Safety, pharmacokinetics and pharmacodynamics of multiple ascending doses of R1663, an oral factor Xa inhibitor, in healthy young subjects coupled with exploration of influence of gender and age

Summary

This study investigated the safety, pharmacokinetics and pharmacodynamics of multiple oral doses of R1663, a factor Xa inhibitor, and explored the influence of age and gender on pharmacokinetics and pharmacodynamics of R1663. This was a single-blind, randomised, placebo-controlled, dose escalation study in 48 healthy male volunteers aged 18 to 44 years. R1663 doses up to 300 mg twice daily or 400 mg once daily were administered for seven days. The exploration of gender and age effect was carried out in separate cohorts of eight male and eight female volunteers aged 45 to 65 years. Multiple oral doses of R1663 were safe and well tolerated. Pharmacokinetics was linear and showed moderate variability. Plasma concentrations peaked at 3 hour. Terminal half-life at steady state was 3–5 hours. Accumulation of R1663 was minimal. R1663 prolonged clotting times, inhibited thrombin generation (peak height and endogenous thrombin potential [ETP]) and anti-factor Xa activity in a concentration-dependent manner without increasing bleeding time. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations. The inhibition was more pronounced on peak height (IC₅₀ = 194 ng/ml) than on ETP (2790 ng/ml). Pharmacokinetics and pharmacodynamics of R1663 appeared not to be substantially affected by age or gender but remained to be confirmed in larger clinical trials including older patients. Meanwhile, dose adjustments based on age and gender are not anticipated.

Keywords

Factor Xa inhibitor - multiple ascending dose study - healthy volunteers - gender and age effect

• References

• 1 Anselm L, Banner DW, Benz J. et al. Discovery of a Factor Xa Inhibitor (3R,4R)-1-(2,2-Difluoro-ethyl)-pyrrolidine-3,4-dicarboxylic acid 3-[(5-chloropyridin-2-yl)-amide] 4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide} as a Clinical Candidate. Bioorganic Med Chem Lett 2010; 20: 5313-5319.
• 2 Depasse F, Busson J, Mnich J. et al. Effect of BAY 59–7939-a novel, oral, direct Factor Xa inhibitor-on clot-bound Factor Xa activity in vitro. J Thromb Haemost. 2005 03. Abstract P1104.
• 3 Meddahi S, Samama MM. Is the inhibition of both clot-associated thrombin and factor Xa more clinically relevant than either one alone?. Blood Coagul Fibrinol 2009; 20: 207-214.
• 4 Turpie AG. Direct Factor Xa and direct thrombin inhibitors: A clinical trial update. Curr Opin Drug Discov Devel 2009; 12: 497-508.
• 5 Mann KG, Brummel K, Butenas S. What is all that thrombin for?. J Thromb Haemost 2003; 01: 1504-1514.
• 6 Ieko M, Tarumi T, Nakabayashi T. et al. Factor Xa inhibitors: new anti-thrombotic agents and their characteristics. Front Biosci 2006; 11: 232-248.
• 7 Eriksson BI, Borris L, Dahl OE. et al. Oral, direct Factor Xa inhibition with BAY 59–7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006; 04: 121-128.
• 8 Turpie AG, Fisher WD, Bauer KA. et al. BAY 59–7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study. J Thromb Haemost 2005; 03: 2479-2486.
• 9 Lassen MR, Gallus A, Raskob GE. et al. Apixaban versus enoxaparin for thrombo-prophylaxis after hip replacement. N Engl J Med 2010; 363: 2487-2498.
• 10 Lassen MR, Raskob GE, Gallus A. et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010; 375: 807-815.
• 11 Granger CB, Alexander JH, McMurray JJ. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
• 12 Raskob G, Cohen AT, Eriksson BI. et al. Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement. A randomised double-blind dose-response study. Thromb Haemost 2010; 104: 642-649.
• 13 Mega JL, Braunwald E, Mohanavelu S. et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009; 374: 29-38.
• 14 Mega JL, Braunwald E, Wiviott SD. et al. Rivaroxaban in Patients with a Recent Acute Coronary Syndrome. N Engl J Med 2012; 366: 9-19.
• 15 Alexander JH, Lopes RD, James S. et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011; 365: 699-708.
• 16 Schmitt C, Pannier A, McIntyre C. et al. Cross-over dose escalation study to assess safety, pharmacokinetics and pharmacodynamics of single doses of R1663, an oral factor Xa inhibitor, in healthy male volunteers. J Clin Pharmacol 2012; 52: 499-510.
• 17 Wittke B, Mackie IJ, Machin SJ. et al. Pharmacokinetics and pharmacodynamics of Ro 44–3888 after single ascending oral doses of sibrafiban, an oral platelet aggregation inhibitor, in healthy male volunteers. Br J Clin Pharmacol 1999; 47: 521-530.
• 18 Gibaldi M, Perrier D Pharmacokinetics. 2nd edition. New York: Marcel Dekker; 1982
• 19 Hemker HC, Giesen P, AlDieri R. et al. The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability. Pathophysiol Haemost Thromb 2002; 32: 249-253.
• 20 Brown DL, Kouides PA. Diagnosis and treatment of inherited factor X deficiency. Haemophilia 2008; 14: 1176-1182.
• 21 Agnelli G, Eriksson BI, Cohen AT. et al. Safety assessment of new antithrombotic agents: lessons from the EXTEND study on ximelagatran. Thromb Res 2009; 123: 488-497.
• 22 Schimanski CC, Burg J, Möhler M. et al. Phenprocoumon-induced liver disease ranges from mild acute hepatitis to (sub-) acute liver failure. J Hepatol 2004; 41: 67-74.
• 23 AL-Mekhaizeem KA, Sherker AH. Heparin-induced hepatotoxicity. Can J Gastroenterol 2001; 15: 527-530.
• 24 Mandemal JW, Boyd RA, DiCarlo LA. Therapeutic Index of Anticoagulants for Prevention of Venous Thromboembolism Following Orthopedic Surgery: A Dose-Response Meta-Analysis. Clin Pharmacol Ther 2011; 90: 820-827.
• 25 Barrett YC, Wang Z, Frost C. et al. Clinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost 2010; 104: 1263-1271.
• 26 Samama MM, Contant G, Spiro TE. et al. Evaluation of the anti-factor Xa chro-mogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost 2012; 107: 379-387.
• 27 Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs 1995; 50: 222-239.
• 28 Beierle I, Meibohm B, Derendorf H. Gender differences in pharmacokinetics and pharmacodynamics. Int J Clin Pharmacol Ther 1999; 37: 529-547.