Summary

This manuscript reports the assessment of pharmacodynamic (PD) markers of anti-coagulation in the first-in-man study with the novel direct Factor Xa (FXa) inhibitor, otamixaban, with a brief description of safety and pharmacokinetic (PK) findings. The study comprised ten consecutive parallel groups of healthy male subjects (6 active, 2 placebo per group). Eight groups received escalating intravenous doses of otamixaban as 6-hour infusions (1.7 to 183 µ g/kg/h) and two groups received a bolus dose (30 or 120 µ g/kg) with a 6-hour infusion (60 or 140 µ g/ kg/h, respectively). PD markers included anti-FXa activity and clotting time measurements, i.e. activated Thromboplastin Time (aPTT), ProthrombinTime (PT), Heptest ? ClottingTime (HCT), and Russell’s Viper Venom-induced clotting Time (RVVT). In ad dition, Endogenous Thrombin Potential (ETP) was assessed in the bolus-plus-infusion dose groups.Otamixaban was well tolerated. Otamixaban plasma concentrations increased with escalating dose, were maximal at the end-of-infusion (Ceoi), and decreased rapidly as the infusion was stopped. Anti-FXa activity coincided with otamixaban plasma concentrations and clotting time measurements followed the same pattern. Maximal changes from baseline at C eoi were 1.9 ± 0.2 for aPTT, 2.0 ± 0.2 for PT, 5.1 ± 0.6 for HCT, and 4.5 ± 1.2 for RVVT. Otamixaban inhibited thrombin generation (24% decrease in ETP) and a delay in thrombin generation was noticed in vitro at high concentrations.