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PHARMACOKINETICS

Pharmacokinetics of Otamixaban, a Direct Factor Xa Inhibitor, in Healthy Male Subjects: Pharmacokinetic Model Development for Phase 2/3 Simulation of Exposure

Anne Paccaly, PharmD, Annke Frick, PhD, Shashank Rohatagi, PhD, Jingli Liu, PhD, Umesh Shukla, PhD, Ronald Rosenburg, MD, Markus Hinder, MD and Bradford K. Jensen, PhD

From Sanofi Aventis, Science & Medical Affairs, Bridgewater, New Jersey (Dr Paccaly, Dr Rohatagi, Dr Liu, Dr Shukla, Dr Jensen), and Frankfurt, Germany (Dr Frick, Dr Rosenburg, Dr Hinder). Shashank Rohatagi is currently at Sankyo Pharma Development, Clinical Pharmacology and Pharmacokinetics, Edison, New Jersey. Umesh Shukla is currently at Johnson & Johnson, Experimental Medicine, Pharmaceutical Research & Development, Raritan, New Jersey. Anne Paccaly and Shashank Rohatagi are fellows of ACCP (FCP).

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.

Key Words: FXa inhibitor • otamixaban • pharmacokinetics • model

Address for reprints: Anne Paccaly, PharmD, Sanofi Aventis, 1041 Route 202-206, PO Box 6800, Mail Stop M303A, Bridgewater, NJ 08807-0800.




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M. Cohen, D. L. Bhatt, J. H. Alexander, G. Montalescot, C. Bode, T. Henry, J.-F. Tamby, J. Saaiman, S. Simek, J. De Swart, et al.
Randomized, Double-Blind, Dose-Ranging Study of Otamixaban, a Novel, Parenteral, Short-Acting Direct Factor Xa Inhibitor, in Percutaneous Coronary Intervention: The SEPIA-PCI Trial
Circulation, May 22, 2007; 115(20): 2642 - 2651.
[Abstract] [Full Text] [PDF]


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