title: Pharmacodynamic markers in the early clinical assessment of otamixaban, a direct factor Xa inhibitor.
abstract: 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.
authors.affiliation: Sanofi-aventis, Science and Medical Affairs, Bridgewater, New Jersey 08807-0800, USA. anne.paccaly@sanofi-aventis.com
authors.forename: Anne
authors.initials: A
authors.lastname: Paccaly
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Ozoux
authors.forename: Valeria
authors.initials: V
authors.lastname: Chu
authors.forename: Kelly
authors.initials: K
authors.lastname: Simcox
authors.forename: Vanessa
authors.initials: V
authors.lastname: Marks
authors.forename: Geneviève
authors.initials: G
authors.lastname: Freyburger
authors.forename: Michel
authors.initials: M
authors.lastname: Sibille
authors.forename: Umesh
authors.initials: U
authors.lastname: Shukla
mesh_terms: D000293:Adolescent; D000328:Adult; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013917:Thrombin / Q000378:metabolism
chemical_list: D003497:Cyclic N-Oxides; D065427:Factor Xa Inhibitors; D011725:Pyridines; D013917:Thrombin; D015951:Factor Xa; C435830:otamixaban