Darbepoetin alfa

Darbepoetin alfa (INN) /dɑːrbəˈpoʊɪtɪn/ is a re-engineered form of erythropoietin containing 5 amino acid changes (N30, T32, V87, N88, T90) resulting in the creation of 2 new sites for N-linked carbohydrate addition. It has a 3-fold longer serum half-life compared to epoetin alpha and epoetin beta. It stimulates erythropoiesis (increases red blood cell levels) by the same mechanism as rHuEpo (binding and activating the Epo receptor) and is used to treat anemia, commonly associated with chronic kidney failure and cancer chemotherapy. Darbepoetin is marketed by Amgen under the trade name Aranesp.

Darbepoetin alfa
Clinical data
AHFS/Drugs.comMonograph
MedlinePlusa604022
License data
Pregnancy
category
Routes of
administration		Intravenous, subcutaneous injection
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC815H1317N233O241S5
Molar mass18396.19 g·mol−1
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The medication was approved in September 2001, by the US Food and Drug Administration for treatment of anemia in patients with chronic kidney failure by intravenous or subcutaneous injection.[2] In June 2001, it had been approved by the European Medicines Agency for this indication as well as the treatment of anemia in cancer patients undergoing chemotherapy.[3]

Dr. Reddy's Laboratories launched darbepoetin alfa in India under the brand name ‘Cresp’ in August 2010. This is the world's first follow-on biologic of darbepoetin alfa.

Darbepoetin is produced by recombinant DNA technology in modified Chinese hamster ovary cells.[4] It differs from endogenous erythropoietin (EPO) by containing two more N-linked oligosaccharide chains. It is an erythropoiesis-stimulating 165-amino acid protein.

It is on the World Health Organization's List of Essential Medicines.[5]

Contraindications

Use of darbepoetin alfa is contraindicated in patients with hypersensitivity to the drug, pre-existing uncontrolled hypertension, and pure red cell aplasia.[6]

Adverse effects

Darbepoetin alfa has black box warnings in the United States for increased risk of death, myocardial infarction, stroke, venous thromboembolism, thrombosis of vascular access, and tumor progression or recurrence. To avoid side effects, it is recommended for patients with chronic kidney failure or cancer to use the lowest possible dose needed to avoid red blood cell (RBC) transfusions.[7]

In addition to those listed in the black box warning, use of darbepoetin alfa also increases the risk of cardiovascular problems, including cardiac arrest, arrhythmia, hypertension and congestive heart failure, and edema.[6] A recent study has extended these findings to treatment of patients exhibiting cancer-related anemia (distinct from anemia resulting from chemotherapy).[8] Other reported adverse reactions include increased risk of seizure, hypotension, and chest pain.

Pregnancy and lactation

Darbepoetin alfa is not assigned a pregnancy category in the United States.[1]

It is not known if darbepoetin alfa is excreted in breast milk.[7][1]

Mechanism of action

Darbepoetin alfa binds to the erythropoietin receptor on erythroid progenitor cells, stimulating RBC production and differentiation.[6]

Safety advisories in anemic cancer patients

Amgen sent a "dear stockholders" letter in January, 2007, that highlighted results from a recent anemia of cancer trial, and warned doctors to consider use in that off-label indication with caution.[9]

Amgen advised the U.S. Food and Drug Administration (FDA) as to the results of the DAHANCA 10 clinical trial. The DAHANCA 10 data monitoring committee found that 3-year loco-regional control in subjects treated with Aranesp was significantly worse than for those not receiving Aranesp (p=0.01).

In response to these advisories, the FDA released a Public Health Advisory[10] on March 9, 2007, and a clinical alert[11] for doctors on February 16, 2007, about the use of erythropoeisis-stimulating agents (ESAs) such as epoetin alfa (marketed as Epogen) and darbepoetin alfa. The advisory recommended caution in using these agents in cancer patients receiving chemotherapy or off chemotherapy, and indicated a lack of clinical evidence to support improvements in quality of life or transfusion requirements in these settings.

According to the 2010 update to clinical practice guidelines from the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH), use of ESAs such as darbepoetin alfa in cancer patients is appropriate when following stipulations outlined in FDA-approved labeling.[12]

Society and culture

Like EPO, darbepoetin alfa has the potential to be abused by athletes seeking a competitive advantage. Its use during the 2002 Winter Olympic Games to improve performance led to the disqualification of cross-country skiers Larisa Lazutina of Russia, Olga Danilova of Russia and Johann Mühlegg of Spain from their final races.[13]

Economics

Epogen and Aranesp had more than $6 billion in combined sales in 2006. Procrit sales were about $3.2 billion in 2006.

References
  1. "Darbepoetin alfa (Aranesp) Use During Pregnancy". Drugs.com. 31 December 2018. Retrieved 7 April 2020.
  2. Siegel JP (2001-09-17). "Product Approval Information - Licensing Action". United States Food and Drug Administration. Archived from the original on 2006-10-22. Retrieved 2007-01-27.
  3. "European Public Assessment Report (Abstract)" (PDF). European Medicines Agency. 2001-06-08. Archived from the original (PDF) on 2006-10-17. Retrieved 2007-01-27.
  4. Smith RE, Jaiyesimi IA, Meza LA, Tchekmedyian NS, Chan D, Griffith H, et al. (April 2001). "Novel erythropoiesis stimulating protein (NESP) for the treatment of anaemia of chronic disease associated with cancer". British Journal of Cancer. 84 Suppl 1 (s1): 24–30. doi:10.1054/bjoc.2001.1749. PMC 2363901. PMID 11308271.
  5. World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
  6. "Darbepoetin Alfa (Lexi-Drugs)". LexiComp. Retrieved 29 October 2014.
  7. "Aranesp- darbepoetin alfa injection, solution Aranesp- darbepoetin alfa solution". DailyMed. Retrieved 7 April 2020.
  8. Pollack A (2007-01-26). "Amgen Finds Anemia Drug Holds Risks in Cancer Use". The New York Times. Retrieved 2007-01-27.
  9. Amgen (2007). "Amgen 2007 Annual Report and Financial Summary".
  10. "FDA Public Health Advisory: Erythropoiesis-Stimulating Agents (ESAs): Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp)". Food and Drug Administration. Archived from the original on 2007-05-28. Retrieved 2007-06-05.
  11. "Information for Healthcare Professionals: Erythropoiesis Stimulating Agents (ESA)". Food and Drug Administration. Archived from the original on 2007-05-15. Retrieved 2007-06-05.
  12. Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, et al. (November 2010). "American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer". Journal of Clinical Oncology. 28 (33): 4996–5010. doi:10.1200/jco.2010.29.2201. PMC 2988667. PMID 20975064. Archived from the original on 2014-11-03.
  13. McGrath M, Portal G (30 January 2002). "New drugs give cheats the edge". BBC News Online. Retrieved 3 November 2014.
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