Increased Potency and Decreased Elimination of Lamifiban, a GPIIb-IIIa Antagonist, in Patients with Severe Renal Dysfunction

Gustav Lehne; Knut P. Nordal; Karsten Midtvedt; Timothy Goggin; Frank Brosstad

doi:10.1055/s-0037-1615027

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1998; 79(06): 1119-1125
DOI: 10.1055/s-0037-1615027

Rapid Communication

Schattauer GmbH

Increased Potency and Decreased Elimination of Lamifiban, a GPIIb-IIIa Antagonist, in Patients with Severe Renal Dysfunction

Gustav Lehne

¹From the Departments of Clinical Pharmacology, Drug Research Unit, Oslo, Norway

,

Knut P. Nordal

²Internal Medicine, The National Hospital, Rikshospitalet, Oslo, Norway

,

Karsten Midtvedt

²Internal Medicine, The National Hospital, Rikshospitalet, Oslo, Norway

,

Timothy Goggin

³Department of Clinical Pharmacology, F. Hoffmann-La Roche AG, Basel, Switzerland

,

Frank Brosstad

²Internal Medicine, The National Hospital, Rikshospitalet, Oslo, Norway

› Author Affiliations

Abstract

Summary

Activation of the platelet membrane receptor glycoprotein (GP) IIb-IIIa is essential for thrombus formation. The novel nonpeptide GPIIb-IIIa antagonist, lamifiban, represents a promising approach for antiplatelet therapy in patients with cardiovascular disease. Since renal impairment frequently occurs in these patients, we designed a phase I study to assess the tolerability, pharmacodynamics and pharmacokinetics of lamifiban in patients with renal impairment. Four healthy volunteers (Group 1) with creatinine clearance (CLCR) >75 ml/min, eight patients (Group 2) with mild to moderately impaired renal function (CLCR 30-74 ml/min) and eight patients (Group 3) with severe renal impairment (CLCR 10-29 ml/min) were studied. They received stepwise increased doses of lamifiban intravenously (IV). There was a linear relationship between the systemic clearance of the drug and renal function (R² = 0.86). The mean plasma concentration required for half-maximal inhibition of thrombin-receptor agonist peptide (TRAP) induced platelet aggregation (EC₅₀) ex vivo was 21, 28 and 11 ng/ml in Groups 1, 2 and 3. The patients in Group 3 were sensitized to the anti-platelet effect allowing an 18-fold dosage reduction without compromising the pharmacodynamics. In conclusion, the decreased clearance of lamifiban may act in concert with increased potency of the drug in patients with severe renal impairment, and the drug dosage should be reduced accordingly.

Full Text

References

References
1 Stein B, Fuster V, Halperin JL, Chesebro JH. Antithrombotic therapy in cardiac disease. An emerging approach based on pathogenesis and risk. Circulation 1989; 80: 1501-13.
2 Ginsberg MH, Xiaoping D, O’Toole TE, Loftus JC, Plow EF. Platelet inte-grins. Thromb Haemost 1993; 70: 87-93.
3 Weiss HJ, Hawiger J, Ruggeri ZM, Turitto VT, Thiagarajan P, Hoffmann T. Fibrinogen-independent platelet adhesion and thrombus formation on subendothelium mediated by glycoprotein IIb-IIIa complex at high shear rate. J Clin Invest 1989; 83: 288-97.
4 Ellis SG, Bates ER, Schaible T, Weisman HF, Pitt B, Topol EJ. Prospects for the use of antagonists to the platelet glycoprotein IIb/IIIa receptor to prevent post-angioplasty restenosis and thrombosis. J Am Coll Cardiol 1991; 17: 89B-95B.
5 Barnathan ES, Schwartz JS, Taylor L, Laskey WK, Kleaveland JP, Kuss-maul WG, Hirshfeld Jr. JW. Aspirin and dipyridamole in the prevention of acute coronary thrombosis complicating coronary angioplasty. Circulation 1987; 76: 125-34.
6 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.
7 Coller BS. Platelets and thrombolytic therapy. N Engl J Med 1990; 322: 33-42.
8 Harker LA. Platelets and vascular thrombosis. N Engl J Med 1994; 330: 1006-7.
9 Tenaglia AN, Fortin DF, Califf RM, Frid DJ, Nelson CL, Gardner L, Miller M, Navetta FI, Smith JE, Tcheng JE. et al. Predicting the risk of abrupt vessel closure after angioplasty in an individual patient. J Am Coll Cardiol 1994; 24: 1004-11.
10 Coller BS, Anderson K, Weisman HF. New antiplatelet agents: platelet GPIIb/IIIa antagonists. Thromb Haemost 1995; 74: 302-8.
11 The EPIC Investigators.. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994; 330: 956-61.
12 Carteaux JP, Steiner B, Roux S. Ro 44-9883, a new non-peptidic GPIIbGPIIIa antagonist prevents platelet loss in a guinea pig model of extracorporeal circulation. Thromb Haemost 1993; 70: 817-21.
13 Kouns WC, Roux S, Steiner B. Human platelet GPIIb-IIIa receptor blockade as a therapeutic strategy. Curr Opin Invest Drugs 1993; 2: 475-94.
14 Alig L, Edenhofer A, Hadvary P, Hurzeler M, Knopp D, Muller M, Steiner B, Trzeciak A, Weller T. Low molecular weight, non-peptide fibrinogen receptor antagonists. J Med Chem 1992; 35: 4393-407.
15 Weller T, Alig L, Muller MH, Kouns WC, Steiner B. Fibrinogen receptor antagonists – a novel class of promising antithrombotics. Drugs Fut 1994; 19: 461-76.
16 Theroux P, Kouz S, Roy L, Knudtson ML, Diodati JG, Marquis JF, Nasmith J, Fung AY, Boudreault JR, Delage F, Dupuis R, Kells C, Bokslag M, Steiner B, Rapold HJ. Platelet membrane receptor glycoprotein IIb/IIIa antagonism in unstable angina. The Canadian Lamifiban Study. Circulation 1996; 94: 899-905.
17 Aguirre FV, Topol EJ, Ferguson JJ, Anderson K, Blankenship JC, Heuser RR, Sigmon K, Taylor M, Gottlieb R, Hanovich G. for the EPIC investigator. Bleeding complications with the chimeric antibody to platelet glyco-protein IIb/IIIa integrin in patients undergoing percutaneous coronary intervention. Circulation 1995; 91: 2882-90.
18 Remuzzi G. Bleeding in renal failure. Lancet 1988; 1: 1205-8.
19 Di Minno G, Martinez J, McKean ML, De La Rosa J, Burke JF, Murphy S. Platelet dysfunction in uremia. Multifaceted defect partially corrected by dialysis. Am J Med 1985; 79: 552-9.
20 Remuzzi G, Benigni A, Dodesini P, Schieppati A, Livio M, De Gaetano G, Day SS, Smith WL, Pinca E, Patrignani P, Patrono C. Reduced platelet thromboxane formation in uremia. Evidence for a functional cyclooxygenase defect. J Clin Invest 1983; 71: 762-8.
21 Gawaz MP, Dobos G, Spath M, Schollmeyer P, Gurland HJ, Mujais SK. Impaired function of platelet membrane glycoprotein IIb-IIIa in end-stage renal disease. J Am Soc Nephrol 1994; 5: 36-46.
22 Harrington RA, Moliterno DJ, van der Werf F, Keech A, Kleiman N, Bhapkar M, Rames A, Peek M, Topol EJ, Califf RM, Armstrong PW. for the PARAGON investigators. Delaying and preventing ischemic events in patients with acute coronary syndromes using the platelet glycoprotein IIb/IIIa inhibitor lamifiban. J Am Coll Cardiol 1997; 29: 409A.
23 Eknoyan G, Brown CH. Biochemical abnormalities of platelets in renal failure. Evidence for decreased platelet serotonin, adenosine diphosphate and Mg-dependent adenosine triphosphatase. Am J Nephrol 1981; 1: 17-23.
24 Di Minno G, Martinez J, McKean ML, De La Rosa J, Burke JF, Murphy S. Platelet dysfunction in uremia. Multifaceted defect partially corrected by dialysis. Am J Med 1985; 79: 552-9.
25 Smith MC, Dunn MJ. Impaired platelet thromboxane production in renal failure. Nephron 1981; 29: 133-7.
26 Ware JA, Clark BA, Smith M, Salzman EW. Abnormalities of cytoplasmic Ca2+ in platelets from patients with uremia. Blood 1989; 73: 172-6.
27 Vlachoyannis J, Schoeppe W. Adenylate cyclase activity and cAMP content of human platelets in uraemia. Eur J Clin Invest 1982; 12: 379-81.
28 Gold HK, Gimple LW, Yasuda T, Leinbach RC, Werner W, Holt R, Jordan R, Berger H, Collen D, Coller BS. Pharmacodynamic study of F(ab’)2 fragments of murine monoclonal antibody 7E3 directed against human platelet glycoprotein IIb/IIIa in patients with unstable angina pectoris. J Clin Invest 1990; 86: 651-9.
29 Van de Werf F. Clinical trials with glycoprotein IIb/IIIa receptor antagonists in acute coronary syndromes. Thromb Haemostas 1997; 78: 210-3.