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.