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Darbepoetin Alfa (ARANESP®)
Darbepoetin alfa is an erythropoiesis-stimulating protein closely related to erythropoietin (Epo). It is produced in Chinese hamster ovary cells by recombinant DNA technology. Darbepoetin is a 165-amino acid protein that differs from recombinant human EPO (rh-Epo) in that darbepo contains 5 N-linked oligosaccharide chains, whereas rh-Epo has only 3. The 2 additional N-glycosylation sites result from amino acid substitutions in the Epo peptide backbone. The additional carbohydrate chains increase the molecular weight of the glycoprotein from 30 to 37 kD and prolongs its half-life.
Darbepoetin stimulates erythropoiesis by the same mechanism as endogenous erythropoetin (Epo). Epo is produced in the kidney and released into the bloodstream in response to hypoxia. It interacts with progenitor stem cells to increase erythrocyte production. In patients with chronic renal failure (CRF), Epo production is impaired, and this is believed to be the primary cause of anemia in these patients.
Darbepoetin is indicated for the treatment of anemia associated with chronic renal failure, including patients on dialysis and patients not on dialysis.
- The terminal half-life of darbepoetin is approximately 3-fold longer than that of rh-Epo (t½ = 4 - 13 hours) regardless of the route of administration (IV or SC).
- Following IV administration to adult CRF patients, darbepoetin serum concentration-vs-time profile is bi-phasic, with a t½α of approximately 1.4 hours and t½β of approximately 21 hours.
- Following subcutaneous (SC) administration, the absorption is slow and rate-limiting, and the t½
β is 49 hours (range: 27 to 89 hours). The peak concentration occurs at 34 hours (range: 24 to 72 hours) post-SC administration in adult CRF patients, and bioavailability is approximately 37% (range: 30% to 50%).
- The distribution of darbepoetin in adult CRF patients is predominantly confined to the vascular space (approximately 60 mL/kg). With once weekly dosing, steady-state serum levels are achieved within 4 weeks.
- Darbepoetin is contraindicated in patients with uncontrolled hypertension or patients with known hypersensitivity to darbepoetin alfa or any of the excipients.
- Darbepoetin alfa and other erythropoietic therapies may increase the risk of cardiovascular events, including death, in patients with CRF.
- Blood pressure should be controlled adequately before initiation of therapy with darbepoetin alfa.
- Seizures have occurred in patients with CRF participating in clinical trials of Darbepoetin alfa and Epoetin alfa. During the first several months of therapy, blood pressure and the presence of premonitory neurologic symptoms should be monitored closely.
Darbepoetin alfa™ is available in two solutions, an albumin solution and a polysorbate solution
- Polysorbate Solution: 25 µg/mL, 40 µg/mL, 60 µg/mL, 100 µg/mL and 200 µg/mL.
- Albumin Solution: 25 µ g/mL, 40 µg/mL, 60 µg/ mL, 100 µg/mL and 200 µg/mL
- The recommended starting dose of darbepoetin alfa for the treatment of anemia in CRF patients is 0.45 µ
g/kg body weight, administered as a single IV or SC injection once weekly. Doses should be titrated to not exceed a target hemoglobin concentration of 12 g/dL.
- Conversion From Epoetin alfa to Darbepoetin alfa: the starting weekly dose of Darbepoetin alfa should be estimated on the basis of the weekly epoetin alfa dose at the time of substitution (table 1). Doses should then be titrated to maintain the target hemoglobin. Darbepoetin alfa should be administered once a week if the patient was receiving EPO alfa 2 to 3 times weekly and once every 2 weeks if the patient was receiving EPO alfa once per week. The route of administration should be maintained.
Table 1 Estimated darbepoetin alfa starting Doses (µg/week) based on previous epoetin alfa dose (Units/week) |
|
Previous Weekly Epoetin alfa Dose (Units/week) |
Weekly Darbepoetin alfa ™ Dose (µ
g/week) |
|
< 2,500 |
6.25 |
|
2,500 to 4,999 |
12.5 |
|
5,000 to 10,999 |
25 |
|
11,000 to 17,999 |
40 |
|
18,000 to 33,999 |
60 |
|
34,000 to 89,999 |
100 |
|
> 90,000 |
200 |
- The most commonly reported adverse reactions are :
- Infection (including sepsis, bacteremia, pneumonia, peritonitis, and abscess) (27 %).
- Hypertension (23%) or hypotension (22 %)
- Myalgia (21%)
- Headache (16 %)
- Diarrhea (16%).
- The most frequently reported serious adverse reactions are vascular access thrombosis (8 %), congestive heart failure (6 %), sepsis, and cardiac arrhythmia (10 %).
No formal drug interaction studies of darbepoetin alfa with other medications commonly used in CRF patients have been performed.
- http://www.aranesp.com
- Nissenson AR Novel erythropoiesis stimulating protein for managing the anemia of chronic kidney disease. Am J Kidney Dis. 2001;38(6):1390-7.
- Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Brit J Cancer 2001; 84 (Suppl 1): 3-10.
- Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998; 339: 584-90.
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