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Published on 1 July 2007

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A step forward in the treatment of anaemia in patients with chronic kidney disease

teaser

Stanisław Niemczyk
MD PhD

Deputy Head

Łukasz Wozniacki
MD

Intern

Department of Nephrology, Dialysis Therapy and Internal Medicine
Public Central Teaching Hospital
Medical University of Warsaw
Poland

E: stanislaw.niemczyk@am.edu.pl

Erythropoietin deficiency is the main cause of anaemia in patients with chronic kidney disease (CKD). This common and debilitating condition is associated with cardiovascular ­morbidity and subsequent mortality, reduced quality of life and accelerated renal disease progression.(1,2)

Since erythropoiesis-stimulating agents (ESAs) were first introduced in the 1980s, they have become a cornerstone of anaemia therapy. ­Currently, three ESAs are available for the treatment of renal ­anaemia: epoetin alfa, epoetin beta and ­darbepoetin alfa. The presently approved ESA therapies are based on intravenous (IV) or subcutaneous (SC) injections, usually once to three times a week, which is a cumbersome schedule for medication requiring continuous, long-term administration and frequent dose adjustments due to haemoglobin cycling.(3) Such a therapeutic strategy contributes to increased workload for health providers and an increased total cost of treatment.(4)

CERA, the first continuous erythropoietin ­receptor activator, is in development for treating anaemia at extended dosing intervals in patients who have CKD and who are in pre-dialysis or dialysis ­programmes. CERA is a chemically synthesised complex ­molecule which differs from human ­erythropoietin by i­ntegration of amide bonds between amino groups on the N-terminus or lysine residues and methoxypolyethylene glycol butanoic acid. The resulting ­molecule has a molecular weight of approximately 60,000 Da (native erythropoietin size is 30.4 kDa).(5) ­While erythropoietin is rapidly ­internalised and degraded following receptor ­binding, the evidence suggests that CERA associates more slowly with the erythropoietin receptor, resulting in lower binding affinity compared with epoetin. As a consequence CERA is eliminated more slowly by receptor-mediated uptake and degradation, resulting in a higher plasma concentration of CERA over longer times, which in turn provides continuous stimulation of
erythropoiesis.(6–8)

The lower binding affinity for the erythropoietin receptor, combined with different pharmacological properties (eg, prolonged half-life), indicate that extended administration intervals and a ­stable erythropoietic response may be feasible with CERA. Recent studies aimed at evaluating the pharmacokinetic and pharmacodynamic properties of CERA have confirmed this assumption. The first fully reported, open-label, randomised study which involved 16 ESA-naive patients with CKD showed that CERA has a prolonged and comparable half-life after intravenous (IV) (mean 134 h) and subcutaneous (SC) (mean 139 h) administration when used in a single dose of 0.4 μg/kg IV or 0.8 μg/kg SC, respectively.(3) The absolute ­bioavailability of ­subcutaneous CERA was calculated to be 52%, which is consistent with previous findings in healthy subjects, and approximately 40–60% higher in comparison with epoetins and ­darbepoetin alfa that were administered subcutaneously.(9–11) The reticulocyte response, measured by reticulocyte count, peaked at a median of eight days after drug administration and then returned to levels that were close to baseline by day 21. No change in mean haemoglobin concentration was noted after single administration of both IV and SC CERA.

Safety and tolerability of CERA were comparable to that of existing ESAs.

The ability to administer ESAs during haemodialysis (HD) or haemofiltration (HF) has advantages in terms of flexibility of administration schedule. An in vitro study by Dougherty et al showed that ­during four-hour HD or HF there was no significant change in the CERA concentration in serum and ­undetectable levels in the ultrafiltrate.(12) Furthermore, CERA appeared to behave similarly to serum ­proteins, showing ­identical changes in its ­concentration during HF. Therefore, HD or HF with standard membranes does not remove CERA from circulating blood, ­suggesting that the new erythropoietic agent can be administered at any time during these procedures without affecting efficacy. This may offer flexibility and convenience to patients and dialysis staff.

Achieving and maintaining stable haemoglobin levels within a narrow range (eg 11–12 g/dl), as ­recommended in the US National Kidney Foundation Kidney Dialysis Outcomes Quality Initiative (NKF-K/DOQI) guidelines, is one of the key challenges in anaemia management.(13) The kinetics of currently available ESA therapy result in episodic peaks and troughs in serum epoetin levels, which has been correlated with haemoglobin fluctuation and suboptimal management of anaemia.(3,14) Therefore, despite the undoubted successes of epoetin alfa and darbepoetin alfa in clinical practice, there is a need for further advances in the treatment and maintaining renal anaemia at a stable level.

The most recent phase II and III studies have examined the efficacy of SC and IV CERA in maintaining haemoglobin at dosing intervals of up to four weeks in patients receiving dialysis previously maintained on ­epoetin.15–17 In one study, 572 patients were ­randomised to SC ­epoetin once to three times a week, SC CERA once every two weeks or SC CERA once every four weeks for 52 weeks. In a second study, 673 patients were randomised to IV epoetin once to three times a week, IV CERA once every two weeks or IV CERA once every four weeks for 52 weeks. The primary endpoint for both studies was the mean change in haemoglobin between baseline and a predetermined evaluation period (weeks 29–36). The data from these studies showed that both IV and SC administration of CERA every two weeks or every four weeks maintained haemoglobin ­levels in ­dialysis patients who were converted from ­epoetin alfa or beta at more frequent doses (see Figures 1 and 2). This strongly suggests that CERA, through the extended dosing intervals, may provide a ­significant advance in anaemia management.

[[HPE33_fig1_41USE]]

[[HPE33_fig2_42USE]]

In conclusion, CERA is an innovative erythropoietic agent with prolonged half-life acting differently at the receptor level that elicits a dose-dependent erythropoietic response. Pharmacokinetic ­studies showed that CERA has low systemic clearance, approximately 50% higher bioavailability and three- and seven-fold longer half-life compared with ­darbepoetin alfa SC and epoetin alfa SC, respectively.(10,11) Recent studies indicate that CERA administered at extended ­intervals may offer greater convenience with no compromise in efficacy and safety for the treatment of anaemia in patients with CKD.

References
1. Levin A. Nephrol Dial Transplant 2002;17 Suppl 5:8-13.
2. Fink JC, Blahut SA, Reddy M, et al. Am J Kidney Dis 2001;37:348-55.
3. Fishbane S, Berns JS. Kidney Int 2005;68:1337-43.
4. Smith DH, Gullion CM, Nichols G, et al. J Am Soc Nephrol 2004;15:1300-6.
5. Davis JM, Arakawa T, Strickland TW,  et al. Biochemistry 1987:26;2633-8.
6. Macdougall IC, Bailon P,  Tare T, et al. J Am Soc Nephrol 2003,14:769A.
7. Jelkmann W. Intern Med 2004;43:649-59.
8. Brandt M, Lanzendörfer M, Frische J, et al. EDTA 2006, SO018.
9. Macdougall IC, Robson R, Opatrzna S, et al. Clin J Am Soc Nephrol 2006;1:1211-5.
10. Halstenson CE, Macres M, Katz SA.
et al. Clin Pharmacol Ther 1991;50:702-12.
11. Macdougall IC, Gray SJ, Elston O,
et al. J Am Soc Nephrol 1999;10:2392-5.
12. Dougherty FC, Leypoldt JK, Cheung AH, et al. Poster presentation at ERA-EDTA Congress, Lisbon, Portugal, 15–18 May 2004.
13. National Kidney Foundation. Am J Kidney Dis 2006;47(5 Suppl 3):1-145.
14. Berns JS, Elzein H, Lynn RI, et al. Kidney Int 2003;64:1514-21.
15. Sułowicz W, Locatelli F, Balla J, et al. Poster presented at EDTA, Glasgow, Scotland, 15–18 July 2006.
16. Levin NW, Fishbane S, Zeig S, et al. Poster presented at EDTA, Glasgow, Scotland, 15–18 July 2006.
17. De Francisco AL, Sułowicz W, Klinger M, et al. Int J Clin Pract 2006;60:1687-96.



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