title: Pharmacokinetics of otamixaban, a direct factor Xa inhibitor, in healthy male subjects: pharmacokinetic model development for phase 2/3 simulation of exposure.
abstract: The pharmacokinetics of otamixaban was investigated in healthy male subjects over a wide range of intravenous doses, with duration of administration varying between 1-minute infusions (bolus dose) and 24-hour infusions, using noncompartmental and multicompartmental methods. A global compartmental analysis (2 and 3 compartments) generated a single set of pharmacokinetic parameters, regardless of infusion rate and duration, and took into account the 30% decrease in clearance and volume of distribution observed over the dose range. The 2-compartment model was retained to predict bolus plus 3-hour-infusion doses of otamixaban for future phase (2/3) studies. Otamixaban exhibited in healthy subjects several interesting pharmacokinetic features in view of its potential therapeutic use in coronary thrombosis: a rapid plasma distribution and elimination, a well-described dose-exposure relationship, a low intersubject variability in plasma exposure, and a mixed renal and biliary excretion with constant renal clearance.
authors.affiliation: Sanofi Aventis, 1041 Route 202-206, PO Box 6800, Mail Stop M303A, Bridgewater, NJ 08807-0800, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Paccaly
authors.forename: Annke
authors.initials: A
authors.lastname: Frick
authors.forename: Shashank
authors.initials: S
authors.lastname: Rohatagi
authors.forename: Jingli
authors.initials: J
authors.lastname: Liu
authors.forename: Umesh
authors.initials: U
authors.lastname: Shukla
authors.forename: Ronald
authors.initials: R
authors.lastname: Rosenburg
authors.forename: Markus
authors.initials: M
authors.lastname: Hinder
authors.forename: Bradford K
authors.initials: BK
authors.lastname: Jensen
mesh_terms: D000293:Adolescent; D000328:Adult; D001711:Biotransformation; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D003497:Cyclic N-Oxides; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D011725:Pyridines; C435830:otamixaban