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Clinical Pharmacokinetics

, Volume 42, Issue 12, pp 1043–1057 | Cite as

Pharmacodynamic and Pharmacokinetic Properties of Enoxaparin

Implications for Clinical Practice
  • Jawed Fareed
  • Debra Hoppensteadt
  • Jeanine Walenga
  • Omer Iqbal
  • Qing Ma
  • Walter Jeske
  • Taqdees Sheikh
Review Article

Abstract

Enoxaparin is a low-molecular-weight heparin (LMWH) that differs substantially from unfractionated heparin (UFH) in its pharmacodynamic and pharmacokinetic properties. Some of the pharmacodynamic features of enoxaparin that distinguish it from UFH are a higher ratio of anti-Xa to anti-IIa activity, more consistent release of tissue factor pathway inhibitor, weaker interactions with platelets and less inhibition of bone formation. Enoxaparin has a higher and more consistent bioavailability after subcutaneous administration than UFH, a longer plasma half-life and is less strongly bound to plasma proteins. These properties mean that enoxaparin provides a more reliable anticoagulant effect without the need for laboratory monitoring, and also offers the convenience of once-daily administration. Clinical studies have confirmed that these pharmacological advantages translate into improved outcomes. There are important pharmacokinetic and pharmacodynamic differences between enoxaparin, other LMWHs and UFH, and therefore these molecules cannot be regarded as interchangeable.

Keywords

Enoxaparin Abciximab Dalteparin Tissue Factor Pathway Inhibitor Nadroparin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The expert advice of Dr Dominick Argenti of Johnson and Johnson, Titusville, NJ, USA is gratefully acknowledged. We also acknowledge the expert assistance of Dr Mandy Wong and Dr Jacqueline Mason in the preparation of this manuscript. There were no sources of funding or conflicts of interest directly relevant to the content of this review.

References

  1. 1.
    Hirsh J, Warkentin TE, Raschke R, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1998; 114 (5 Suppl.): 489S–510SPubMedCrossRefGoogle Scholar
  2. 2.
    Frydman A. Low-molecular-weight heparins: an overview of their pharmacodynamics, pharmacokinetics and metabolism in humans. Haemostasis 1996; 26 Suppl. 2: 24–38PubMedGoogle Scholar
  3. 3.
    Kandrotas RJ. Heparin pharmacokinetics and pharmacodynamics. Clin Pharmacokinetics 1992; 22(5): 359–74CrossRefGoogle Scholar
  4. 4.
    Weitz JI, Hudoba M, Massel D, et al. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 385–91PubMedCrossRefGoogle Scholar
  5. 5.
    Walker AM, Jick H. Predictors of bleeding during heparin therapy. JAMA 1980; 244: 1209–12PubMedCrossRefGoogle Scholar
  6. 6.
    Ginsberg JS, Kowalchuk G, Hirsh J, et al. Heparin effect on bone density. Thromb Haemost 1990; 64: 286–9PubMedGoogle Scholar
  7. 7.
    Hirsh J, Levine MN. Low molecular weight heparin. Blood 1992; 79: 1–17PubMedGoogle Scholar
  8. 8.
    Fareed J, Jeske W, Hoppensteadt D, et al. Are all available low-molecular-weight heparin preparations the same? Semin Thromb Hemost 1996; 22Suppl. 1: 77–91PubMedGoogle Scholar
  9. 9.
    Brieger D, Dawes J. Production method affects the pharmacokinetic and ex vivo biological properties of low molecular weight heparins. Thromb Haemost 1997; 77: 317–22PubMedGoogle Scholar
  10. 10.
    Cohen M, Demeers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease: efficacy and safety of subcutaneous enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med 1997; 337: 447–52PubMedCrossRefGoogle Scholar
  11. 11.
    Fareed J, Walenga JM, Hoppensteadt D, et al. Comparative study on the in vitro and in vivo activities of seven low-molecular-weight heparins. Haemostasis 1988; 18 Suppl. 3: 3–15PubMedGoogle Scholar
  12. 12.
    Padilla A, Gray E, Pepper DS, et al. Inhibition of thrombin generation by heparin and low molecular weight (LMW) heparins in the absence and presence of platelet factor 4 (PF4). Br J Haematol 1992; 82: 406–13PubMedCrossRefGoogle Scholar
  13. 13.
    Fareed J, Walenga JM, Hoppensteadt D, et al. Biochemical and pharmacologic inequivalence of low molecular weight heparins. Ann N Y Acad Sci 1989; 556: 333–53PubMedCrossRefGoogle Scholar
  14. 14.
    Béguin S, Lindhout T, Hemker HC. The mode of action of heparin in plasma. Thromb Haemost 1988; 60: 457–62PubMedGoogle Scholar
  15. 15.
    Bara L, Bloch MF, Zitoun D, et al. Comparative effects of enoxaparin and unfractionated heparin in healthy volunteers on prothrombin consumption in whole blood during coagulation, and release of tissue factor pathway inhibitor. Thromb Res 1993; 69: 443–52PubMedCrossRefGoogle Scholar
  16. 16.
    Matthiasson SE, Lindblad B, Stjernquist U, et al. The haemorrhagic effect of low molecular weight heparins, dermatan sulphate and hirudin. Haemostasis 1995; 25: 203–11PubMedGoogle Scholar
  17. 17.
    Bang CJ, Berstad A, Talstad I. Haemorrhagic effects of unfractionated and two low molecular weight heparins, enoxaparin and fragmin, in rats. Haemostasis 1991; 21: 30–6PubMedGoogle Scholar
  18. 18.
    Bendz B, Hansen J-B, Andersen TO, et al. Partial depletion of tissue factor pathway inhibitor during subcutaneous administration of unfractionated heparin, but not with two low molecular weight heparins. Br J Haematol 1999; 107: 756–62PubMedCrossRefGoogle Scholar
  19. 19.
    Hansen J-B, Sandset PM, Huseby KR, et al. Differential effect of unfractionated heparin and low molecular weight heparin on intravascular tissue factor pathway inhibitor: evidence for a difference in antithrombotic action. Br J Haematol 1998; 101: 638–46PubMedCrossRefGoogle Scholar
  20. 20.
    Bendetowicz AV, Kai H, Knebel R, et al. The effect of subcutaneous injection of unfractionated and low molecular weight heparin on thrombin generation in platelet rich plasma: a study in human volunteers. Thromb Haemost 1994; 72: 705–12PubMedGoogle Scholar
  21. 21.
    Schoen P, Lindhout T, Franssen J, et al. Low molecular weight heparin-catalyzed inactivation of factor Xa and thrombin by antithrombin III: effect of platelet factor 4. Thromb Haemost 1991; 66: 435–41PubMedGoogle Scholar
  22. 22.
    Beguin S, Mardiguian J, Lindhout T, et al. The mode of action of low molecular weight heparin preparation (PK10169) and two of its major components on thrombin generation in plasma. Thromb Haemost 1989; 61: 30–4PubMedGoogle Scholar
  23. 23.
    Messmore Jr HL, Griffin B, Fareed J, et al. In vitro studies of the interaction of heparin, low molecular weight heparin and heparinoids with platelets. Ann N Y Acad Sci 1989; 556: 217–32PubMedCrossRefGoogle Scholar
  24. 24.
    Cade JF, Buchanan MR, Boneu B, et al. A comparison of the antithrombotic and haemorrhagic effects of low molecular weight heparin fractions: the influence of the method of preparation. Thromb Res 1984; 35: 613–25PubMedCrossRefGoogle Scholar
  25. 25.
    Brace LD, Fareed J, Tomeo J, et al. Biochemical and pharmacological studies on the interaction of PK 10160 and its subfractions with human platelets. Haemostasis 1986; 16: 93–105PubMedGoogle Scholar
  26. 26.
    Xiao Z, Theroux P. Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor. Circulation 1998; 97: 251–6PubMedCrossRefGoogle Scholar
  27. 27.
    Fernandez F, N’guyen P, Van Ryn J, et al. Hemorrhagic doses of heparin and other glycosaminoglycans induce a platelet defect. Thromb Res 1986; 43: 491–5PubMedCrossRefGoogle Scholar
  28. 28.
    Mirshahi M, Soria J, Neuhart E, et al. Effect of heparin and enoxaparin on platelet interaction with fibrin clots. Thromb Res 1992; 65: 187–91PubMedCrossRefGoogle Scholar
  29. 29.
    Van Rijn JLML, Trillou M, Mardiguian T, et al. Selective binding of heparins to human endothelial cells: implications for pharmacokinetics. Thromb Res 1987; 45: 211–22PubMedCrossRefGoogle Scholar
  30. 30.
    Zammit A, Pepper DS, Dawes J. Interaction of immobilised unfractionated and LMW heparins with proteins in whole human plasma. Thromb Haemost 1993; 70: 951–8PubMedGoogle Scholar
  31. 31.
    Young E, Cosmi B, Weitz J, et al. Comparison of the nonspecific binding of unfractionated heparin and low molecular weight heparin (enoxaparin) to plasma proteins. Thromb Haemost 1993; 70: 625–30PubMedGoogle Scholar
  32. 32.
    Young E, Wells P, Holloway S, et al. Ex-vivo and in-vitro evidence that low molecular weight heparins exhibit less binding to plasma proteins than unfractionated heparin. Thromb Haemost 1994; 71: 300–4PubMedGoogle Scholar
  33. 33.
    Bhandari M, Hirsh J, Weitz JI, et al. The effects of standard and low molecular weight heparin on bone nodule formation in vitro. Thromb Haemost 1998; 80: 413–7PubMedGoogle Scholar
  34. 34.
    Fareed J, Walenga JM, Hoppensteadt DA, et al. Laboratory studies on the intravenous and subcutaneous administration of PK 10169 in man. Haemostasis 1986; 16: 123–38PubMedGoogle Scholar
  35. 35.
    Montalescot G, Philippe F, Ankri A, et al. Early increase of von Willebrand factor predicts adverse outcome in unstable coronary artery disease: beneficial effects of enoxaparin. French Investigators of the ESSENCE Trial. Circulation 1998; 98: 294–9PubMedCrossRefGoogle Scholar
  36. 36.
    Hodl R, Hubert K, Kraxner W, et al. Comparison of effects of dalteparin and enoxaparin on hemostatic parameters and von Willebrand factor in patients with unstable angina pectoris or non-ST-segment elevation acute myocardial infarction. Am J Cardiol 2002; 89(5): 589–92PubMedCrossRefGoogle Scholar
  37. 37.
    Montalescot G, Collet JP, Lison L, et al. Effects of various anticoagulant treatments on von Willebrand factor release in unstable angina. J Am Coll Cardiol 2000; 36(1): 110–4PubMedCrossRefGoogle Scholar
  38. 38.
    Cornelli U, Fareed J. Human pharmacokinetics of low molecular weight heparins. Semin Thromb Hemost 1999; 25 Suppl. 3: 57–61PubMedGoogle Scholar
  39. 39.
    Dawes J. Comparison of the pharmacokinetics of enoxaparin (Clexane®) and unfractionated heparin. Acta Chir Scand 1990; 156 (556 Suppl.): 68–74Google Scholar
  40. 40.
    Azizi M, Veyssier-Belot C, Alhenc-Gelas M, et al. Comparison of biological activities of two low molecular weight heparins in 10 healthy volunteers. Br J Clin Pharmacol 1995; 40: 577–84PubMedGoogle Scholar
  41. 41.
    Collignon 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: 630–40PubMedGoogle Scholar
  42. 42.
    Eriksson BI, Soderberg K, Widlund L, et al. A comparative study of three low-molecular weight heparins (LMWH) and unfractionated heparin (UH) in healthy volunteers. Thromb Haemost 1995; 73: 398–401PubMedGoogle Scholar
  43. 43.
    Frydman AM, Bara L, Le Roux Y, et al. The antithrombotic activity and pharmacokinetics of enoxaparine, a low molecular weight heparin, in humans given single subcutaneous doses of 20 to 80mg. J Clin Pharmacol 1988; 28: 609–18PubMedGoogle Scholar
  44. 44.
    Bara L, Billaud E, Gramond G, et al. Comparative pharmacokinetics of a low molecular weight heparin (PK 10169) and unfractionated heparin after intravenous and subcutaneous administration. Thromb Res 1985; 39: 631–6PubMedCrossRefGoogle Scholar
  45. 45.
    Samama MM, Gerotziafas GT. Comparative pharmacokinetics of LMWHs. Semin Thromb Hemost 2000; 26 Suppl. 1: 31–8PubMedCrossRefGoogle Scholar
  46. 46.
    Bendetowicz AV, Beguin S, Caplain H, et al. Pharmacokinetics and pharmacodynamics of a low molecular weight heparin (enoxaparin) after subcutaneous injection, comparison with unfractionated heparin: a three way cross over study in human volunteers. Thromb Haemost 1994; 71: 305–13PubMedGoogle Scholar
  47. 47.
    Rabah MM, Premmereur J, Graham M, et al. Usefulness of intravenous enoxaparin for percutaneous coronary intervention in stable angina pectoris. Am J Cardiol 1999; 84: 1391–5PubMedCrossRefGoogle Scholar
  48. 48.
    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 (enoxaparin) after intravenous injection in normal volunteers. Br J Haematol 1991; 77: 201–8PubMedCrossRefGoogle Scholar
  49. 49.
    Bara L, Samama M. Pharmacokinetics of low molecular weight heparins. Acta Chir Scand Suppl 1988; 543: 65–72PubMedGoogle Scholar
  50. 50.
    Boneu B, Caranobe C, Sie P. Pharmacokinetics of heparin and low molecular weight heparin. Baillieres Clin Haematol 1990; 3: 531–44PubMedCrossRefGoogle Scholar
  51. 51.
    Cadroy Y, Pourrat J, Baladre MF, et al. Delayed elimination of enoxaparin in patients with chronic renal insufficiency. Thromb Res 1991; 63: 385–90PubMedCrossRefGoogle Scholar
  52. 52.
    Eldor A. Thrombophilia, thrombosis and pregnancy. Thromb Haemost 2001; 86(1): 104–11PubMedGoogle Scholar
  53. 53.
    Sanson BJ, Lensing AW, Prins MH, et al. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 668–72PubMedGoogle Scholar
  54. 54.
    Casele HL, Laifer SA, Woelkers DA, et al. Changes in the pharmacokinetics of the low-molecular-weight heparin enoxaparin sodium during pregnancy. Am J Obstet Gynecol 1999; 181 (5 Pt 1): 1113–7PubMedCrossRefGoogle Scholar
  55. 55.
    Gibson JL, Ekevall K, Walker I, et al. Puerperal thromboprophylaxis: comparison of the anti-Xa activity of enoxaparin and unfractionated heparin. Br J Obstet Gynaecol 1998; 105: 795–7PubMedCrossRefGoogle Scholar
  56. 56.
    Forestier F, Daffos F, Capella-Pavlovsky M. Low molecular weight heparin (PK 10169) does not cross the placenta during the second trimester of pregnancy: study by direct fetal blood sampling under ultrasound. Thromb Res 1984; 34: 557–60PubMedCrossRefGoogle Scholar
  57. 57.
    Arcavi L, Maier A, Caspi A. Safety of enoxaparin in the geriatric population [abstract]. Eur Heart J 1999; 20 Suppl. 1: 285Google Scholar
  58. 58.
    Massicotte P, Adams M, Marzinotto V, et al. Low-molecular weight heparin in pediatric patients with thrombotic disease: a dose finding study. J Pediatr 1996; 128: 313–8PubMedCrossRefGoogle Scholar
  59. 59.
    Punzalen RC, Hillery CA, Montgomery RR, et al. Low-molecular-weight heparin in thrombotic disease in children and adolescents. J Pediatr Hematol Oncol 2000; 22(2): 137–4CrossRefGoogle Scholar
  60. 60.
    Sanderink G, LeLiboux A, Jariwala N, et al. Enoxaparin pharmacokinetics and pharmacodynamics in renal impairment [abstract]. J Am Coll Cardiol 2001; 37(2) Suppl. A: 229ACrossRefGoogle Scholar
  61. 61.
    Bruno R, Vivier N, Veyrat-Follet C, et al. Population pharmacokinetics and pharmacokinetic-pharmacodynamic relationships for docetaxel. Invest New Drugs 2001; 19: 163–9PubMedCrossRefGoogle Scholar
  62. 62.
    Busby LT, Weyman A, Rodgers GM. Excessive anticoagulation in patients with mild renal insufficiency receiving long-term therapeutic enoxaparin. Am J Hematol 2001; 67(1): 54–6PubMedCrossRefGoogle Scholar
  63. 63.
    Gerlach AT, Pickworth KK, Seth SK, et al. Enoxaparin and bleeding complications: a review in patients with and without renal insufficiency. Pharmacotherapy 2000; 20(7): 771–5PubMedCrossRefGoogle Scholar
  64. 64.
    Inverso SM, Cohen M, Antman EM, et al. Safety and efficacy of unfractionated heparin versus enoxaparin in obese patients and patients with severe renal impairment: analysis from the ESSENCE and TIMI 11B studies [abstract]. J Am Coll Cardiol 2001; 37(2) Suppl. A: 365ACrossRefGoogle Scholar
  65. 65.
    Follea G, Laville M, Pozet N, et al. Pharmacokinetic studies of standard heparin and low molecular weight heparin in patients with chromic renal failure. Haemostasis 1986; 16: 147–51PubMedGoogle Scholar
  66. 66.
    Brophy DF, Wazny LD, Gehr TW, et al. The pharmacokinetics of subcutaneous enoxaparin in end-stage renal disease. Pharmacotherapy 2001; 21(2): 169–74PubMedCrossRefGoogle Scholar
  67. 67.
    Przedlacki J, Bogdanska-Straszynska B, Sawicka B, et al. Antithrombotic activity of low molecular weight heparin (enoxaparin) during hemodialysis in patients with terminal kidney failure [in Polish]. Pol Arch Med Wewn 1993; 91: 438–45Google Scholar
  68. 68.
    Sanderink G, LeLiboux A, Jariwala N, et al. Enoxaparin pharmacokinetics and pharmacodynamics in obese [abstract]. J Am Coll Cardiol 2001; 37(2) Suppl. A: 229ACrossRefGoogle Scholar
  69. 69.
    Cipolle RJ, Seifert RD, Neilan BA, et al. Heparin kinetics: variables related to disposition and dosage. Clin Pharmacol Ther 1981; 29: 387–93PubMedCrossRefGoogle Scholar
  70. 70.
    Goodman SG, Cohen M, Bigonzi F, et al. Randomized trial of low molecular weight heparin (enoxaparin) versus unfractionated heparin for unstable coronary artery disease: one-year results of the ESSENCE study: efficacy and safety of subcutaneous enoxaparin in non-Q wave coronary events. J Am Coll Cardiol 2000; 36(3): 693–8PubMedCrossRefGoogle Scholar
  71. 71.
    Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction: results of the thrombolysis in myocardial infarction (TIMI) IIB trial. Circulation 1999; 100: 1593–601PubMedCrossRefGoogle Scholar
  72. 72.
    The FRAX. I.S. Study Group. Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of unstable angina or non-Q wave myocardial infarction: FRAX.I.S. Eur Heart J 1999; 20: 1553–62CrossRefGoogle Scholar
  73. 73.
    Long-term low-molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease Investigators. Lancet 1999; 354: 701–7CrossRefGoogle Scholar
  74. 74.
    Michalis LK, Papamichail N, Katsouras CS, et al. Enoxaparin versus tinzaparin in the management of unstable coronary artery disease (EVET Study) [abstract]. J Am Coll Cardiol 2001; 37(2): 365ACrossRefGoogle Scholar
  75. 75.
    Zidar JP. Low-molecular-weight heparins in coronary stenting (the ENTICES trial): ENoxaparin and TIClopidine after Elective Stenting. Am J Cardiol 1998; 82: 29L–32LPubMedCrossRefGoogle Scholar
  76. 76.
    Kereiakes DJ, Young J, Broderick TM, et al. Therapeutic adjuncts for immediate transfer to the catheterization laboratory in patients with acute coronary syndromes. Am J Cardiol 2000; 86 Suppl. 12B: 10M–7MPubMedCrossRefGoogle Scholar
  77. 77.
    Young JJ, Kereiakes DJ, Grines CL, et al. Low-molecular weight heparin therapy in percutaneous coronary intervention: the NICE 1 and NICE 4 Trials. J Invasive Cardiol 2000; 12 Suppl. E: E14–8PubMedGoogle Scholar
  78. 78.
    Kereiakes DJ, Grines C, Fry E, et al. National investigators collaborating on enoxaparin: enoxaparin and abciximab adjunctive pharmacotherapy during percutaneous coronary intervention. J Invasive Cardiol 2001; 13(4): 272–8PubMedGoogle Scholar
  79. 79.
    Planes A, Vochelle N, Mazas F, et al. Prevention of post-operative venous thrombosis: a randomized trial comparing unfractionated heparin with low molecular weight heparin in patients undergoing total hip replacement. Thromb Haemost 1988; 60: 407–10PubMedGoogle Scholar
  80. 80.
    The German Hip Arthroplasty Trial (GHAT) Group. Prevention of deep vein thrombosis with low molecular-weight heparin in patients undergoing total hip replacement: a randomized trial. Arch Orthop Trauma Surg 1992; 111(2): 110–20CrossRefGoogle Scholar
  81. 81.
    Nightingale SL. From the food and drug administration [letter]. JAMA 1993; 270: 1672PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  • Jawed Fareed
    • 1
  • Debra Hoppensteadt
    • 1
  • Jeanine Walenga
    • 2
  • Omer Iqbal
    • 1
  • Qing Ma
    • 1
  • Walter Jeske
    • 2
  • Taqdees Sheikh
    • 3
  1. 1.Department of PathologyLoyola University Medical CenterMaywoodUSA
  2. 2.Cardiovascular InstituteLoyola University Medical CenterMaywoodUSA
  3. 3.AnesthesiologyLoyola University Medical CenterMaywoodUSA

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