EP42675, a synthetic parenteral dual-action anticoagulant: pharmacokinetics, pharmacodynamics, and absence of interactions with antiplatelet drugs.
BACKGROUND
EP42675 is a first-in-class, synthetic, parenteral, anticoagulant combining in a single molecule a direct thrombin inhibitor and an indirect factor Xa(FXa) inhibitor.


OBJECTIVE
To investigate the safety, pharmacokinetics, and pharmacodynamics of EP42675 and its interaction with aspirin, clopidogrel, and unfractionated heparin (UFH).


METHODS
In study 1, healthy male subjects were administered intravenously single-ascending doses (1-10 mg) of EP42675 or placebo. In study 2, healthy male subjects were administered intravenously a single dose of 5 mg EP42675 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 EP42675 was administered, and subjects were then randomized to receive a single dose of UFH (30 or 60 IU kg(-1) ) or placebo.


CONCLUSIONS
Mild bleedings were the only drug-related adverse events. EP42675 pharmacokinetics were dose-proportional and characterized by a low clearance, a small volume of distribution, a long terminal half-life. EP42675 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. EP42675 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.
University Hospital Pontchaillou, Rennes, France; GETBO EA 3878, Brest, France.
P
P
Gueret
C
C
Krezel
E
E
Fuseau
P L M
PL
van Giersbergen
M
M
Petitou
E
E
Neuhart
D000925:Anticoagulants / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004311:Double-Blind Method; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D009844:Oligosaccharides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D010919:Placebos; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
D000925:Anticoagulants; C547751:EP 42675; D009844:Oligosaccharides; D010919:Placebos; D010975:Platelet Aggregation Inhibitors
anticoagulants; antithrombins; factor Xa; pharmacokinetics; phase 1 clinical trials