J Clin Pharmacol
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PHARMACOKINETICS AND PHARMACODYNAMICS

Pharmacokinetic/Pharmacodynamic Relationships for Otamixaban, a Direct Factor Xa Inhibitor, in Healthy Subjects

Anne Paccaly, PharmD, Annke Frick, PhD, Marie-Laure Ozoux, PharmD, Valeria Chu, PhD, Ronald Rosenburg, MD, Markus Hinder, MD, Umesh Shukla, PhD and Bradford K. Jensen, PhD

From sanofi aventis, Science & Medical Affairs: Bridgewater, New Jersey (Dr Paccaly, Dr Chu, Dr Shukla, Dr Jensen); Frankfurt, Germany (Dr Frick, Dr Rosenburg, Dr Hinder); and Vitry-Alfortville, France (Dr Ozoux). Dr Shukla's current affiliation is Experimental Medicine, Johnson & Johnson Pharmaceutical Research & Development, Raritan, New Jersey.

Direct pharmacokinetic/pharmacodynamic relationships for otamixaban were investigated after rising doses in healthy subjects using mixed-effect modeling. Activated partial thromboplastin time, prothrombin time, dilute prothrombin time, and Russell's viper venom–induced clotting time (RVVT) related linearly, whereas Heptest clotting time (HCT) followed a sigmoidal Emax model. The pharmacokinetic/pharmacodynamic response (slope) and their corresponding interindividual variability (seconds per ng/mL, [% coefficient of variation]) were 0.263 (29%) for Russell's viper venom–induced clotting time, 0.117 (10%) for dilute prothrombin time, 0.058 (19%) for activated partial thromboplastin time, and 0.021 (11%) for prothrombin time. For Heptest clotting time, the parameter estimates with their corresponding interindividual variability (% coefficient of variation) were 71 ng/mL (30%) for EC50, 186 seconds (64%) for Emax, and 17 seconds (16%) for E0. The model predicted otamixaban plasma concentrations to double the clotting times that were close to those observed. These pharmacokinetic/pharmacodynamic relationships, together with the predictable pharmacokinetics, allowed the anticoagulant effect at given doses of otamixaban to be foreseen in healthy subjects.

Key Words: otamixaban • pharmacokinetics • pharmacodynamics • antithrombotic agents • anticoagulants

Address for reprints: Anne Paccaly, PharmD, sanofi aventis, 1041 Route 202-206, Mail Stop M303A, Bridgewater, NJ 08807-0800; e-mail: anne.paccaly{at}sanofi-aventis.com.


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