Semin Thromb Hemost 2000; Volume 26(Number s1): 031-038
DOI: 10.1055/s-2000-9497
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Comparative Pharmacokinetics of LMWHs

Meyer M. Samama, Grigoris T. Gerotziafas
  • Service d'Hématologie Biologique, Hôpital Hôtel-Dieu de Paris, Paris, France
Further Information

Publication History

Publication Date:
31 December 2000 (online)

 

ABSTRACT

A variety of pharmaceutical preparations of low-molecular-weight heparins (LMWHs) are available. They belong to the same family of compounds-ie, heparin derivatives with a narrow distribution of mean molecular weights (MWs). LMWHs have different methods of preparation, which result in variations in mean MW, distribution of MW, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles. The mean MW of these compounds ranges from 3600 to 6500 daltons. The ratio of anti-Xa (aXa) and anti-IIa (aIIa) activities of the different LMWHs ranges from 1.5 to >10. After subcutaneous (SC) injection of a prophylactic or therapeutic dose, the peak values for plasma aXa or aIIa activity may vary twofold to threefold because of differences in bioavailability, plasma clearance (Clplasma), and half-life (t1/2). The injection of equivalent amounts of product, based on aXa and aIIa international units (IU), may result in different areas under the curve for the respective activities. Although tinzaparin has a high aIIa specific activity per milligram (and consequently, a low aXa/aIIa ratio), SC injection of 40 mg of enoxaparin (4000 aXa IU) results in a higher aXa peak value in patients with total hip replacement than 4500 aXa IU of tinzaparin. Differences in aIIa and aXa peak activities are more striking when high doses of LMWHs are used. The activated partial thromboplastin time (aPTT) can be significantly prolonged, an effect that is related to aIIa and aXa activity. The volume of distribution of LMWHs is of the same order of magnitude as that of the plasma volume. The mean retention time of aXa activity varies from 5.2 (dalteparin) to ∼7 h (enoxaparin, nadroparin). Bioavailability of prophylactic doses of LMWHs ranges from 86% (dalteparin) to 98% (enoxaparin, nadroparin). PK parameters appear to be minimally affected by a patient's age. The Clplasma is different for each LMWH: 16 mL/min enoxaparin, 21 mL/min nadroparin, 33 mL/min dalteparin, 19 mL/min reviparin, and 22 mL/min tinzaparin. Accumulation of product has been observed for almost all LMWHs in patients with renal insufficiency.

LMWHs are effective and safe for treatment or prophylaxis of venous thromboembolism during pregnancy, because they do not cross the placenta. No data are available regarding the passage of LMWHs into the milk in lactating women. Although LMWHs are also effective in prevention and treatment of thromboembolic disease in children, optimal use of these agents in pediatric patients has not been determined. In summary, the PD and PK of LMWHs have been well documented and have demonstrated that LMWHs have a more predictable response, a greater bioavailability, and a longer aXa t1/2 than unfractionated heparin. However, their distribution of MW affects their physicochemical and biological proper-ties, as well as PK characteristics. The concept of aXa/aIIa ratio (determined in vitro) does not account for the differing PK of aXa and aIIa activity in circulating blood.

KEYWORD

Pharmacokinetic and pharmacodynamic characteristics and differences - low-molecular-weight heparins - anti-Xa and aIIa activity

REFERENCES

  • 1 Bergqvist D. Low-molecular-weight heparins.  J Intern Med . 1996;  240 63-72
    CrossrefPubMedGoogle Scholar
  • 2 Weitz J I. Low-molecular-weight heparins.  N Engl J Med . 1997;  337 688-698
    CrossrefPubMedGoogle Scholar
  • 3 Samama M M, Cohen A T, Darmon J Y. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group.  N Engl J Med . 1999;  341 793-800
    CrossrefPubMedGoogle Scholar
  • 4 Hemker H C, Beguin S. Mode of action of unfractionated and low-molecular-weight heparins on the generation of thrombin in plasma.  Haemostasis . 1990;  20(suppl 1) 81-92
    PubMedGoogle Scholar
  • 5 Beguin S, Lindhout T, Hemker H C. The mode of action of heparin in plasma.  Thromb Haemost . 1988;  60 457-462
    PubMedGoogle Scholar
  • 6 Gerotziafas G T, Bara L, Bloch M F, Makris P E, Samama M M. Comparative effects of synthetic pentasaccharide, low-molecular-weight heparin, unfractionated heparin and recombinant hirudin on the generation of factor VIIa and prothrombin activation after coagulation of human plasma.  Blood Coagul Fibrinolysis . 1998;  9 571-580
    PubMedGoogle Scholar
  • 7 Bara L, Bloch M F, Zitoun D. 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;  69 443-452
    CrossrefPubMedGoogle Scholar
  • 8 Dautzenberg M D, Bara L, Cornu P, Samama M. Specific anti-Xa activity of LMWH (Kabi 2165, CY 216, PK 10169) against the first international standard of LMWH: A collaborative study.  Thromb Haemost . 1990;  64 490-491 ((letter))
    PubMedGoogle Scholar
  • 9 Frydman A M, Bara L, Le Roux Y. The antithrombotic activity and PK of enoxaparine, a low molecular weight heparin, in humans given single subcutaneous doses of 20 to 80 mg.  J Clin Pharmacol . 1988;  28 609-618
    PubMedGoogle Scholar
  • 10 Azizi M, Veyssier-Belot C, Alhenc-Gelas M. Comparison of biological activities of two low molecular weight heparins in 10 healthy volunteers.  Br J Clin Pharmacol . 1995;  40 577-584
    PubMedGoogle Scholar
  • 11 Eriksson B I, Soderberg K, Widlund L. A comparative study of three low-molecular weight heparins (LMWH) and unfractionated heparin (UH) in healthy volunteers.  Thromb Haemost . 1995;  73 398-401
    PubMedGoogle Scholar
  • 12 Friedel H A, Balfour J A. Tinzaparin. A review of its pharmacology and clinical potential in the prevention and treatment of thromboembolic disorders.  Drugs . 1994;  48 638-660
    CrossrefPubMedGoogle Scholar
  • 13 Stiekema J C, Van Griensven M J, Van Dinther G T, Cohen A F. A cross-over comparison of the anti-clotting effects of three low molecular weight heparins and glycosaminoglycuronan.  Br J Clin Pharmacol . 1993;  36 51-56
    PubMedGoogle Scholar
  • 14 Collignon F, Frydman A, Caplain H. 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
    PubMedGoogle Scholar
  • 15 Pedersen P C, Østergaard P B, Hedner U, Bergqvist D, Mätzsch T. Pharmacokinetics of a low molecular weight heparin, logiparin, after intravenous and subcutaneous administration to healthy volunteers.  Thromb Res . 1991;  61 477-487
    CrossrefPubMedGoogle Scholar
  • 16 Simoneau G, Bergmann J F, 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
    CrossrefPubMedGoogle Scholar
  • 17 Frydman A. Low-molecular-weight heparins: An overview of their pharmacodynamics, pharmacokinetics and metabolism in humans.  Haemostasis . 1996;  26(suppl 2) 24-38
    PubMedGoogle Scholar
  • 18 Jeske W, Fareed J, Eschenfelder V. Biochemical and pharmacologic characteristics of Reviparin, a low-molecular-mass heparin.  Semin Thromb Hemost . 1997;  23 119-128
    PubMedGoogle Scholar
  • 19 Bara L, Planès A, Samama M M. Occurrence of thrombosis and haemorrhage, relationship with anti-Xa, anti-IIa activities, and D-dimer plasma levels in patients receiving low molecular weight heparin, enoxaparin or tinzaparin, to prevent deep vein thrombosis after hip surgery.  Br J Haematol . 1999;  104 230-240
    PubMedGoogle Scholar
  • 20 Charbonnier B A, Fiessinger J N, Banga J D. Comparison of a once daily with a twice daily subcutaneous low molecular weight heparin regimen in the treatment of deep vein thrombosis. FRAXODI group.  Thromb Haemost . 1998;  79 897-901
    PubMedGoogle Scholar
  • 21 Planès A, Samama M M, Lensing A WA. Prevention of deep vein thrombosis after hip replacement. Comparison between two low-molecular-weight heparins, tinzaparin and enoxaparin.  Thromb Haemost . 1999;  81 22-25
    PubMedGoogle Scholar
  • 22 Bratt G, Tornebohm E, Widlund 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
    CrossrefPubMedGoogle Scholar
  • 23 Verstraete M. Pharmacotherapeutic aspects of unfractionated and low molecular weight heparins.  Drugs . 1990;  40 498-530
    PubMedGoogle Scholar
  • 24 Boneu B, Caranobe C, Sie P. Pharmacokinetics of heparin and low molecular weight heparin.  Baillieres Clin Haematol . 1990;  3 531-544
    PubMedGoogle Scholar
  • 25 Laforest M D, Colas-Linhart N, Guiraud-Vitaux F. 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;  77 201-208
    PubMedGoogle Scholar
  • 26 Cadroy Y, Pourrat J, Baladre M F. Delayed elimination of enoxaparin in patients with chronic renal insufficiency.  Thromb Res . 1991;  63 385-390
    CrossrefPubMedGoogle Scholar
  • 27 Mismetti P, Laporte-Simitsidis S, Navarro C. Aging and venous thromboembolism influence the pharmacodynamics of the anti-factor Xa and anti-thrombin activities of a low-molecular-weight heparin (nadroparin).  Thromb Haemost . 1998;  79 1162-1165
    PubMedGoogle Scholar
  • 28 Troy S, Fruncillo R, Ozawa T. Absolute and comparative subcutaneous bioavailability of ardeparin sodium, a low-molecular-weight heparin.  Thromb Haemost . 1997;  78 871-875
    PubMedGoogle Scholar
  • 29 Andrew M, Boneu B, Cade J. Placental transport of low-molecular-weight heparin in the pregnant sheep.  Br J Haematol . 1985;  59 103-108
    PubMedGoogle Scholar
  • 30 Pautas E, Siguret V, Wipff C. Tinzaparin administered once daily in elderly (175 anti-Xa IU/kg) : A pharmacokinetic study over 10 days.  Zeitschrift fur Gerontologie und Geriatrie . 1999;  32 1014 ((Abstr))
    PubMedGoogle Scholar
  • 31 Blomback M, Bremme K, Hellgren M, Lindberg H. A pharmacokinetic study of dalteparin (Fragmin) during late pregnancy.  Blood Coagul Fibrinolysis . 1998;  9 343-350
    PubMedGoogle Scholar
  • 32 Pettila V, Kaaja R, Leinonen P. Thromboprophylaxis with low-molecular-weight heparin (dalteparin) in pregnancy.  Thromb Res . 1999;  96 275-282
    CrossrefPubMedGoogle Scholar
  • 33 Blomback M, Bremme K, Hellgren M, Siegbahn A, Lindberg H. Thromboprophylaxis with low-molecular-mass heparin, `Fragmin' (dalteparin), during pregnancy-A longitudinal safety study.  Blood Coagul Fibrinolysis . 1998;  9 1-9
    PubMedGoogle Scholar
  • 34 Harenberg J, Schneider D, Heilmann L, Wolf H. Lack of anti-factor Xa activity in umbilical cord vein samples after subcutaneous administration of heparin or low molecular mass heparin in pregnant women.  Haemostasis . 1993;  23 314-320
    PubMedGoogle Scholar
  • 35 Sutor A H, Massicotte P, Leaker M, Andrew M. Heparin therapy in pediatric patients.  Semin Thromb Hemost . 1997;  23 303-319
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Streif W, Mitchell L G, Andrew M. Antithrombotic therapy in children.  Curr Opin Pediatr . 1999;  11 56-64
    CrossrefPubMedGoogle Scholar
  • 37 Massicotte P, Adams M, Marzinotto V, Brooker L A, Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: A dose finding study.  J Pediatr . 1996;  128 313-318
    CrossrefPubMedGoogle Scholar
  • 38 Fijnvandraat K, Nurmohamed M T, Peters M, Vanamstel S LBP, TenCate J W. A cross-over dose-finding study investigating a low molecular weight heparin (Fragmin℗) in six children on chronic-hemodialysis.  Thromb Haemost . 1993;  69 649 ((Abstr))
    PubMedGoogle Scholar
  • 39 Hashikura Y, Kawasaki S, Okumura N. Prevention of hepatic artery thrombosis in pediatric liver transplantation.  Transplantation . 1995;  60 1109-1112
    PubMedGoogle Scholar
  • 40 Gagnadoux M F, Charbit M, Beurton D. Renal transplantation in children under five years of age. Experience at the Hopital des Enfants-Malades.  Ann Pediatr (Paris) . 1993;  40 108-111
    PubMedGoogle Scholar