Open Multicentre Study of the P _2T Receptor Antagonist AR-C69931MX Assessing Safety, Tolerability and Activity in Patients with Acute Coronary Syndromes

Summary

Platelet aggregation is the central process in the pathophysiology of acute coronary syndromes. ADP contributes to thrombosis by activating platelets, and AR-C69931MX is a specific antagonist of this process acting at the P _2T receptor. At 5 hospitals, 39 patients with unstable angina or non-Q wave myocardial infarction, who were receiving aspirin and heparin, were administered intravenous AR-C69931MX with stepped dose increments over 3 h to a plateau of either 2 μg/kg/min for 21 h (Part 1; n = 12) or up to 69 h (Part 2; n = 13) or 4 μg/kg/min for up to 69 h (Part 3: n = 14). Safety parameters, platelet aggregation (PA) induced by ADP 3 μmol/L (impedance aggregometry), bleeding time (BT) and plasma concentrations of AR-C69931XX were assessed. AR-C69931MX was well tolerated. 33 patients completed the study. There were no deaths at 30 days and no serious adverse events attributed to AR-C69931MX. Trivial bleeding (56%) was common. At 24 h, mean inhibition of PA was 96.0 ± 8.6, 94.9 ± 14.4 and 98.7 ± 2.1% and BT was 9.5 ± 8.4, 14.0 ± 9.7 and 16.0 ± 11.1 min for Parts 1, 2 and 3 respectively. At 1 h post-infusion, mean inhibition of PA was 36.2 ± 39.2, 20.7 ± 25.9 and 40.7 ± 36.7% respectively. 90% patients had a plasma half-life for AR-C69931XX of 9 min. In conclusion, AR-C69931MX is a potent, short-acting platelet ADP receptor antagonist suitable for further studies as an antithrombotic agent.

Keywords

Platelet aggregation inhibitors - adenosine diphosphate - P2 receptors - unstable angina - heparin

• References

• 1 Adgey AAJ. An overview of the results of clinical trials with glycoprotein IIb/IIIa inhibitors. Eur Heart J 1998; 19: D10-D21.
• 2 Colman RW, Cook JJ, Niewiarowski S. Mechanisms of platelet aggregation. In: Colman RW, Hirsh J, Marder VJ, Salzman EW. eds. Hemostasis and thrombosis: basic principles and clinical practice. Philadelphia: Lippincott Company; 1994: 508-23.
• 3 Gachet C, Hechler B, Leon C, Vial C, Leray C, Ohlmann P, Cazenave J-P.. Activation of ADP receptors and platelet function. Thromb Haemost 1997; 78: 271-5.
• 4 Kunapuli SP. Functional characterization of platelet ADP receptors. Platelets 1998; 9: 343-51.
• 5 Jin J, Kunapuli SP. Coactivation of two different G protein-coupled receptors is essential for ADP-induced platelet aggregation. Proc Natl Acad Sci USA 1998; 95: 8070-4.
• 6 Hechler B, Eckly A, Ohlmann P, Cazenave J-P, Gachet C. The P2Y₁ receptor, necessary but not sufficient to support full ADP-induced platelet aggregation, is not the target of the drug clopidogrel. Br J Haematol 1998; 103: 858-66.
• 7 Storey RF, Sanderson HM, White AE, May JA, Cameron KE, Heptinstall S. The central role of the P _2T receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity. Br J Haematol 2000; 110: 925-34.
• 8 Cattaneo M, Akkawat B, Lecchi A, Cimminiello C, Capitanio AM, Mannucci PM. Ticlopidine selectively inhibits human platelet responses to adenosine diphosphate. Thromb Haemost 1991; 66: 694-9.
• 9 Savi P, Nurden P, Nurden A, Levy-Toledano S, Herbert JM. Clopidogrel: a review of its mechanism of action. Platelets 1998; 9: 251-5.
• 10 Geiger J, Honig-Liedl P, Schanzenbacher P, Walter U. Ligand specificity and ticlopidine effects distinguish three human platelet ADP receptors. Eur J. Pharmacol 1998; 351: 235-46.
• 11 Antiplatelet Trialists’ Collaboration.. Collaborative overview of randomised trials of antiplatelet therapy. I: Prevention of death, myocardial infarction and stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J 1994; 308: 81-106.
• 12 CAPRIE Steering Committee.. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329-39.
• 13 Schror K. The basic pharmacology of ticlopidine and clopidogrel. Platelets 1993; 4: 252-61.
• 14 Boneu B, Destelle G. on behalf of the Study Group.. Platelet anti-aggregating activity and tolerance of clopidogrel in atherosclerotic patients. Thromb Haemost 1996; 76: 939-43.
• 15 Humphries RG, Robertson MJ, Leff P. A novel series of P_2T purinoceptor antagonists: definition of the role of ADP in arterial thrombosis. Trends in Pharmacol Sci 1995; 16: 179-81.
• 16 Ingall AH, Dixon J, Bailey A, Coombs ME, Cox D, McInally JI, Hunt SF, Kindon ND, Teobald BJ, Willis PA, Humphries RG, Leff P, Clegg JA, Smith JA, Tomlinson W. Antagonists of the platelet P _2T receptor: a novel approach to antithrombotic therapy. J Med Chem 1999; 42: 213-20.
• 17 Rao AK, Pratt C, Berke A, Jaffe A, Ockene I. Thrombolysis in Myocardial Infarction (TIMI) Trial-Phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988; 11: 1-11.
• 18 Mark DB, Braunwald E. Medical Management of Unstable Angina. In: Fuster V, Ross R, Topol EJ. eds. Atherosclerosis and Coronary Artery Disease. Vol. 2. Philadelphia: Lippincott-Raven; 1996: 1315-26.
• 19 Jarvis GE, Nassim MA, Humphries RG, Kirk IP, Tomlinson W, Cusworth EA, Midha A, Perrett JH, Mobbs EJ, Hammersley MD, Watts IS. The P _2T antagonist AR-C69931MX is a more effective inhibitor of ADP-induced platelet aggregation than clopidogrel.. Blood 1999; 94 (Suppl. 01) 22a.
• 20 Storey RF, Henderson RA, Wilcox RG, Heptinstall S. Superior antiplatelet effects of AR-C69931MX compared to clopidogrel in patients with ischemic heart disease. Haematologica 2000; 85 (the Platelet ADP Receptor Suppl.) 92.
• 21 Collignon F, Frydman A, Caplain H, Ozoux ML, Le Roux Y, Bouthier J, Thebault JJ. Comparison of the pharmacokinetic profiles of three low molecular mass heparins – dalteparin, enoxaparin and nadroparin – administered subcutaneously in healthy volunteers (doses for prevention of thromboembolism). Thromb Haemost 1995; 73: 630-40.
• 22 Price CP, Alberti KGMM. Biochemical Assessment of Liver Function. In: Wright R, Millward-Sadler G, Alberti K, Carran S. eds. Liver and Biliary Disease. London: Bailliere Tindall; 1985: 455-93.
• 23 Sonnenblick M, Oren A, Jacobsonn W. Hyper-transaminasemia with heparin therapy. Br Med J 1975; 3: 77.
• 24 Jacobsson F, Dellborg M, Swahn E, Wallentin L. Tolerance and safety of cangrelor, a novel purin receptor antagonist, used as a platelet aggregation inhibitor in the acute coronary syndrome.. J Am Coll Cardiol 2000; 35 A 343A.
• 25 Simoons ML, Jan de Boer M, van den Brand MJ, van Miltenburg AJ, Hoorntje JC, Heyndrickx GR, van der Wieken LR, de Bono D, Rutsch W, Schaible TF, Weisman HF, Klootwijk P, Nijssen KM, Stibbe J, de Feyter PJ. European Cooperative Study Group.. Randomized trial of a GPIIb/IIIa platelet receptor blocker in refractory unstable angina. Circulation 1994; 89: 596-603.
• 26 Tcheng JE, Harrington RA, Kottke-Marchant K, Kleiman NS, Ellis SG, Kereiakes DJ, Mick MJ, Navetta FI, Smith JE, Worley SJ, Miller JA, Joseph DM, Sigmon KN, Kitt MM, du Mee CP, Califf RM, Topol EJ. for the IMPACT Investigators.. Multicenter, randomized, double-blind, placebo-controlled trial of the platelet integrin glycoprotein IIb/IIIa blocker Integrilin in elective coronary intervention. Circulation 1995; 91: 2151-7.
• 27 Kleiman NS, Raizner AE, Jordan R, Wang AL, Norton D, Mace KF, Joshi A, Coller BS, Weisman HF. Differential inhibition of platelet aggregation induced by adenosine diphosphate or a thrombin receptor-activating peptide in patients treated with bolus chimeric 7E3 Fab: implications for inhibition of the internal pool of GPIIb/IIIa receptors. J Am Coll Cardiol 1995; 26: 1665-71.
• 28 Kereiakes DJ, Kleiman NS, Ferguson JJ, Masud AZ, Broderick TM, Abbottsmith CW, Runyon JP, Anderson LC, Anders RJ, Dreiling RJ, Hantsbarger GL, Bryzinski B, Topol EJ. for the Oral Glycoprotein IIb/IIIa Receptor Blockade to Inhibit Thrombosis (ORBIT) Trial Investigators.. Pharmacodynamic efficacy, clinical safety, and outcomes after prolonged platelete glycoprotein IIb/IIIa receptor blockade with oral xemilofiban: results of a multicenter, placebo-controlled, randomized trial. Circulation 1998; 98: 1268-78.
• 29 Kereiakes DJ, Kleiman NS, Ambrose J, Cohen M, Rodriguez S, Palabrica T, Herrmann HC, Sutton JM, Weaver WD, McKee DB, Fitzpatrick V, Sax FL. Randomized, double-blind, placebo-controlled dose-ranging study of tirofiban (MK-383) platelet IIb/IIIa blockade in high risk patients undergoing coronary angioplasty. J Am Coll Cardiol 1996; 27: 536-42.
• 30 Simpfendorfer C, Kottke-Marchant K, Lowrie M, Anders RJ, Burns DM, Miller DP, Cove CS, DeFranco AC, Ellis SG, Moliterno DJ, Raymond RE, Sutton JM, Topol EJ. First chronic platelet glycoprotein IIb/IIIa integrin blockade: a randomized, placebo-controlled pilot study of xemilofiban in unstable angina with percutaneous coronary interventions. Circulation 1997; 96: 76-81.
• 31 Lehne G, Nordal KP, Midtvedt K, Goggin T, Brosstad F. Increased potency and decreased elimination of lamifiban, a GPIIb-IIIa antagonist, in patients with severe renal dysfunction. Thromb Haemost 1998; 79: 1119-25.
• 32 Tsao PW, Forsythe MS, Mousa SA. Dissociation between the anti-aggregatory and anti-secretory effects of platelet integrin alpha IIb beta 3 (GPIIb/IIIa) antagonists, c7E3 and DMP728. Thromb Res 1997; 88: 137-46.
• 33 The PURSUIT. Trial Investigators.. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998; 339: 436-43.
• 34 The Platelet Receptor Inhibition in Ischemic Syndromes Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators.. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998; 338: 1488-97.
• 35 The PARAGON Investigators.. International, Randomized, Controlled Trial of Lamifiban (a Platelet Glycoprotein IIb/IIIa Inhibitor), heparin, or both in Unstable Angina. Circulation 1998; 97: 2386-95.
• 36 Storey RF, Curry SN, Heptinstall S. In vitro evidence supporting direct platelet P2T receptor antagonism as an alternative strategy to glycoprotein IIb/IIIa receptor antagonism. Heart 2000; 83 (Suppl. 01) 17.