First in man study of EP217609, a new long-acting, neutralisable parenteral antithrombotic with a dual mechanism of action.
EP217609 is a parenteral antithrombotic compound combining in one molecule an indirect anti-factor Xa inhibitor, a direct thrombin active site inhibitor and a biotin moiety.


OBJECTIVE
The aim of the study is to investigate the safety, pharmacokinetics and pharmacodynamics of single ascending intravenous doses of EP217609.


METHODS
In this randomised double-blind placebo-controlled study, healthy male subjects were administered intravenously single ascending doses (1, 3 or 10 mg) of EP217609 or placebo. Each treatment group consisted of 10 subjects of whom 8 received EP217609 and 2 received placebo.


CONCLUSIONS
All doses of EP217609 were well tolerated. A total of five treatment-emergent adverse events were reported, all considered unrelated, but no bleedings or other significant adverse events occurred during this study. In both plasma and urine, there was a strong correlation between EP217609 concentrations as measured by anti-factor IIa and Xa specific bioassays indicating that the two pharmacological activities of EP217609 did not dissociate in vivo. EP217609 pharmacokinetics were dose proportional and characterised by a low clearance, a small volume of distribution and a terminal half-life of 20.4 h. The long half-life was reflected in long-lasting, dose-dependent effects on activated and ecarin clotting time, thrombin and prothrombin time, activated partial thromboplastin time, thrombin generation time and anti-factor Xa activity. Pharmacokinetic/pharmacodynamic modelling indicated that the concentration of EP217609 producing 50 % of the pharmacodynamic effect was 3400 and 2210 ng/mL for activated clotting time and anti-factor Xa activity, respectively. These results warranted further clinical development of EP217609.


BACKGROUND
• There is a limited number of neutralisable anticoagulants, particularly when rapid neutralisation is required. • Synthetic anti-Xa compounds have predictable pharmacokinetic profiles. However, problems with thrombin rebound remain because of the inability to inhibit clot-bound thrombin.


CONCLUSIONS
• This manuscript provides a comprehensive investigation of the pharmacokinetics, pharmacodynamics and safety of EP217609, and the results were the basis of future clinical studies in both healthy subjects and patients. • The pharmacokinetic/pharmacodynamic modelling provided information for dose selection in such future studies.
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.
Pierre
P
Gueret
University Hospital Cochin, Paris, France.
S
S
Combe
Endotis Pharma, Romainville, France.
C
C
Krezel
EMF Consulting, Aix en Provence, France.
E
E
Fuseau
Van Giersbergen Consulting, Wuenheim, France.
P L M
PL
van Giersbergen
Endotis Pharma, Romainville, France.
M
M
Petitou
Endotis Pharma, Romainville, France.
E
E
Neuhart
D000293:Adolescent; D000328:Adult; D000991:Antithrombins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D001710:Biotin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D001780:Blood Coagulation Tests; D004311:Double-Blind Method; D015951:Factor Xa / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009844:Oligosaccharides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D013917:Thrombin / Q000378:metabolism; D055815:Young Adult
D000991:Antithrombins; C547750:EP 217609; D009844:Oligosaccharides; D001710:Biotin; D013917:Thrombin; D015951:Factor Xa
Dual thrombin and indirect Xa inhibition; EP217609; First in man; Healthy subjects; Pharmacokinetics and pharmacodynamics