Comparing ESA Dosing Regimens for Anemic Kidney Disease PatientsNAAC Review Published: October 21, 2009
Although the FDA-approved starting dose of epoetin alfa for the correction of anemia in patients with chronic kidney disease (CKD) is 50-100 IU/kg, given subcutaneously three times per week (TIW), several studies report that hemoglobin (Hb) levels can be achieved and maintained within a specified target range when epoetin alfa is administered up to every 4 weeks. In fact, physicians often use once-weekly (QW) and biweekly (Q2W) dosing intervals to obtain an Hb target range in this patient population. Decreasing the frequency of injections could have a variety of benefits, including reducing the time spent in clinics and offices, increasing lifestyle flexibility, decreasing the utilization of healthcare services, and potentially improving compliance among CKD patients.
The dosage of epoetin alfa is individualized to maintain the Hb level within the target range of 11-12 g/dL or between 10 g/dL and 12 g/dL. Although the serum half-life of epoetin alfa ranges from 12-43 hours, the pharmacodynamic effect is evident by increased red blood cell counts for weeks to months. This suggests that dosing of epoetin alfa at extended intervals may be a potential treatment option. However, randomized studies have not been conducted to compare extended dosing regimens to the approved TIW dosing regimen. As a result, Pergola et al conducted a study to test the hypothesis that extended dosing regimens of epoetin alfa would be as safe and effective as the FDA-approved TIW dosing regimens.
The study was a randomized, open label, multicenter study conducted in the United States at 77 centers between August 2006 and February 2008. This was a three-phase study consisting of a 2-week screening phase, 44-week open label treatment phase (with a 22-week initiation and maintenance period followed by a 22-week safety period), and a 4-week posttreatment phase.
The study population consisted of 375 patients with CKD who satisfied all inclusion and exclusion criteria. These patients were randomly assigned by a ration of 1:1:1 to receive either (1) TIW for 22 weeks, then QW for 22 weeks; (2) QW for 44 weeks: or (3) Q2W for 44 weeks. The primary efficacy endpoint was the change in Hb level from baseline to the average of the Hb values over the last 8 weeks of treatment through week 22. The secondary efficacy endpoint was the proportion of subjects with an increase in Hb level ≥1 g/dL from baseline by week 9.
The authors concluded that extended dosing regimens were not inferior to the standard FDA TIW dosing regimen when used to treat anemia in subjects with stage 3-4 CKD. In fact, among extended dosing regimens, Hb levels rose at a somewhat slower rate and were less likely to exceed the Hb ceiling.
Pergola PE, Gartenberg G, Fu M, Wolfson M, Rao S, Bowers P. A Randomized Controlled Study of Weekly and Biweekly Dosing of Epoetin Alfa in CKD Patients With Anemia. Clin J Am Soc Nephrol. 2009 Sep 17.
NAAC Expert Commentary
This study provides further evidence of the difference between pharmacokinetics and pharmacodynamics when using ESAs. The authors are able to show that a short acting agent (half-life of 8 hours) can be given as infrequently as once per week with no loss of efficacy. Longer dosing intervals incur a dose penalty, however, which the authors characterize as “relatively modest.” However, a 35% increase in dose requirement is in fact quite substantial. In addition, patients who had the Q2W dosing had more blood transfusions than the patients in the shorter dosing interval groups. The authors explained that most of the transfusions occurred due to other medical circumstances, but it is unlikely that this finding occurred randomly.
The increased dose required for significant extension of the dosing interval would make this approach untenable in the anticipated environment of bundled payments for dialysis services. On the other hand, for patients not yet on dialysis, this study shows that one can extend the dosing interval of a short half-life ESA, with a resulting increase in convenience for the patient, while not necessarily needing to use a longer half-life ESA. Unfortunately, until our understanding of the basic physiology improves, we will be continuing to use ESAs in a largely empirical fashion rather than based on the important and distinctive pharmacokinetics and pharmacodynamics of individual agents.
Last Updated: October 21, 2009
View original published article at PubMed
http://www.anemia.org/professionals/reviews/content.php?contentid=000450§ionid=00014
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