subjects: Adult; Anticoagulants; Anticoagulants - adverse effects; Anticoagulants - blood; Anticoagulants - pharmacokinetics; Anticoagulants - pharmacology; Antidotes - adverse effects; Antidotes - pharmacokinetics; Antidotes - pharmacology; Avidin - adverse effects; Avidin - blood; Avidin - pharmacokinetics; Avidin - pharmacology; Biomedical and Life Sciences; Biomedicine; Biotin - adverse effects; Biotin - analogs & derivatives; Biotin - blood; Biotin - pharmacokinetics; Biotin - pharmacology; Blood Coagulation Tests; Clinical Trial; Crotalid Venoms - antagonists & inhibitors; Factor Xa; Health; Humans; Kinetics; Male; Metalloendopeptidases - antagonists & inhibitors; Oligosaccharides - adverse effects; Oligosaccharides - blood; Oligosaccharides - pharmacokinetics; Oligosaccharides - pharmacology; Pharmacology; Pharmacology/Toxicology; Young Adult
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-016-2143-9

Introduction EP217609 is a representative of a new class of synthetic parenteral anticoagulants with a dual mechanism of action. It combines in a single molecule a direct thrombin inhibitor and an indirect factor Xa inhibitor. EP217609 can be neutralized by a specific antidote avidin, which binds to the biotin moiety of EP217609. Purpose The primary objective was to assess the neutralization of EP217609 by avidin in healthy subjects. Secondary objectives were to define the optimal avidin monomer/EP217609 molar ratio to achieve an adequate neutralization of EP217609 and to assess the safety and tolerability of EP217609 and avidin. Methods Healthy subjects ( n  = 36) were randomized to a 3 by 3 replicated Latin square design between 3 EP217609 doses (4, 8, 12 mg) and 3 avidin monomer/EP217609 molar ratios (1:1; 2:1; 3:1). EP217609 was administered as a single intravenous bolus, and avidin as a 30-min intravenous infusion, starting 90 min after EP217609 administration. Results Overall, EP217609 and avidin were well tolerated. One subject experienced a benign and transient typical pseudo-allergic reaction. The administration of EP217609 resulted in dose-dependent increases in pharmacodynamic markers. Avidin triggered a rapid and irreversible neutralization of EP217609 without rebound effect. Adequate neutralization of the anticoagulant activity was achieved with both 2:1 and 3:1 avidin monomer/EP217609 molar ratios. All safety parameters did not show any treatment-emergent clinically relevant changes or abnormalities in any dose group. Conclusions These results will allow further investigation in patients requiring a neutralizable anticoagulant as those undergoing cardiac surgery. Study registration EudraCT number 2010-020216-10.