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Differentiating Factors Between Erythropoiesis-Stimulating Agents

A Guide to Selection for Anaemia of Chronic Kidney Disease

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Abstract

Endogenous erythropoietin (EPO) consists of a central polypeptide core covered by post-translationally linked carbohydrates. Three of the four currently available erythropoiesis stimulating agents (ESA) — epoetin-α, epoetin-β and epoetin-ω — are composed of an identical amino acid sequence, but glycosylation varies as a result of type- and host cell-specific differences in the production process.

Epoetin-α and epoetin-β resemble each other with respect to molecular characteristics and pharmacokinetic data, although epoetin-β has a higher molecular weight, a lower number of sialylated glycan residues and possibly slight pharmacokinetic advantages such as a longer terminal elimination half-life. A serious adverse effect of long-term administration of ESA is pure red cell aplasia. This effect has been observed predominantly with subcutaneous use of epoetin-α produced outside the US after albumin was removed from the formulation. In comparison with the intravenous route, subcutaneous administration of epoetin has been reported to have a dose-sparing effect in some studies. Epoetin-β has been the subject of studies aimed at proving efficacy with a reduced administration frequency but results are not unequivocal.

Epoetin-co is produced in a different host cell than all other erythropoietic agents, hence glycosylation and pharmacokinetics are different. Small-scale clinical studies found epoetin-ω to be slightly more potent than epoetin-α.

Epoetin-δ is a recently approved agent produced by human cells that are genetically engineered to transcribe and translate the EPO gene under the control of a newly introduced regulatory DNA sequence. However, epoetin-δ is not yet on the market and few data are available.

The erythropoietin analogue darbepoetin-α carries two additional glycosylation sites that permit a higher degree of glycosylation. Consequently, in comparison with the other epoetins, darbepoetin-a has a longer serum half-life and a higher relative potency, which further increases with extension of the administration interval. Dosage requirements of darbepoetin-α do not appear to differ between the intravenous and subcutaneous routes of administration. The less frequent administration of darbepoetin-α in comparison to the other epoetins may reduce drug costs in the long term, but the variability in dosage or dosage frequency required within a single patient is high.

Further studies should be aimed at defining predictors of the individual demand for erythropoietic agents, thereby allowing nephrologists to prescribe a cost-effective, individualised regimen.

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Notes

  1. Use of brand names is for product identification purposes only and does not imply endorsement.

References

  1. Wu H, Liu X, Jaenisch R, et al. Generation of committed erythroid BFU-E and CFU-E progenitors does nor require erythropoietin or the erythropoietin receptor. Cell 1995; 83: 59–67

    Article  PubMed  CAS  Google Scholar 

  2. Lin CS, Lim SK, D’Agati V, et al. Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis. Genes Dev 1996; 10: 154–64

    Article  PubMed  CAS  Google Scholar 

  3. Sawada K, Krantz SB, Dai CH, et al. Purification of human blood burst-forming units-erythroid and demonstration of the evolution of erythropoietin receptors. J Cell Physiol 1990; 142: 219–30

    Article  PubMed  CAS  Google Scholar 

  4. Wickrema A, Krantz SB, Winkelmann JC, et al. Differentiation and erythropoietin receptor gene expression in human erythroid progenitor cells. Blood 1992; 80: 1940–9

    PubMed  CAS  Google Scholar 

  5. Koury MJ, Sawyer ST, Brandt SJ. New insights into erythropoiesis. Curr Opin Hematol 2002; 9: 93–100

    Article  PubMed  Google Scholar 

  6. Koury ST, Bondurant MC, Koury MJ. Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization. Blood 1988; 71: 524–37

    PubMed  CAS  Google Scholar 

  7. Deicher R, Hörl WH. Anaemia as a risk factor for the progression of chronic kidney disease. Curr Opin Nephrol Hypertens 2003; 12: 139–43

    Article  PubMed  CAS  Google Scholar 

  8. Eckardt KU. Pathophysiology of renal anemia. Clin Nephrol 2000; 53 Suppl. 1: S2–8

    PubMed  CAS  Google Scholar 

  9. Bosman DR, Winkler AS, Marsden JT, et al. Anemia with erythropoietin deficiency occurs early in diabetic nephropathy. Diabetes Care 2001; 24: 495–9

    Article  PubMed  CAS  Google Scholar 

  10. Tan CC, Eckardt KU, Firth J, et al. Feedback modulation of renal and hepatic erythropoietin messenger RNA in response to graded anemia and hypoxia. Am J Physiol 1992; 263: F474–F81

    PubMed  CAS  Google Scholar 

  11. Hsu CY, McCulloch CE, Curhan GC. Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: results from the Third National Health and Nutrition Examination Survey. J Am Soc Nephrol 2002; 13: 504–10

    Article  PubMed  Google Scholar 

  12. Foley RN, Parfrey PS, Harnett JD, et al. The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease. Am J Kidney Dis 1996; 28: 53–61

    Article  PubMed  CAS  Google Scholar 

  13. Levin A, Singer J, Thompson CR, et al. Prevalent left ventricular hypertrophy in the predialysis population: identifying opportunities for intervention. Am J Kidney Dis 1996; 27: 347–54

    Article  PubMed  CAS  Google Scholar 

  14. Mayer G, Hörl WH. Cardiovascular effects of increasing hemoglobin in chronic renal failure. Am J Nephrol 1996; 16: 263–7

    Article  PubMed  CAS  Google Scholar 

  15. Dordal MS, Wang FF, Goldwasser E. The role of carbohydrate in erythropoietin action. Endocrinology 1985; 116: 2293–9

    Article  PubMed  CAS  Google Scholar 

  16. Cheetham JC, Smith DM, Aoki KH, et al. NMR structure of human erythropoietin and a comparison with its receptor bound conformation. Nat Struct Biol 1998; 5: 861–6

    Article  PubMed  CAS  Google Scholar 

  17. Syed RS, Reid SW, Li C, et al. Efficiency of signalling through cytokine receptors depends critically on receptor orientation. Nature 1998; 395: 511–6

    Article  PubMed  CAS  Google Scholar 

  18. Yamaguchi K, Akai K, Kawanishi G, et al. Effects of sitedirected removal of N-glycosylation sites in human erythropoietin on its production and biological properties. J Biol Chem 1991; 266: 20434–9

    PubMed  CAS  Google Scholar 

  19. Storring PL, Tiplady RJ, Gaines Das RE, et al. Lectin-binding assays for the isoforms of human erythropoietin: comparison of urinary and four recombinant erythropoietins. J Endocrinol 1996; 150: 401–12

    Article  PubMed  CAS  Google Scholar 

  20. Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Br J Cancer 2001; 84 Suppl. 1: 3–10

    Article  PubMed  CAS  Google Scholar 

  21. Takeuchi M, Takasaki S, Shimada M, et al. Role of sugar chains in the in vitro biological activity of human erythropoietin produced in recombinant Chinese hamster ovary cell. J Biol Chem 1990; 265: 12127–30

    PubMed  CAS  Google Scholar 

  22. Wasley LC, Timony G, Murtha P, et al. The importance of N-and O-linked oligosaccharides for the biosynthesis and in vitro and in vivo biologic activities of erythropoietin. Blood 1991; 77: 2624–32

    PubMed  CAS  Google Scholar 

  23. Hoglund M. Glycosylated and non-glycosylated recombinant human granulocyte colony-stimulating factor (rhG-CSF): what is the difference? Med Oncol 1998; 15: 229–33

    Article  PubMed  CAS  Google Scholar 

  24. Jelkmann W. The enigma of the metabolic fate of circulating erythropoietin (Epo) in view of the pharmacokinetics of the recombinant drugs rhEpo and NESP. Eur J Haematol 2002; 69: 265–74

    Article  PubMed  CAS  Google Scholar 

  25. Lezon CE, Martinez MP, Conti MI, et al. Plasma disappearance of exogenous erythropoietin in mice under different experimental conditions. Endocrine 1998; 8: 331–3

    Article  PubMed  CAS  Google Scholar 

  26. Widness JA, Veng-Pedersen P, Schmidt RL, et al. In vivo 125I-erythropoietin pharmacokinetics are unchanged after anesthesia, nephrectomy and hepatectomy in sheep. J Pharmacol Exp Ther 1996; 279: 1205–10

    PubMed  CAS  Google Scholar 

  27. Macdougall IC, Roberts DE, Coles GA, et al. Clinical pharmacokinetics of epoetin (recombinant human erythropoietin). Clin Pharmacokinet 1991; 20: 99–113

    Article  PubMed  CAS  Google Scholar 

  28. Veng-Pedersen P, Widness JA, Pereira LM, et al. Kinetic evaluation of nonlinear drug elimination by a disposition decomposition analysis: application to the analysis of the nonlinear elimination kinetics of erythropoietin in adult humans. J Pharm Sci 1995; 84: 760–7

    Article  PubMed  CAS  Google Scholar 

  29. Chapel SH, Veng-Pedersen P, Schmidt RL, et al. Receptorbased model accounts for phlebotomy-induced changes in erythropoietin pharmacokinetics. Exp Hematol 2001; 29: 425–31

    Article  PubMed  CAS  Google Scholar 

  30. Skibeli V, Nissen-Lie G, Torjesen P. Sugar profiling proves that human serum erythropoietin differs from recombinant human erythropoietin. Blood 2001; 98: 3626–34

    Article  PubMed  CAS  Google Scholar 

  31. Halstenson CE, Macres M, Katz SA, et al. Comparative pharmacokinetics and pharmacodynamics of epoetin alfa and epoetin beta. Clin Pharmacol Ther 1991; 50: 702–12

    Article  PubMed  CAS  Google Scholar 

  32. Stockenhuber F, Loibl U, Gottsauner-Wolf M, et al. Pharmacokinetics and dose response after intravenous and subcutaneous administration of recombinant erythropoietin in patients on regular haemodialysis treatment or continuous ambulatory peritoneal dialysis. Nephron 1991; 59: 399–402

    Article  PubMed  CAS  Google Scholar 

  33. Nimtz M, Martin W, Wray V, et al. Structures of sialylated oligosaccharides of human erythropoietin expressed in recombinant BHK-21 cells. Eur J Biochem 1993; 213: 39–56

    Article  PubMed  CAS  Google Scholar 

  34. Macdougall IC, Gray SJ, Elston O, et al. Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol 1999; 10: 2392–5

    PubMed  CAS  Google Scholar 

  35. Macdougall IC. Novel erythropoiesis stimulating protein. Semin Nephrol 2000; 20: 375–81

    PubMed  CAS  Google Scholar 

  36. Scott SD. Dose conversion from recombinant human erythropoietin to darbepoetin alfa: recommendations from clinical studies. Pharmacotherapy 2002; 22: 160S–5S

    Article  PubMed  CAS  Google Scholar 

  37. Allon M, Kleinman K, Walczyk M, et al. Pharmacokinetics and pharmacodynamics of darbepoetin alfa and epoetin in patients undergoing dialysis. Clin Pharmacol Ther 2002; 72: 546–55

    Article  PubMed  CAS  Google Scholar 

  38. Sasaki H, Bothner B, Dell A, et al. Carbohydrate structure of erythropoietin expressed in Chinese hamster ovary cells by a human erythropoietin cDNA. J Biol Chem 1987; 262: 12059–76

    PubMed  CAS  Google Scholar 

  39. Starring PL, Tiplady RJ, Gaines Das RE, et al. Epoetin alfa and beta differ in their erythropoietin isoform compositions and biological properties. Br J Haematol 1998; 100: 79–89

    Article  Google Scholar 

  40. Powell JS, Berkner KL, Lebo RV, et al. Human erythropoietin gene: high level expression in stably transfected mammalian cells and chromosome localization. Proc Natl Acad Sci U S A 1986; 83: 6465–9

    Article  PubMed  CAS  Google Scholar 

  41. Nimtz M, Wray V, Rudiger A, et al. Identification and structural characterization of a mannose-6-phophate containing oligomannosidic N-glycan from human erythropoietin secreted by recombinant BHK-21 cells. FEBS Lett 1995; 365: 203–8

    Article  PubMed  CAS  Google Scholar 

  42. Conradt HS, Nimtz M, Dittmar KE, et al. Expression of human interleukin-2 in recombinant baby hamster kidney, Ltk-, and Chinese hamster ovary cells: structure of O-linked carbohydrate chains and their location within the polypeptide. J Biol Chem 1989; 264: 17368–73

    PubMed  CAS  Google Scholar 

  43. Transkaryotic therapies [online]. Available from URL: http://www.tktx.com [Accessed 2003 Dec 22]

  44. Bailon P, Pahlke W, Brandt M, et al. CERA (continuous erythropoiesis receptor activator) for the treatment of renal anaemia: a new agent with an innovative mechanism of action [abstract]. Nephrol Dial Transplant 2003; Suppl. 4: 166

    Google Scholar 

  45. Tare N, Pill J, Hösel W, et al. Preclinical pharmacodynamics and pharmacokinetics on CERA (continuous erythropoiesis receptor activator): a new erythropoetic agent for anaemia management in patients with kidney disease [abstract]. Nephrol Dial Transplant 2003; Suppl. 4: 166

    Google Scholar 

  46. Reigner B, Jordan P, Pannier A, et al. Phase I studies of the new erythropoietic agent, CERA (continuous erythropoiesis receptor activator): demonstration of a dose-dependent response [abstract]. Nephrol Dial Transplant 2003; Suppl. 4: 167

    Google Scholar 

  47. National Kidney Foundation. K/DOQI Clinical practice guidelines for anemia of chronic kidney disease 2000. Guideline 11. Am J Kidney Dis 2001; 37 (1 Suppl.): S182–238

    Article  Google Scholar 

  48. European best practice guidelines for the management of anaemia in patients with chronic renal failure: Working Party for European Best Practice Guidelines for the Management of Anaemia of Anaemia in Patients with Chronic Renal Failure. Nephrol Dial Transplant 1999; 14 Suppl. 5: 1–50

    Article  Google Scholar 

  49. Yu AW, Leung CB, Li PK, et al. Pain perception following subcutaneous injections of citrate-buffered and phophate-buffered epoetin alpha. Int J Artif Organs 1998; 21: 341–3

    PubMed  CAS  Google Scholar 

  50. Veys N, Dhondt A, Lameire N. Pain at the injection site of subcutaneously administered erythropoietin: phophate-buffered epoetin alpha compared to citrate-buffered epoetin alpha and epoetin beta. Clin Nephrol 1998; 49: 41–4

    PubMed  CAS  Google Scholar 

  51. St Peter WL, Lewis MJ, Macres MG. Pain comparison after subcutaneous administration of single-dose formulation versus multidose formulation of epogen in hemodialysis patients. Am J Kidney Dis 1998; 32: 470–4

    Article  CAS  Google Scholar 

  52. Gershon SK, Luksenburg H, Coté TR, et al. Pure red-cell aplasia and recombinant erythropoietin [letter]. N Engl J Med 2002; 346: 1584–6

    Article  PubMed  Google Scholar 

  53. Locatelli F, Del Vecchio. Erythropoietic proteins and antibody-mediated pure red cell aplasia: where are we now and where do we go from here? Nephrol Dial Transplant. In press

  54. Besarab A, Reyes CM, Hornberger J. Meta-analysis of subcutaneous versus intravenous epoetin in maintenance treatment of anemia in hemodialysis patients. Am J Kidney Dis 2002; 40: 439–46

    Article  PubMed  CAS  Google Scholar 

  55. Jacobs C, Hörl WH, Macdougall IC, et al. European Best Practice Guidelines 9–13; anaemia management. Nephrol Dial Transplant 2000; 15 Suppl. 4: 33–42

    Article  PubMed  Google Scholar 

  56. De Schoenmakere G, Lameire N, Dhondt A, et al. The haematopoietic effect of recombinant human erythropoietin in haemodialysis is independent of the mode of administration (i.V. or s.c.). Nephrol Dial Transplant 1998; 13: 1770–5

    Article  PubMed  Google Scholar 

  57. Kaufman JS, Reda DJ, Fye CL, et al. Subcutaneous compared with intravenous epoetin in patients receiving hemodialysis: Department of Veterans Affairs Cooperative Study Group on Erythropoietin in Hemodialysis Patients. N Engl J Med 1998; 339: 578–83

    Article  PubMed  CAS  Google Scholar 

  58. Cody J, Daly C, Campbell M, et al. Frequency of administration of recombinant human erythropoietin for anaemia of end-stage renal disease in dialysis patients (Cochrane Review). Available in The Cochrane Library [database on disk and CD ROM]. Updated quarterly. The Cochrane Collaboration; issue 4. Oxford: Update Software, 2002

    Google Scholar 

  59. Locatelli F, Baldamus CA, Villa G, et al. Once-weekly compared with three-times-weekly subcutaneous epoetin β: results from a randomized, multicenter, therapeutic-equivalence study. Am J Kidney Dis 2002; 40: 119–25

    Article  PubMed  CAS  Google Scholar 

  60. Cheung WK, Goon BL, Guilfoyle MC, et al. Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin after single and multiple subcutaneous doses to healthy subjects. Clin Pharmacol Ther 1998; 64: 412–23

    Article  PubMed  CAS  Google Scholar 

  61. Eschbach JW. Treatment of anemia of chronic kidney disease. Am J Kidney Dis 2001; 37: 191–4

    Article  Google Scholar 

  62. Besarab A. Physiological and pharmacodynamic considerations for route of EPO administration. Semin Nephrol 2000; 20: 364–74

    PubMed  CAS  Google Scholar 

  63. Besarab A, Flaharty KK, Erslev AJ, et al. Clinical pharmacology and economics of recombinant human erythropoietin in end-stage renal disease: the case for subcutaneous administration. J Am Soc Nephrol 1992; 2: 1405–16

    PubMed  CAS  Google Scholar 

  64. Cheung W, Minton N, Gunawardena K. Pharmacokinetics and pharmacodynamics of epoetin alfa once weekly and three times weekly. Eur J Clin Pharmacol 2001; 57: 411–8

    Article  PubMed  CAS  Google Scholar 

  65. Piccoli A, Malagoli A, Komninos G, et al. Subcutaneous epoetin-alpha every one, two and three weeks in renal anemia. J Nephrol 2002; 15: 565–74

    PubMed  CAS  Google Scholar 

  66. Grzeszczak W, Sulowicz W, Rutowski B, et al. on behalf of the European Collaborative Group. Once weekly and once fortnightly (every two weeks) subcutaneous epoetin beta is effective in PD patients with chronic renal anaemia [abstract]. Nephrol Dial Transplant 2002; 17 Suppl. 1: 24, O76

    Google Scholar 

  67. Hörl WH. A need for an individualized approach to end-stage renal disease patients. Nephrol Dial Transplant 2002; 17 Suppl. 6: 17–21

    Article  PubMed  Google Scholar 

  68. Acharya VN, Sinha DK, Almeida AF, et al. Effect of low dose recombinant human omega erythropoietin (rHuEPO) on anaemia in patients on hemodialysis. J Assoc Physicians India 1995; 43: 539–42

    PubMed  CAS  Google Scholar 

  69. Sikole A, Spasovski G, Zafirov D, et al. Epoetin omega for treatment of anemia in maintenance hemodialysis patients. Clin Nephrol 2002; 57: 237–45

    PubMed  CAS  Google Scholar 

  70. Bren A, Kandus A, Varl J, et al. A comparison between epoetin omega and epoetin alfa in the correction of anemia in hemodialysis patients: a prospective, controlled crossover study. Artif Organs 2002; 26: 91–7

    Article  PubMed  CAS  Google Scholar 

  71. Milutinovic S, Plavljanic D, Orsanic D. Once weekly erythropoietin omega is safe and effective in treatment of anemia in dialysis patients [abstract]. J Am Soc Nephrol 2002; 13: 463A

    Google Scholar 

  72. Locatelli F, Olivares J, Walker R, et al. Novel erythropoiesis stimulating protein (NESP) administered subcutaneously corrects anemia in subjects with chronic renal insufficiency (CRI) when administered at a reduced dose frequency compared with recombinant-human erythropoietin (r-HuEPO) [abstract]. J Am Soc Nephrol 2000; 11: A1486

    Google Scholar 

  73. Macdougall IC, Matcham J, Gray SJ. Correction of anaemia with darbepoetin alpha in patients with chronic kidney disease receiving dialysis. Nephrol Dial Transplant 2003; 18: 576–81

    Article  PubMed  CAS  Google Scholar 

  74. Aljama P, Bommer J, Canaud B, et al. Practical guidelines for the use of NESP in treating renal anaemia. Nephrol Dial Transplant 2001; 16 Suppl. 3: 22–8

    Article  PubMed  CAS  Google Scholar 

  75. Nissenson AR, Swan SK, Lindberg JS, et al. Randomized, controlled trial of darbepoetin alfa for the treatment of anemia in hemodialysis patients. Am J Kidney Dis 2002; 40: 110–8

    Article  PubMed  CAS  Google Scholar 

  76. Hörl WH, Holzer H, Mayer GJ. Treatment of renal anemia with darbepoetin alfa: results of an Austrian multicenter study [in German]. Wien Klin Wochenschr 2002; 114: 967–71

    PubMed  Google Scholar 

  77. Nissenson AR. Dosing darbepoetin alfa [letter]. Am J Kidney Dis 2002; 40: 872

    Article  PubMed  Google Scholar 

  78. Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Ann Intern Med 1989; 111: 992–1000

    CAS  Google Scholar 

  79. Walker R, on behalf of the European/Australian 20000144 Study Group. Aranesp™ (Darbepoetin alfa) administered at a reduced frequency of once every 4 weeks (Q4W) maintains hemoglobin levels in patients with chronic kidney disease (CKD) receiving dialysis [abstract]. Am J Kidney Dis 2002; 39: A33

    Google Scholar 

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Acknowledgements

No sources of funding were used to assist in the preparation of the manuscript. Non-personal research grants to the Division of Nephrology and Dialysis, Department of Medicine III, University of Vienna, are provided by Amgen, Baxter, Jansen-Cilag and Roche. Professor Dr Dr W.H. Hörl, FRCP, is a consultant to Baxter and Amgen. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.

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    Robert Deicher & Walter H. Hörl

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Deicher, R., Hörl, W.H. Differentiating Factors Between Erythropoiesis-Stimulating Agents. Drugs 64, 499–509 (2004). https://doi.org/10.2165/00003495-200464050-00004

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