NDLI: First in man study of EP217609, a new long-acting, neutralisable parenteral antithrombotic with a dual mechanism of action

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First in man study of EP217609, a new long-acting, neutralisable parenteral antithrombotic with a dual mechanism of action

Content Provider	Springer Nature Link
Author	Gueret, Pierre Combe, S. Krezel, C. Fuseau, E. Giersbergen, P. L. M. Petitou, M. Neuhart, E.
Copyright Year	2016
Abstract	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.The aim of the study is to investigate the safety, pharmacokinetics and pharmacodynamics of single ascending intravenous doses of EP217609.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.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.What is already known about this subject:• 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.What this study adds:• 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.
Starting Page	1041
Ending Page	1050
Page Count	10
File Format	PDF
ISSN	00316970
Journal	European Journal of Clinical Pharmacology
Volume Number	72
Issue Number	9
e-ISSN	14321041
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2016-06-03
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	EP217609 Healthy subjects Dual thrombin and indirect Xa inhibition First in man Pharmacokinetics and pharmacodynamics Pharmacology/Toxicology
Content Type	Text
Resource Type	Article
Subject	Pharmacology Pharmacology (medical)

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First in man study of EP217609, a new long-acting, neutralisable parenteral antithrombotic with a dual mechanism of action

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First in man study of EP217609, a new long-acting, neutralisable parenteral antithrombotic with a dual mechanism of action