Subject(s)
Cyclic N-Oxides/administration & dosage , Pyridines/administration & dosage , Tyrosine/analogs & derivatives , Adult , Biomarkers/blood , Blood Coagulation/drug effects , Cyclic N-Oxides/pharmacokinetics , Drug Therapy, Combination , Factor Xa Inhibitors , Humans , Male , Partial Thromboplastin Time , Platelet Aggregation/drug effects , Pyridines/pharmacokinetics , Tirofiban , Tyrosine/administration & dosage , Tyrosine/pharmacokineticsABSTRACT
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 microg/kg/h) and two groups received a bolus dose (30 or 120 microg/kg) with a 6-hour infusion (60 or 140 microg/ kg/h, respectively). PD markers included anti-FXa activity and clotting time measurements, i.e. activated Thromboplastin Time (aPTT), Prothrombin Time (PT), Heptest Clotting Time (HCT), and Russell's Viper Venom-induced clotting Time (RVVT). In addition, 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 (C(eoi)), 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.
