Aranesp™ : a new erythropoiesis-stimulating protein

Aranesp™ : a new erythropoiesis-stimulating protein

Christine Chmielewski

Erythrocyte production is controlled by a biofeedback sequence that starts when the kidneys secrete the natural hormone erythropoietin in response to tissue hypoxia. This red blood cell-stimulating hormone initiates a cascade that causes cellular precursors in the bone marrow to evolve, resulting in the formation of mature red blood cells. In patients with chronic kidney disease (CKD), the progressive destruction of renal tissue impedes the kidney’s ability to produce appropriate quantities of erythropoietin. The resulting normocytic, normochromic anemia is one of the most well-documented manifestations of CKD.

Anemia arises early in the course of CKD, increasing in severity as the volume of functional kidney tissue declines. When left untreated, anemia is associated with a wide spectrum of adverse outcomes, including increases in (a) left ventricular hypertrophy and other cardiovascular disorders, (b) mortality, and (c) hospitalization; and decreases in (d) quality of life, (e) exercise capacity, (f) cognitive function, and (g) sexual function (Besarab & Schmidt, 2002).

Over the past decade, therapeutic application of Epoetin alfa has led to a steady increase in hemoglobin (Hb) levels among dialysis patients, resulting in a new standard of care for treating the anemia of CKD. This progressive increase in Hb levels has been driven by the publication of clinical reports that have consistently demonstrated the benefits of higher Hb levels. However, data also indicate that anemia remains underrecognized and undertreated in patients with chronic renal insufficiency (CRI). For example, a retrospective analysis that evaluated the quality of care immediately before the initiation of dialysis found that only 23% of patients were being treated for anemia, despite the fact that 68% had hematocrit levels below 30% (n = 131,484) (Obrador, Ruthazer, Arora, Kausz, & Pereira, 1999). Recently, the Food and Drug Administration approved darbepoetin alfa, a novel erythropoiesis-stimulating protein with a prolonged duration of action that offers an attractive therapeutic alternative for treating the anemia of CKD.

Indications/Actions/Study Results

Darbepoetin alfa is indicated for the treatment of the anemia of CKD in patients with either CRI or end stage renal disease (Amgen Inc., 2001). Darbepoetin alfa’s unique molecular structure of five carbohydrate chains and

up to 22 sialic acid residues contributes to its prolonged duration of action. In a comparative clinical trial, intravenous (IV) darbepoetin alfa had a half-life approximately three times longer than comparative doses of Epoetin alfa – 25.3 hours, compared with 8.45 hours (p = 0.0008, n = 21) (Amgen Inc., 2001; Macdougall et al., 1999).

Clinical studies have demonstrated that administering darbepoetin alfa once a week or every other week yields results comparable to twice- or thrice-weekly Epoetin alfa. In a study conducted by Locatelli et al. (2001), 166 people with CRI who were not receiving or have not received Epoetin were randomized to receive a subcutaneous (SC) dose of either 0.45 mcg/kg of darbepoetin alfa once a week, or 50 U/kg of Epoetin alfa twice a week. Doses of both medications were adjusted as necessary to maintain Hb levels in the study range of 11 to 13 g/dl. After 24 weeks, 93% of darbepoetin alfa patients and 92% of Epoetin alfa patients had achieved the target Hb level. The slope plotting the increase in Hb was similar for both medications, illustrating that once weekly darbepoetin alfa was as effective as twice-weekly Epoetin alfa in achieving target Hb levels.

A clinical trial to evaluate the efficacy of prolonged dosing intervals in patients with CRI yielded comparable results. In this study, 23 patients with early CRI received darbepoetin alfa every other week. After 10 weeks of therapy, 96% had achieved the study target Hb level of 11 to 13 g/dl; the median dose was 50 mcg (range 30 to 130 mcg) (Suranyi, Walker, Jackson, Feaster, & McDermott-Vitak, 2001).

Similar results have been observed in dialysis patients. Nissenson et al. (2000) conducted a double-blind study in which hemodialysis patients who were previously maintained on Epoetin alfa (n = 169) were switched to weekly darbepoetin alfa. The researchers found that patients were able to successfully maintain baseline Hb levels within the target range with a median weekly darbepoetin alfa dose of 0.53 mcg/kg (range, 0.30 to 0.93 mcg/kg).

Contraindications

Darbepoetin alfa is contraindicated in patients with either uncontrolled hypertension or known hypersensitivity to the active substance or any of the inactive ingredients.

Side Effects/Adverse Reactions

In controlled clinical studies, there were no important differences in adverse event rates between patients receiving darbepoetin alfa and patients receiving Epoetin alfa. Some of the adverse events reported during clinical studies are typically associated with CKD or else are recognized complications of dialysis and, therefore, may not necessarily be attributed to darbepoetin alfa therapy. The most common adverse events observed following treatment with darbepoetin alfa include hypertension (23%), hypotension (22%), and myalgias (21%). As with all therapeutic proteins, there is a potential for immunogenicity. However, within the confines of currently available assays, no clinical events related to the development of antibodies to darbepoetin alfa have been detected (Amgen Inc., 2001).

Usual Dosage/Routes of Administration

Darbepoetin alfa for injection is manufactured in an albumin-containing solution in five concentrations: 25 mcg/1 ml, 40 mcg/1 ml, 60 mcg/1 ml, 100 mcg/1 ml, and 200 mcg/1 ml vials. Although an albumin-free, polysorbate-based solution is also produced. It is currently not available in the United States.

The recommended starting dose of darbepoetin alfa for patients with CKD and anemia who have not previously received an erythropoiesis-stimulating protein is 0.45 mcg/kg body weight administered as a single IV or SC injection once a week. For patients who were previously maintained on an erythropoiesis-stimulating protein, the starting dose should be estimated on the basis of the baseline dose of Epoetin alfa. (Please refer to the darbepoetin alfa package insert for estimated conversion doses.) Because of its longer serum half-life, darbepoetin alfa should be administered less frequently than Epoetin alfa: once a week for patients who were receiving Epoetin alfa two or three times a week, and once every other week for patients who were receiving Epoetin alfa once a week. Doses should be titrated no more frequently than once a month on the basis of individual patient response. Many patients can eventually be maintained on every-other-week dosing (Amgen Inc., 2001). On the basis of clinical experience, nurses can expect typical maintenance doses of 25 mcg for patients receiving darbepoetin alfa weekly, or 60 mcg for those receiving the medication every other week.

Nursing Implications

Darbepoetin alfa administration requires nurses to apply many of the familiar anemia management strategies used with Epoetin alfa therapy. First, following the initiation of darbepoetin alfa or after a change in dose, the Hb should be assessed weekly for at least 4 weeks until it has stabilized. Hb increases that exceed 1.0 g/dl during any 2-week period should be avoided. Once target levels have been achieved, the Hb should be monitored at regular intervals.

Second, blood pressure should be routinely monitored during therapy. During clinical trials, approximately 40% of patients required initiation of or increases in antihypertensive therapy, especially during the early phase of treatment when the Hb was increasing.

Third, patients should be routinely assessed for conditions that may result in hyporesponse to therapy. For example, iron status should be evaluated for all patients before and during treatment, and most patients will eventually require supplemental iron therapy to maintain serum ferritin and transferrin saturation greater than 100 ng/ml and 20%, respectively (Amgen Inc., 2001). As is the case with other erythropoietic stimulants, patients receiving darbepoetin alfa should be educated about the importance of ongoing therapy to maintaining target Hb levels and the potential side effects associated with therapy.

With the approval of darbepoetin alfa and the apparent increased attention on anemia management throughout the CKD spectrum, nephrology nurses may be asked to assume responsibility for anemia management in patients with CRI as well as patients with ESRD. The reduced frequency of administration associated with darbepoetin alfa may simplify the anemia management process for nurses and patients. Other potential benefits include fewer needle sticks, a decreased need for office visits, a decrease in patient expenses (for travel and co-pay costs), and less disruption to patients’ lives. This is especially appealing for those who receive outpatient care. Additional clinical studies and practical nursing experience are required to determine the other potential benefits and management nuances associated with this new therapeutic option.

References

Amgen Inc. (2001). Aranesp[TM] (darbepoetin alfa) for injection. Package Insert. Thousand Oaks, CA: Author.

Besarab, A., & Schmidt, R. (2002). Anemia and Epoetin use: Anemia in patients with end-stage renal disease. In A.R. Nissenson & R.N. Fine (Eds.), Dialysis therapy (3rd ed.) (pp. 309-317). Philadelphia: Hanley & Felfus, Inc.

Locatelli, F., Olivares, J., Walker, R., Wilkie, M., Jenkins, B., Dewey, C., & Gray, S.J. (2001). Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency. Kidney International, 60, 741-747.

Macdougall, I.C., Gray, S.J., Elston, O., Breen, C., Jenkins, B., Browne, J., & Egrie, J. (1999). Pharmacokinetics of novel erythropoiesis stimulating protein compared with Epoetin alfa in dialysis patients. Journal of the American Society of Nephrology, 10, 2392-2395.

Nissenson, A.R., Swan, S.K., Lindberg, J.S., Soroka, S.D., McDermott-Vitak, A.D., Wang, C., Picarello, N., & Beatey, R. (2000). Novel erythropoiesis stimulating protein (NESP) safely maintains hemoglobin concentration levels in hemodialysis patients as effectively as r-HuEPO when administered once weekly. Journal of the American Society of Nephrology, 11, 1326A. Abstract.

Obrador, G.T., Ruthazer, R., Arora, P., Kausz, A.T., & Pereira, B.J.G. (1999). Prevalence of and factors associated with suboptimal care before initiation of dialysis in the United States. Journal of the American Society of Nephrology, 10, 1793-1800.

Suranyi, M., Walker, R., Jackson, L., Feaster, J., & McDermott-Vitak, A. (2001). Novel erythropoiesis stimulating protein (NESP) administered once every other week corrects anemia in patients with chronic renal insufficiency (CRI). Journal of the American Society of Nephrology, 12, 1873A. Abstract.

The Medication Review section of the Nephrology Nursing Journal presents information on medications administered to individuals with nephrologic disorders. Readers wishing to contribute to this column should contact Kim Bremer, department editor, for assistance. For specific guidelines, see any February issue of the Nephrology Nursing Journal. The opinions and assertions contained herein are the private views of the contributors and do not necessarily reflect the views of the American Nephrology Nurses’ Association.

Christine Chmielewski, MS, CRNP, CNN, CS, is a Nephrology Nurse Practitioner at Edward J. Filippone, MD, PC, & Associates, in Philadelphia, PA.

Note: This article was reviewed by Michael Josbena, MS, RPh, President, Wordsmiths Health Communications.

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