Pharmacology Update
Darbepoetin Alfa—A New Treatment for Anemia Associated with CRF
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Darbepoetin alfa, a new recombinant erythropoietic protein recently approved by the FDA for the treatment of anemia associated with chronic renal failure (CRF). Darbepoetin, known as novel erythropoiesis stimulating protein, has a longer serum half-life than epoetin alfa which allows for less frequent dosing. The new drug is a hyperglycosylated analog of recombinant human erythropoietin (epoetin alfa) produced by recombinant DNA technology using Chinese hamster ovary cells. Amgen markets it under the trade name Aranesp.
Indication
Darbepoetin is indicated for the treatment of anemia associated with CRF. It is indicated for both predialysis and dialysis patients.1
Dosage
The recommended starting dose for correcting anemia is 0.45 µg/kg given as a single intravenous or subcutaneous dose once weekly. The dose should be adjusted to achieve and maintain target hemoglobin not to exceed 12 g/dL. Dose adjustments should not be made more frequently than once monthly. If hemoglobin is increasing and approaching 12 mg/dL, the dose should be reduced by about 25%. If hemoglobin continues to increase, the dose should be temporarily withheld until the level begins to decrease. The dose of darbepoetin alfa should then be reinstated at 25% of the previous dose. If hemoglobin increases > 1.0 g/dL in a 2-week period the dose should also be reduced by 25%.1
In many patients, particularly those in predialysis, maintenance dose may be lower than the starting dose.
Epoetin alfa may be converted to darbepoetin alfa based on the weekly dose of epoetin alfa.1 The estimated starting dose for darbepoetin alfa is 6.25 µg for patients on < 2500 units of epoetin alfa weekly; 12.5 µg for 2500-4999; 25 µg for 5000-10,999; 40 µg for 11,000-17,999; 60 µg for 18,000-33,999; 100 µg for 34,000-89,999; and 200 µg for 90,000 or greater. Patients previously receiving epoetin alfa 2-3 times a week should be administered darbepoetin alfa once weekly. Those receiving epoetin alfa once weekly should be administered darbepoetin alfa every 2 weeks.
Darbepoetin alfa is supplied as 25 µg, 45 µg, 60 µg, 100 µg, and 200 µg/mL in single 1 mL vials. The vials should not be shaken, diluted, or mixed with other drug solutions.1
Potential Advantages
Darbepoetin alfa has an elimination half-life about 3-fold longer than epoetin alfa (25.3 h vs 8.5 h) which permits less frequent dosing.2 Darbepoetin alfa can be dosed once weekly or once every other week compared to epoetin alfa, which is generally dosed from 1 to 3 times a week.
Potential Disadvantages
Darbepoetin alfa is only FDA approved for use in CRF and not as adjunct to chemotherapy or other types of anemia. There is a theoretical potential for the formation of neutralizing antibodies, however, the incidence of antibody development has not been adequately studied.1
Comments
Darbepoetin alfa was developed by increasing the carbohydrate content of epoetin alfa. The resulting molecule has a 52% carbohydrate content compared to 40% for epoetin alfa and a lower isoelectric point. The 2 drugs have the same mechanism of action. By binding to the erythropoietin receptor on erythroid progenitor cells, they stimulate the proliferation and differentiation of erythrocytes.3 Darbepoetin’s activity in terms of anemia correction in CRF patients is comparable to that of recombinant erythropoietin (epoetin alfa) in previously untreated patients as well as those previously maintained on recombinant epoetin alfa.3,4 Side effects also appear to be comparable between the 2 drugs.
Darbepoetin alfa is priced roughly comparable to that of epoetin alfa. Darbepoetin is about $4 per µg compared to about $1.10 per 100 unit for epoetin alfa. Depending on the equivalent dose used, darbepoetin alfa may be less expensive or more expensive than epoetin alfa. For example, 2500 units twice a week of epoetin alfa costs $225 per month. The corresponding dose of darbepoetin alfa, 25 µg once weekly, is priced at $400. However, 25,000 units 3 times a week of epoetin alfa would cost $3300 per month, while the corresponding dose of darbepoetin alfa is $1600 (100 µg weekly). A 5000 unit of epoetin once weekly at the cost of $220 per month would be similar to $200 per month for darbepoetin alfa (25 µg every 2 weeks). These are estimated starting doses and the maintenance doses may differ.
Clinical Implications
Darbepoetin alfa provides a formulation with comparable efficacy and side effects but less frequent dosing compared to epoetin alfa. This may be especially beneficial to patients not currently on dialysis. Amgen has studied darbepoetin alfa as adjunct to chemotherapy and has filed for a supplemental licensing for this indication.
Dr. Chan, Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA, and Dr. Elliott, Chair, Formulary Committee, Northern California Kaiser Permanente, and Assistant. Clinical Professor of Medicine, University of California-San Francisco, are Associate Editors of Internal Medicine Alert.
References
1. Aranesp Product Information. Amgen Inc. September 2001.
2. Macdougall IC, et al. J Am Soc Nephrol. 1999;10: 2392-2395.
3. Macdougall IC. Semin Nephrol. 2000;20:375-381.
4. Locatelli F, et al. Kidney Int. 2001;60:741-747.
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