title: Neutralization of EP217609, a new dual-action FIIa/FXa anticoagulant, by its specific antidote avidin: a phase I study.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  BACKGROUND
  EudraCT number 2010-020216-10.
authors.affiliation: Haemostasis Department, University Hospital Pontchaillou, 2 rue Henri Le Guilloux, 35033, Rennes Cedex, France. pierre.gueret@chu-rennes.fr.|GETBO EA 3878, Brest, France. pierre.gueret@chu-rennes.fr.
authors.forename: P
authors.initials: P
authors.lastname: Gueret
authors.affiliation: University Hospital Cochin, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Combe
authors.affiliation: Endotis Pharma, Romainville, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Krezel
authors.affiliation: EMF Consulting, Aix en Provence, France.
authors.forename: E
authors.initials: E
authors.lastname: Fuseau
authors.affiliation: Van Giersbergen Consulting, Wuenheim, France.
authors.forename: P L M
authors.initials: PL
authors.lastname: van Giersbergen
authors.affiliation: Endotis Pharma, Romainville, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Petitou
authors.affiliation: Endotis Pharma, Romainville, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Neuhart
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000931:Antidotes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001360:Avidin / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001710:Biotin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D001780:Blood Coagulation Tests; D003435:Crotalid Venoms / Q000037:antagonists & inhibitors; D015951:Factor Xa; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D009844:Oligosaccharides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D000931:Antidotes; D003435:Crotalid Venoms; C547750:EP 217609; D009844:Oligosaccharides; D001360:Avidin; D001710:Biotin; D015951:Factor Xa; C478420:FIIa; D008666:Metalloendopeptidases
keywords: Avidin; Dual thrombin and indirect Xa inhibition; EP217609; Healthy subjects; Pharmacokinetics and pharmacodynamics; Reversal