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EP 42675, a synthetic parenteral dual‐action anticoagulant: pharmacokinetics, pharmacodynamics, and absence of interactions with antiplatelet drugs
Author(s) -
Gueret P.,
Krezel C.,
Fuseau E.,
Giersbergen P. L. M.,
Petitou M.,
Neuhart E.
Publication year - 2014
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12453
Subject(s) - pharmacodynamics , pharmacokinetics , anticoagulant , medicine , pharmacology , platelet aggregation , action (physics) , platelet , physics , quantum mechanics
Summary Background EP 42675 is a first‐in‐class, synthetic, parenteral, anticoagulant combining in a single molecule a direct thrombin inhibitor and an indirect factor Xa (FXa) inhibitor. Objectives To investigate the safety, pharmacokinetics, and pharmacodynamics of EP 42675 and its interaction with aspirin, clopidogrel, and unfractionated heparin ( UFH ). Subjects and Methods In s tudy 1, healthy male subjects were administered intravenously single‐ascending doses (1–10 mg) of EP 42675 or placebo. In s tudy 2, healthy male subjects were administered intravenously a single dose of 5 mg EP 42675 on day 1 followed by oral administration of aspirin (100 mg) and clopidogrel (75 mg) once daily from day 8 to 21. On day 15, a second dose of 5 mg EP 42675 was administered, and subjects were then randomized to receive a single dose of UFH (30 or 60 IU kg −1 ) or placebo. Results and Conclusions Mild bleedings were the only drug‐related adverse events. EP 42675 pharmacokinetics were dose‐proportional and characterized by a low clearance, a small volume of distribution, a long terminal half‐life. EP 42675 pharmacodynamics were characterized by a long‐lasting, dose‐dependent increase in activated clotting time, ecarin clotting time, thrombin time, anti‐FXa activity, activated partial thromboplastin time, prothrombin time, and a decrease in endogenous thrombin potential, measured by a thrombin generation test. Dose‐dependent additive effects were seen with UFH on coagulation tests. EP 42675 had no additive effect on the inhibition of platelet aggregation induced by aspirin and clopidogrel. These results warrant further clinical development of this new class of anticoagulant.