Pharmacokinetics of otamixaban, a direct factor Xa inhibitor, in healthy male subjects: pharmacokinetic model development for phase 2/3 simulation of exposure.
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.
Paccaly
Anne
A
Sanofi Aventis, 1041 Route 202-206, PO Box 6800, Mail Stop M303A, Bridgewater, NJ 08807-0800, USA.
Frick
Annke
A
Rohatagi
Shashank
S
Liu
Jingli
J
Shukla
Umesh
U
Rosenburg
Ronald
R
Hinder
Markus
M
Jensen
Bradford K
BK
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*
D003497:Cyclic N-Oxides; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D011725:Pyridines; C435830:otamixaban