Pharmacodynamic markers in the early clinical assessment of otamixaban, a direct factor Xa inhibitor

Anne Paccaly; Marie-Laure Ozoux; Valeria Chu; Kelly Simcox; Vanessa Marks; Geneviève Freyburger; Michel Sibille; Umesh Shukla

doi:10.1160/TH05-05-0347

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 94(06): 1156-1163
DOI: 10.1160/TH05-05-0347

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Pharmacodynamic markers in the early clinical assessment of otamixaban, a direct factor Xa inhibitor

Anne Paccaly

¹Sanofi-aventis, Science and Medical Affairs Bridgewater New Jersey, USA

,

Marie-Laure Ozoux

²Vitry-Alfortville, France

,

Valeria Chu

¹Sanofi-aventis, Science and Medical Affairs Bridgewater New Jersey, USA

,

Kelly Simcox

¹Sanofi-aventis, Science and Medical Affairs Bridgewater New Jersey, USA

,

Vanessa Marks

³Croix de Berny, France

,

Geneviève Freyburger

⁴4 Laboratoire d’Hématologie Hôpital Pellegrin, Bordeaux, France

,

Michel Sibille

⁵5 Association de Recherche Thérapeutique, Centre Hospitalier Lyon-Sud, France

,

Umesh Shukla^*

¹Sanofi-aventis, Science and Medical Affairs Bridgewater New Jersey, USA

› Author Affiliations

Abstract

Summary

This manuscript reports the assessment of pharmacodynamic (PD) markers of anti-coagulation in the first-in-man study with the novel direct Factor Xa (FXa) inhibitor, otamixaban, with a brief description of safety and pharmacokinetic (PK) findings. The study comprised ten consecutive parallel groups of healthy male subjects (6 active, 2 placebo per group). Eight groups received escalating intravenous doses of otamixaban as 6-hour infusions (1.7 to 183 μg/kg/h) and two groups received a bolus dose (30 or 120 μg/kg) with a 6-hour infusion (60 or 140 μg/ kg/h, respectively). PD markers included anti-FXa activity and clotting time measurements, i.e. activated Thromboplastin Time (aPTT), ProthrombinTime (PT), Heptest^® ClottingTime (HCT), and Russell’s Viper Venom-induced clotting Time (RVVT). In addition, Endogenous Thrombin Potential (ETP) was assessed in the bolus-plus-infusion dose groups. Otamixaban was well tolerated. Otamixaban plasma concentrations increased with escalating dose, were maximal at the end-of-infusion (C_eoi), and decreased rapidly as the infusion was stopped. Anti-FXa activity coincided with otamixaban plasma concentrations and clotting time measurements followed the same pattern. Maximal changes from baseline at C_eoi were 1.9 ± 0.2 for aPTT, 2.0 ± 0.2 for PT, 5.1 ± 0.6 for HCT, and 4.5 ± 1.2 for RVVT. Otamixaban inhibited thrombin generation (24% decrease in ETP) and a delay in thrombin generation was noticed in vitro at high concentrations.

Keywords

Anti-coagulation - FXa inhibitor - otamixaban - pharmacodynamic markers - RVVT

Full Text

References

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