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

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 10mg) 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 20.4h. 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 2210ng/mL for activated clotting time and anti-factor Xa activity, respectively. These results warranted further clinical development of EP217609. • 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. • 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.