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

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

^* Current address: Clinical Drug Evaluation, Johnson & Johnson Pharmaceutical Research & Development, Raritan, New Jersey, USA

• References

• 1 Shah PK. Pathophysiology of plaque rupture and the concept of plaque stabilization. Cardiol Clin 2003; 21: 303-14, v.
• 2 Braunwald E, Antman EM, Beasley JW. et al ACC/ AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction–2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). Circulation 2002; 106: 1893-900.
• 3 Bertrand ME, Simoons ML, Fox KA. et al Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2002; 23: 1809-40.
• 4 Leadley Jr. RJ. Coagulation factor Xa inhibition: biological background and rationale. Curr Top Med Chem 2001; 1: 151-9.
• 5 Chu V, Brown K, Colussi D. et al Pharmacological characterization of a novel factor Xa inhibitor, FXV673. Thromb Res 2001; 103: 309-24.
• 6 Rebello SS, Bentley RG, Morgan SR. et al Antithrombotic efficacy of a novel factor Xa inhibitor, FXV673, in a canine model of coronary artery thrombolysis. Br J Pharmacol 2001; 133: 1190-8.
• 7 Hauptmann J, Sturzebecher J. Synthetic inhibitors of thrombin and factor Xa: from bench to bedside. Thromb Res 1999; 93: 203-41.
• 8 Hara T, Yokoyama A, Ishihara H. et al DX-9065a, a new synthetic, potent anticoagulant and selective inhibitor for factor Xa. Thromb Haemost 1994; 71: 314-9.
• 9 Kaiser B. Thrombin and factor Xa inhibitors. Drugs of the Future 1998; 23: 423-36.
• 10 Tobu M, Iqbal O, Hoppensteadt DA. et al Effects of a synthetic factor Xa inhibitor (JTV-803) on various laboratory tests. Clin Appl Thromb Hemost 2002; 8: 325-36.
• 11 Paccaly A, Ozoux M-L, Frick A. et al Pharmacokinetic/ pharmacodynamic relationships for factor Xa-inhibitor XRP0673 in early drug development (Abstract). J Pharm Sci 2002; 4: W5241.
• 12 Hemker HC, Beguin S. Thrombin generation in plasma: its assessment via the endogenous thrombin potential. Thromb Haemost 1995; 74: 134-8.
• 13 Chantarangkul V, Clerici M, Bressi C. et al Thrombin generation assessed as endogenous thrombin potential in patients with hyper- or hypo-coagulability. Haematologica 2003; 88: 547-54.
• 14 Wielders S, Mukherjee M, Michiels J. et al The routine determination of the endogenous thrombin potential, first results in different forms of hyper- and hypocoagulability. Thromb Haemost 1997; 77: 629-36.
• 15 Hemker HC, Giesen PL, Ramjee M. et al The thrombogram: monitoring thrombin generation in platelet-rich plasma. Thromb Haemost 2000; 83: 589-91.
• 16 Hemker HC, Giesen P, Al Dieri R. et al Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33: 4-15.
• 17 Paccaly A, Frick A, Rohatagi S. et al Pharmacokinetics of otamixaban, a direct factor Xa inhibitor, in healthy male subjects: Pharmacokinetic Model Development for Phase II/III Simulation of Exposure. J Clin Pharmacol 2005; 45.
• 18 Murayama N, McMahon H, Young CG. et al Pharmacokinetics of the anticoagulant 14C-DX-9065a in the healthy male volunteer after a single intravenous dose. Xenobiotica 2000; 30: 515-21.
• 19 Walenga JM, Jeske WP, Bara L. et al Biochemical and pharmacologic rationale for the development of a synthetic heparin pentasaccharide. Thromb Res 1997; 86: 1-36.
• 20 Ieko M, Tarumi T, Takeda M. et al Synthetic selective inhibitors of coagulation factor Xa strongly inhibit thrombin generation without affecting initial thrombin forming time necessary for platelet activation in hemostasis. J Thromb Haemost 2004; 2: 612-8.
• 21 Dyke CK, Becker RC, Kleiman NS. et al First experience with direct factor Xa inhibition in patients with stable coronary disease: a pharmacokinetic and pharmacodynamic evaluation. Circulation 2002; 105: 2385-91.
• 22 Becker RC, Alexander JH, Dyke C. et al Effect of the novel direct factor Xa inhibitor DX-9065a on thrombin generation and inhibition among patients with stable atherosclerotic coronary artery disease. Thromb Res. 2005 Epub ahead of print.
• 23 Murayama N, Tanaka M, Kunitada S. et al Tolerability, pharmacokinetics, and pharmacodynamics of DX-9065a, a new synthetic potent anticoagulant and specific factor Xa inhibitor, in healthy male volunteers. Clin Pharmacol Ther 1999; 66: 258-64.
• 24 Shimbo D, Osende J, Chen J. et al Antithrombotic effects of DX-9065a, a direct factor Xa inhibitor: a comparative study in humans versus low molecular weight heparin. Thromb Haemost 2002; 88: 733-8.
• 25 Alexander JH, Dyke CK, Yang H. et al Initial experience with factor-Xa inhibition in percutaneous coronary intervention: the XaNADU-PCI Pilot. J Thromb Haemost 2004; 2: 234-41.