EP42675, a New Dual Action Anticoagulant: Pharmacodynamic and Pharmacokinetic Profile, and Interactions with Acetylsalicylic Acid, Clopidogrel, and Unfractionated Heparin.

Abstract 2090

Poster Board II-67

EP42675 is the first representative of a new class of synthetic parenteral anticoagulants with a dual mechanism of action. EP42675 is an indirect factor Xa inhibitor (antithrombin binding pentasaccharide: fondaparinux analog) and a direct free and clot-bound thrombin (factor IIa) active site inhibitor (peptidomimetic: α-NAPAP analog). EP42675 was assessed in two phase I trials: (i) a randomized double-blind placebo-controlled single ascending dose study, where a single intravenous (IV) bolus of 1, 3, or 10 mg was administered to 3 groups of healthy male subjects (6 EP42675 and 2 matching placebo per group); (ii) a study assessing the effect of acetylsalicylic acid (ASA) plus clopidogrel, and unfractionated heparin (UFH) on pharmacokinetics (PK) and pharmacodynamics (PD) of EP42675. In this study, 24 healthy male subjects received 5 mg of EP42675 as an IV bolus on day 1, then ASA 100 mg and 75 mg clopidogrel from day 8 to 21. On day 15, they received a second IV bolus of 5 mg of EP42675 and were immediately randomized in 3 groups to receive either placebo, UFH 30 IU/Kg or UFH 60 IU/Kg, thus mimicking the rescue use of UFH in complicated percutaneous coronary interventions (PCI). EP42675 plasma concentrations were measured using anti-Xa and anti-IIa activity specific bioassays (Biomnis, France). EP42675 PD was assessed by global: thrombin generation test (TGT) and activated clotting time (ACT: ACT+ cartridge, Hemochron Signature Elite®, Gamida), and specific coagulation tests performed on a STA-R Evolution® automaton: prothrombin time (PT: Neoplastine CI plus Diagnostica Stago), activated partial thromboplastin time (aPTT: PTTA Diagnostica Stago), ecarin clotting time (ECT: Ecarine Diagnostica Stago), anti Xa activity expressed as ΔDO/min (Biophen Heparin Hyphen Biomed®), and thrombin time using purified human alpha thrombin (TT: Hemoclot Thrombin Inhibitors, Hyphen Biomed®). TGT performed on platelet poor plasma (PPP) were triggered with PPP reagent high (20 pM recombinant human tissue factor and 4 μM phospholipids, Biodis) on a Calibrated Automated Thrombogram (CAT^™: Diagnostica Stago). The EP42675 plasma concentrations, measured by both anti-IIa and anti-Xa bioassays, showed a high and significant correlation (r=0.99, p<0.0001) indicating that the two active moieties of EP42675 did not dissociate. The plasma concentration versus time curves showed a marked distribution phase followed by a slow terminal phase and a less than proportional increase in exposure with increasing dose, with a half-life between 44.1 and 55.3 hours. EP42675 increased ACT, TGT lag time, TT, aPTT, PT, ECT, and anti-Xa activity. Maximum anticoagulant effect was reached within 2 minutes after bolus injection and lasted for more than 72 hours. The higher sensitivity of the TT test compared to the ECT test is explained by the higher selectivity of the EP42675 antithrombin moiety for the human alpha thrombin. A decrease in TGT endogenous thrombin potential was observed with a complete inhibition of thrombin generation at peak in the 10 mg dose group. The apparent lack of dose response at lower concentrations is likely to be due to interactions between the EP42675 antithrombin moiety with the alpha2 macroglobulin-thrombin complex. As anticipated, the co-administration of UFH induced a dose-dependent further increase in ACT, TGT lag time, TT, aPTT, PT, and anti-Xa activity, while the combination of ASA and clopidogrel did not influence the PK or PD of EP42675. The intra- and inter-subject variability was low for both PK and PD parameters. EP42675 was well tolerated. The only drug-related adverse events were mild hematoma at injection or blood sampling site in 6 subjects, mild gingival hemorrhage in 7 subjects, and mild epistaxis in one subject. No change in liver function tests was observed.

These data provide useful information for designing future clinical studies with a single-dose anticoagulant treatment in patients with acute coronary syndrome undergoing PCI, and treated with various combinations of antithrombotic drugs.