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Pharmacokinetics and Pharmacodynamics of Low-Molecular-Weight Heparins and Glycoprotein IIb/IIIa Receptor Antagonists in Renal Failure

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Abstract

Data regarding the use of low-molecular-weight heparins (LMWHs) and glycoprotein (GP) IIb/IIIa receptor antagonists in patients with renal failure are limited. Renal failure has the potential to increase the risk of adverse drug events associated with LMWHs and GP IIb/IIIa receptor antagonists. This is due to changes in the pharmacokinetic and pharmacodynamic profiles of these agents in patients with renal failure. Until more data are available, clinicians should consider alternative therapies in this patient population.

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References

  1. Cabtu TG, Ellerbeck EF, Yun SW, Castine SD, Kornhauser DM. Drug prescribing for patients with changing renal function. Am J Hosp Pharm 1992;49:2944–2948.

    Google Scholar 

  2. Smith JW, Seidl LG, Cluff LE. Studies on the epidemiology of adverse drug reactions. V. Clinical factors influencing susceptibility. Ann Intern Med 1966;65:629–640.

    Google Scholar 

  3. Bates DW, Spell N, Cullen DJ, et al. The costs of adverse drug events in hospitalized patients. JAMA 1997;277:307–311.

    Google Scholar 

  4. Classen DC, Pestotnik SL, Evans S, Lloyd JF, Burke JP. Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and attributable mortality. JAMA 1997;277:301–306.

    Google Scholar 

  5. Bates DW, Leape LL, Cullen DJ, et al. Effect of computerized physician order entry and a team intervention on prevention of serious medication errors. JAMA 1998;280:311–316.

    Google Scholar 

  6. Weitz JI. Low–molecular–weight heparins. NEJM 1997;337:688–698.

    Google Scholar 

  7. Agnelli G. Pharmacologic activities of heparin chains: should our past knowledge be revised? Haemostasis 1996;26(suppl. 2):2–9.

    Google Scholar 

  8. Samama MM, Poller L. Contemporary laboratory monitoring of low molecular weight heparins. Clin Lab Med 1995;15:119–123.

    Google Scholar 

  9. Kessler CM. Low molecular weight heparins: practical considerations. Semin Hematol 1997;34(suppl. 4):35–42.

    Google Scholar 

  10. Laforest MD, Colas Linhart N, Guiraud–Vitaux F, et al. Pharmacokinetics and biodistribution of technetium 99m labelled standard heparin and a low molecular weight heparin after intravenous injection in normal volunteers. Br J Haematol 1991;77:201–208.

    Google Scholar 

  11. Collingnon F, Frydman A, Caplain H, et al. 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;73:630–640.

    Google Scholar 

  12. Eriksson BI, Soderberg K, Widlund L, et al. A comparative study of three low–molecular–weight heparins (LMWH) and unfractionated heparin (UF) in healthy volunteers. Thromb Haemost 1995;73:398–401.

    Google Scholar 

  13. Bratt G, Torenbohm E, Wildlund L, Lockner D. Low molecular weight heparin (KABI 2165, Fragmin®): pharmacokinetics after intravenous and subcutaneous administration in human volunteers. Thromb Res 1986;42:613–620.

    Google Scholar 

  14. Rostin M, Montastruc JL, Houin G, et al. Pharmacodynamics of CY 216 in healthy volunteers: interindividual variations. Fundam Clin Pharmacol 1990;4:17–23.

    Google Scholar 

  15. Harenberg J, Wurzner B, Zimmermann R, Schettler G. Bioavailability and antagonization of the low molecular weight heparin CY 216 in man. Thromb Res 1986;44:549–554.

    Google Scholar 

  16. Pedersen PC, Ostergaard PB, Hedner U, Bergqvist D, Matzsch T. Pharmacokinetics of a low molecular weight heparin, logaparin, after intravenous and subcutaneous administration to healthy volunteers. Thromb Res 1991;61:477–487.

    Google Scholar 

  17. Troy S, Fruncillo R, Ozawa T, et al. The dose proportionality of the pharmacokinetics of ardeparin, a low molecular weight heparin, in healthy volunteers. J Clin Pharmacol 1995;35:1194–1199.

    Google Scholar 

  18. Simoneau G, Bergmann JF, Kher A, Soria C, Tobelem G. Pharmacokinetics of a low molecular weight heparin (Fragmin®) in young and elderly subjects. Thromb Res 1992;66:603–607.

    Google Scholar 

  19. Frydman AM, Bara L, Roux YL, et al. The antithrombotic activity and pharmacokinetics of enoxaparin, a low molecular weight heparin, in humans given single subcutaneous doses of 20 to 80 mg. J Clin Pharmacol 1988;28:609–618.

    Google Scholar 

  20. Freedman MD, Leese P, Prasad R, Hayden D. An evaluation of the biological response to Fraxaparine®, (a low molecular weight heparin) in the healthy individual. J Clin Pharmacol 1990;30:720–727.

    Google Scholar 

  21. Nader HB, Walenga JM, Berkowitz SD, et al. Preclinical differentiation of low molecular weight heparins. Semin Thromb Hemost 1999;25(suppl. 3):63–72.

    Google Scholar 

  22. Cadroy Y, Pourrat J, Baladre MF, et al. Delayed elimination of enoxaparin in patients with chronic renal insufficiency. Thromb Res 1991;63:385–390.

    Google Scholar 

  23. Goudable C, Saivin S, Houin G, et al. Pharmacokinetics of low molecular weight heparin (Fraxaparine®) in various stages of chronic renal failure. Nephron 1991;59:543–545.

    Google Scholar 

  24. Gerlach AT, Pickworth KK, Seth SK, et al. Enoxaparin and bleeding complications: a review in patients with and without renal insufficiency. Pharmacotherapy 2000;20:771–775.

    Google Scholar 

  25. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:31–41.

    Google Scholar 

  26. Normiflo® Package Insert. Philidelphia, PA: Wyeth–Ayerst Pharmaceuticals; 2000 Jan.

  27. Chong PH. Glycoprotein IIb/IIIa receptor antagonists in the management of cardiovascular diseases. Am J Health Syst Pharm 1998;55:2363–2386.

    Google Scholar 

  28. Wagner CL, Mascelli MA, Neblock DS, et al. Analysis of GPIIb–IIIa receptor number by quantification of 7E3 binding to human platelets. Blood 1996;88:907–914.

    Google Scholar 

  29. Yasuda T, Gold HK, Fallon JT, et al. Monoclonal antibody against the platelet glycoprotein (GP) IIb–IIIa receptor prevents coronary artery reocclusion after reperfusion with recombinant tissue–type plasminogen activator. J Clin Invest 1988;81:1284–1291.

    Google Scholar 

  30. Gold HK, Coller BS, Yasuda T, et al. Rapid and sustained coronary artery recanalization with combined bolus injections of recombinant tissue–type plasminogen activator and monoclonal anti–platelet GPIIb–IIIa antibody in a dog model. Circulation 1988;77:670–677.

    Google Scholar 

  31. Bhattacharya S, Jordan R, Machin S, et al. Blockade of the human platelet GPIIb–IIIa receptor by a murine monoclonal antibody fab fragment (7E3): potent dosedependent inhibition of platelet function. Cardiovasc Drugs Ther 1995;9:665–675.

    Google Scholar 

  32. Benigni A, Boccardo P, Galbusera M, et al. Reversible activation defect of the platelet glycoprotein IIb–IIIa complex in patients with uremia. Am J Kidney Dis 1993;22:312–321.

    Google Scholar 

  33. Eknoyan G, Brown CH. Biochemical abnormalities of platelets in renal failure: Evidence for decreased platelet serotonin, adenosine diphosphate and magnesium–dependent adenosine triphosphatase. Am J Nephrol 1981;1:17–23.

    Google Scholar 

  34. Macconi D, Vigano G, Bisogno G, et al. Defective platelet aggregation in response to platelet–activating factor in uremia associated with low platelet thromboxane A2 generation. Am J Kidney Dis 1992;19:318–325.

    Google Scholar 

  35. Gawaz MP, Dobos G, Spath M, et al. Impaired function of platelet membrane glycoprotein IIb–IIIa in endstage renal disease. J Am Soc Nephrol 1994;5:36–46.

    Google Scholar 

  36. Sreedhara R, Itagaki I, Hakim RM. Uremic patients have decreased shear–induced platelet aggregation mediated by a decreased availability of glycoprotein IIb–IIIa receptors. Am J Kidney Dis 1996;27:355–364.

    Google Scholar 

  37. Remuzzi G, Livio E, Marchiaro G, et al. Bleeding in renal failure: altered platelet function in chronic uraemia only partially corrected by haemodialysis. Nephron 1978;22:347–353.

    Google Scholar 

  38. Noris M, Benigni A, Boccardo P, et al. Enhanced nitric oxide synthesis in uremia: implications for platelet dysfunction and dialysis hypotension. Kidney Int 1993;44:445–450.

    Google Scholar 

  39. Herbelin A, Nguyen AT, Zingraff J, et al. Infiuence of uremia and hemodialysis on circulation interleukin–1 and tumor necrosis factor alpha. Kidney Int 1990;37:116–125.

    Google Scholar 

  40. The IMPACT–II Investigators. Randomized placebocontrolled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT–II. Lancet 1997;349:1422–1428.

    Google Scholar 

  41. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptibatide in patients with acute coronary syndromes. N Eng J Med 1998;339:436–443.

    Google Scholar 

  42. The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 1997;96:1445–1453.

    Google Scholar 

  43. The Platelet Receptor Inhibition in Ischemic Syndrome 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 Eng J Med 1998;338:1488–1497.

    Google Scholar 

  44. Aggrastat® package insert. West Point, PA: Merck and Co., Inc.; 2000 Mar.

  45. Alton KB, Kosoglou T, Baker S, et al. Disposition of 14C–eptifibatide after intravenous administration to healthy men. Clin Ther 1998;20:307–323.

    Google Scholar 

  46. Tcheng JE, Ellis SG, George BS, et al. Pharmacodynamics of chimeric glycoprotein IIb–IIIa integrin antiplatelet antibody fab 7E3 in high–risk coronary angioplasty. Circulation 1994;90:1757–1764.

    Google Scholar 

  47. EPIC Investigators. Use of monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high risk coronary angioplasty. N Eng J Med 1994;330:956–961.

    Google Scholar 

  48. The CAPTURE Investigators. Randomized placebocontrolled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet 1997;349:1429–1435.

    Google Scholar 

  49. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low–dose heparin during percutaneous coronary revascularization. N Eng J Med 1997;336:1689–1696.

    Google Scholar 

  50. The EPISTENT Investigators. Randomized–placebo and balloon–angioplasty–controlled trial to assess safety of coronary stenting with use of platelet glycoprotein IIb/IIIa blockade. Lancet 1998;352: 87–92.

    Google Scholar 

  51. Harrington RA, Kleiman NS, Kottke–Marchant K, et al. Immediate and reversible platelet inhibition after intravenous administration of a peptide glycoprotein IIb/IIIa inhibitor during percutaneous coronary intervention. Am J Cardiol 1995;76:1222–1227.

    Google Scholar 

  52. Phillips DR, Teng W, Arfsten A, et al. Effect of Ca2 +. on GP IIb/IIIa interactions with Integrilin®: enhanced GP IIb/IIIa binding and inhibition of platelet aggregation by reductions in the concentration of ionized calcium in plasma anticoagulated with citrate. Circulation 1997;96:1488–1494.

    Google Scholar 

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Authors and Affiliations

  1. Clinical Pharmacy Specialist, Critical Care, UMass Memorial Medical Center, Worcester, MA, USA

    Brian S. Smith

  2. Boston, MA, USA

    Pritesh J. Gandhi (Assistant Professor of Clinical Pharmacy, Massachusetts College of Pharmacy and Health Sciences)

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  1. Brian S. Smith
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Smith, B.S., Gandhi, P.J. Pharmacokinetics and Pharmacodynamics of Low-Molecular-Weight Heparins and Glycoprotein IIb/IIIa Receptor Antagonists in Renal Failure. J Thromb Thrombolysis 11, 39–48 (2001). https://doi.org/10.1023/A:1008904310194

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