Tinzaparin and other low-molecular-weight heparins: what is the evidence for differential dependence on renal clearance?

Experimental Hematology & Oncology

Torben Balchen²  Kristian B Johansen¹ 

[1] Scientific Advisor, Sjoelundsparken 41, DK-3150, Hellebaek, Denmark;DanTrials ApS, c/o Bispebjerg Hospital, Copenhagen, Denmark

关键词: Non-clinical;    Clinical;    Pharmacodynamics;    Pharmacokinetics;    Renal insufficiency;    Clearance;    Elimination;    Low-molecular-weight heparin (LMWH);    Tinzaparin;   

Others  :  812103
DOI  :  10.1186/2162-3619-2-21

 received in 2013-06-10, accepted in 2013-08-02,  发布年份 2013

【 摘 要 】

Since low-molecular-weight heparins (LMWHs) are eliminated preferentially via the kidneys, the potential for accumulation of these agents (and an increased risk of bleeding) is of particular concern in populations with a high prevalence of renal impairment, such as the elderly and patients with cancer. The risk of clinically relevant accumulation of anticoagulant activity as a result of a reduction in renal elimination appears to differ between LMWHs. This review describes the elimination pathways for LMWHs and assesses whether the relative balance between renal and non-renal (cellular) clearance may provide a mechanistic explanation for the differences in accumulation that have been observed between LMWHs in patients with impaired renal function. Clearance studies in animals, cellular binding studies and clinical studies all indicate that the balance between renal and non-renal clearance is dependent on the molecular weight (MW): the higher the MW of the LMWH, the more the balance is shifted towards non-renal clearance. Animal studies have also provided insights into the balance between renal and non-renal clearance by examining the effect of selective blocking of one of the elimination pathways, and it is most likely that cellular clearance is increased to compensate for decreased renal function. Tinzaparin (6,500 Da) has the highest average MW of the marketed LMWHs, and there is both clinical and preclinical evidence for significant non-renal elimination of tinzaparin, making it less likely that tinzaparin accumulates in patients with renal impairment compared with LMWHs with a lower MW distribution. On the basis of our findings, LMWHs that are less dependent on renal clearance may be preferred in patient populations with a high prevalence of renal insufficiency.

【 授权许可】

   
2013 Johansen and Balchen; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Bisio A, Vecchietti D, Citterio L, Guerrini M, Raman R, Bertini S, Eisele G, Naggi A, Sasisekharan R, Torri G: Structural features of low-molecular-weight heparins affecting their affinity to antithrombin. Thromb Haemost 2009, 102:865-873.
• [2]Hoy SM, Scott LJ, Plosker GL: Tinzaparin sodium: a review of its use in the prevention and treatment of deep vein thrombosis and pulmonary embolism, and in the prevention of clotting in the extracorporeal circuit during haemodialysis. Drugs 2010, 70:1319-1347.
• [3]Monreal M, Falgá C, Valle R, Barba R, Bosco J, Beato JL, Maestre A: Venous thromboembolism in patients with renal insufficiency: findings from the RIETE Registry. Am J Med 2006, 119:1073-1079.
• [4]Launay-Vacher V, Oudard S, Janus N, Gligorov J, Pourrat X, Rixe O, Morere JF, Beuzeboc P, Deray G, On behalf of the Renal Insufficiency and Cancer Medications (IRMA) Study Group: Prevalence of renal insufficiency in cancer patients and implications for anticancer drug management: the renal insufficiency and anticancer medications (IRMA) study. Cancer 2007, 110:1376-1384.
• [5]LEO Laboratories Limited: Innohep® 20,000 IU/ml and Innohep syringe 20,000 IU/ml Summary of Product Characteristics. 2011. http://www.medicines.org.uk/emc/medicine/5176/SPC webcite
• [6]Mahé I, Aghassarian M, Drouet L, Bal Dit-Sollier C, Lacut K, Heilmann JJ, Mottier D, Bergmann JF: Tinzaparin and enoxaparin given at prophylactic dose for eight days in medical elderly patients with impaired renal function: a comparative pharmacokinetic study. Thromb Haemost 2007, 97:581-586.
• [7]Pautas E, Gouin I, Bellot O, Andreux JP, Siguret V: Safety profile of tinzaparin administered once daily at a standard curative dose in two hundred very elderly patients. Drug Saf 2002, 25:725-733.
• [8]Siguret V, Pautas E, Février M, Wipff C, Durand-Gasselin B, Laurent M, Andreux JP, d'Urso M, Gaussem P: Elderly patients treated with tinzaparin (Innohep®) administered once daily (175 anti-Xa IU/kg): anti-Xa and anti-IIa activities over 10 days. Thromb Haemost 2000, 84:800-804.
• [9]Siguret V, Gouin-Thibault I, Pautas E, Leizorovicz A: No accumulation of the peak anti-factor Xa activity of tinzaparin in elderly patients with moderate-to-severe renal impairment: the IRIS substudy. J Thromb Haemost 2011, 9:1966-1972.
• [10]Garcia DA, Baglin TP, Weitz JI, Samama MM: Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012, 141(2 Suppl):e24S-e43S.
• [11]Bara L, Planes A, Samama MM: Occurrence of thrombosis and haemorrhage, relationship with anti-Xa, anti-IIa activities, and D-dimer plasma levels in patients receiving a low molecular weight heparin, enoxaparin or tinzaparin, to prevent deep vein thrombosis after hip surgery. Br J Haematol 1999, 104:230-240.
• [12]Depasse F, González de Suso MJ, Lagoutte I, Fontcuberta J, Borrell M, Samama MM: Comparative study of the pharmacokinetic profiles of two LMWHs - bemiparin (3500 IU, anti-Xa) and tinzaparin (4500 IU, anti-Xa) - administered subcutaneously to healthy male volunteers. Thromb Res 2003, 109:109-117.
• [13]Lane DA, Denton J, Flynn AM, Thunberg L, Lindahl U: Anticoagulant activities of heparin oligosaccharides and their neutralization by platelet factor 4. Biochem J 1984, 218:725-732.
• [14]De Swart CA, Nijmeyer B, Roelofs JM, Sixma JJ: Kinetics of intravenously administered heparin in normal humans. Blood 1982, 60:1251-1258.
• [15]Boneu B, Caranobe C, Gabaig AM, Dupouy D, Sie P, Buchanan MR, Hirsh J: Evidence for a saturable mechanism of disappearance of standard heparin in rabbits. Thromb Res 1987, 46:835-844.
• [16]Young E, Douros V, Podor TJ, Shaughnessy SG, Weitz JI: Localization of heparin and low-molecular-weight heparin in the rat kidney. Thromb Haemost 2004, 91:927-934.
• [17]Palm M, Mattsson C: Pharmacokinetics of heparin and low molecular weight heparin fragment (Fragmin) in rabbits with impaired renal or metabolic clearance. Thromb Haemost 1987, 58:932-935.
• [18]Boneu B, Caranobe C, Cadroy Y, Dol F, Gabaig AM, Dupouy D, Sie P: Pharmacokinetic studies of standard unfractionated heparin, and low molecular weight heparins in the rabbit. Semin Thromb Hemost 1988, 14:18-27.
• [19]Weitz DS, Weitz JI: Update on heparin: what do we need to know? J Thromb Thrombolysis 2010, 29:199-207.
• [20]Boneu B, Buchanan MR, Caranobe C, Gabaig AM, Dupouy D, Sie P, Hirsh J: The disappearance of a low molecular weight heparin fraction (CY 216) differs from standard heparin in rabbits. Thromb Res 1987, 46:845-853.
• [21]Briant L, Caranobe C, Saivin S, Sie P, Bayrou B, Houin G, Boneu B: Unfractionated heparin and CY 216: pharmacokinetics and bioavailabilities of the antifactor Xa and IIa effects after intravenous and subcutaneous injection in the rabbit. Thromb Haemost 1989, 61:348-353.
• [22]Peyrou V, Lormeau JC, Caranobe C, Gabaig AM, Crepon B, Saivin S, Houin G, Sié P, Boneu B: Pharmacological properties of CY 216 and of its ACLM and BCLM components in the rabbit. Thromb Haemost 1994, 72:268-274.
• [23]Palm M, Mattsson C: Pharmacokinetics of fragmin. A comparative study in the rabbit of its high and low affinity forms for antithrombin. Thromb Res 1987, 48:51-62.
• [24]Caranobe C, Petitou M, Dupouy D, Gabaig AM, Sié P, Buchanan MR, Boneu B: Heparin fractions with high and low affinities to antithrombin III are cleared at different rates. Thromb Res 1986, 43:635-641.
• [25]Stehle G, Wunder A, Sinn H, Schrenk HH, Harenberg J, Malsch R, Maier-Borst W, Heene DL: Pharmacokinetic properties of LMW-heparin-tyramine fractions with high or low affinity to antithrombin III in the rat. Semin Thromb Hemost 1997, 23:31-37.
• [26]Caranobe C, Barret A, Gabaig AM, Dupouy D, Sié P, Boneu B: Disappearance of circulating anti-Xa activity after intravenous injection of standard heparin and of a low molecular weight heparin (CY 216) in normal and nephrectomized rabbits. Thromb Res 1985, 40:129-133.
• [27]Johansen KB, Schroeder M, Lundtorp L, Mousa SA: Renal elimination of tinzaparin versus enoxaparin in normal versus nephrectomized rats. J Thromb Haemost 2007, 5(Suppl 2):629. abst P-W
• [28]Øie CI, Olsen R, Smedsrød B, Hansen J-B: Liver sinusoidal endothelial cells are the principal site for elimination of unfractionated heparin from the circulation. Am J Physiol Gastrointest Liver Physiol 2008, 294:G520-G528.
• [29]Harris EN, Baggenstoss BA, Weigel PH: Rat and human HARE/stabilin-2 are clearance receptors for high- and low-molecular-weight heparins. Am J Physiol Gastrointest Liver Physiol 2009, 296:G1191-G1199.
• [30]Pempe EH, Xu Y, Gopalakrishnan S, Liu J, Harris EN: Probing structural selectivity of synthetic heparin binding to stabilin protein receptors. J Biol Chem 2012, 287:20774-20783.
• [31]Schroeder M, Hogwood J, Gray E, Mulloy B, Hackett A-M, Johansen KB: Protamine neutralisation of low molecular weight heparins and their oligosaccharide components. Anal Bioanal Chem 2011, 399:763-771.
• [32]Bârzu T, Van Rijn JL, Petitou M, Molho P, Tobelem G, Caen JP: Endothelial binding sites for heparin. Specificity and role in heparin neutralization. Biochem J 1986, 238:847-854.
• [33]Bârzu T, Molho P, Tobelem G, Petitou M, Caen J: Binding and endocytosis of heparin by human endothelial cells in culture. Biochim Biophys Acta 1985, 845:196-203.
• [34]Vannucchi S, Pasquali F, Porciatti F, Chiarugi V, Magnelli L, Bianchini P: Binding, internalization and degradation of heparin and heparin fragments by cultured endothelial cells. Thromb Res 1988, 49:373-383.
• [35]Eriksson BI, Söderberg K, Widlund L, Wandeli B, Tengborn L, Risberg B: A comparative study of three low-molecular weight heparins (LMWH) and unfractionated heparin (UH) in healthy volunteers. Thromb Haemost 1995, 73:398-401.
• [36]Collignon F, Frydman A, Caplain H, Ozoux ML, Le RY, Bouthier J, Thébault 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, 73:630-640.
• [37]Barrett JS, Hainer JW, Kornhauser DM, Gaskill JL, Hua TA, Sprogel P, Johansen K, Van Lier JJ, Knebel W, Pieniaszek HJ Jr: Anticoagulant pharmacodynamics of tinzaparin following 175 iu/kg subcutaneous administration to healthy volunteers. Thromb Res 2001, 101:243-254.
• [38]Cambus JP, Saivin S, Heilmann JJ, Caplain H, Boneu B, Houin G: The pharmacodynamics of tinzaparin in healthy volunteers. Br J Haematol 2002, 116:649-652.
• [39]Fossler MJ, Barrett JS, Hainer JW, Riddle JG, Ostergaard P, van der Elst E, Sprogel P: Pharmacodynamics of intravenous and subcutaneous tinzaparin and heparin in healthy volunteers. Am J Health Syst Pharm 2001, 58:1614-1621.
• [40]Frydman AM, Bara L, Le Roux Y, Woler M, Chauliac F, Samama MM: The antithrombotic activity and pharmacokinetics 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.