The use of epoetin alfa to correct anemia in patients with chronic kidney disease (CKD) improves exercise tolerance and patient-reported functioning. Although the recommended initiation dosage of epoetin alfa is within 50-100 IU/kg three-times-weekly, several studies reported that the epoetin alfa is still effective in achieving and maintaining hemoglobin (Hb) target levels when given subcutaneously up to every four weeks. The objective of this study was to determine the pharmacokinetics, pharmacodynamics, and safety of giving epoetin alfa to patients who had CKD and who were not on dialysis, using the following dosing regimens: (1) 50 IU/kg three times weekly, (2) 10,000 IU once weekly, (3) 20,000 IU every 2 weeks, and (4) 40,000 IU every 4 weeks. The study was a prospective, open-label, randomized, multicenter study of 39 adult patients with anemia secondary to CKD. Patients were randomly assigned to one of the four regimens using a 1:1:1:1 ratio. Dosage adjustment was not allowed during the study. Patients were given oral elemental iron at a dosage of 200 to 400 mg/day. Patients discontinued the study treatment if Hb levels were ≥13 g/dL or increased by >1 g/dL in any 2-week period. Transfusions of red blood cells were given as necessary. A safety population was created from patients who were randomly assigned and who received one dose or more of the study drug.

The safety population was comprised of 38 patients, of which, 36 (95%) completed the study. Baseline endogenous erythropoietin concentrations ranged from below the quantification limit (<7.8 mU/mL) to 56.8 mU/mL. Erythropoietin concentrations declined multi-exponentially to baseline values by approximately day 8 following: (1) the third scheduled dose of epoetin alfa on day 5 in the three times-weekly group; and (2) after the first dose of epoetin alfa in the once-weekly, every-2-weeks, and every-4-weeks groups on day 1. There was substantial variability associated with most pharmacodynamics parameters (>50% of standard deviation). Mean percentage of reticulocyte responses over 1, 2, and 4 weeks (AUC) were similar for the once-weekly group compared with the three-times-weekly group. Mean percentage of reticulocytes showed a dose-dependent trend for the first week and a similar overall response across all regimens over the first 2 weeks. The reticulocyte response for the every-4-weeks group was initially greater than for the other dosing regimens. Mean overall response, based on Hb levels and total red blood cell count was similar across all dosing regimens, except in the once-weekly group, in which the mean observed overall response was lower over the first week, possibly because of a inter-patient variation. Although there were modest differences among the pharmacokinetics of the four different dosing regimens, the pharmacodynamics effects and safety of the extended interval regimens was comparable to the current recommendations for 50 IU/kg three-times-weekly.

McGowan T, Vaccaro NM, Beaver JS, Massarella J, Wolfson M. Pharmacokinetic and pharmacodynamic profiles of extended dosing of epoetin alfa in anemic patients who have chronic kidney disease and are not on dialysis. Clin J Am Soc Nephrol. 2008 Jul;3(4):1006-14.

NAAC Expert Commentary:
As reported in the article by McGowan et al, the use of epoetin alfa in patients with anemia associated with CKD results in improved exercise tolerance as well as patient perception of better functional levels. The current recommended initiation dosage requires administration of epoetin alfa three-times-weekly. However, several studies have confirmed the effectiveness of off-label dosing schedules where an ESA is administered subcutaneously every 1 to 4 weeks.(1)

In this small scale study of 39 patients, subjects received one of four epoetin alfa dosing regimens, with each regimen providing a similar dose of the medication over a 4-week period. Mean change in hemoglobin levels during the study were similar across the four dosing regimens.

To prevent the progression of CKD, it has become typical for some nephrologists with a substantial CKD patient population to use an extended dosing regimen in the treatment of anemia-related CKD. Significant improvement in exercise tolerance and resultant improvement in quality of life is extremely significant to patients. More notably, the majority of these same patients have greater than two risk factors for cardiovascular disease, the major cause of death and disability for CKD patients.(2) The prevalence rate of CKD has increased by more than 20% in the last decade,(3) causing loss of life and sky-rocketing healthcare costs. Therefore, it is essential to develop a regimen for managing CKD-related anemia that is efficacious, cost effective, and acceptable to the patient. Although this study included the examination of a three-times-weekly dosing regimen, it is important to note that this dosing regimen is rarely practiced by nephrologists.

While larger scale prospective studies are needed to demonstrate that the less frequent epoetin alfa dosing regimens positively affect mortality and morbidity rates as well as improve quality of life, the current study gives some scientific basis to support the practice common among those physicians currently treating anemia of CKD.

References

1. Provenzano R, Bhaduri S, Singh AK, PROMPT Study Group. Clin Nephrol. 2005 Aug;64(2):113-23. Extended epoetin alfa dosing as maintenance treatment for the anemia of chronic kidney disease: the PROMPT study.
2. Greenlund et al. Arch Intern Med. 2004, 164; 181-188, CDC; MMWR Morb Mortal Wkly Rep. 2005;54: 113-117
3. NephrOnline. Link. Accessed: October 27, 2008.

Last Updated: November 7, 2008