Chapter 22: Erythropoietin-Stimulating Agents

OVERVIEW

Erythropoietic stimulating agents (ESA) are recombinant and synthetic erythropoietin (EPO). They are structurally and biologically similar to endogenous EPO and are used in the management of various types of anemia. Drugs in this class are epoetin alfa, darbepoetin alfa, and peginesatide. ESAs work by stimulating the bone marrow to produce red blood cells. Epoetin alfa, sometimes referred to as recombinant human erythropoietin (rHuEPO), is an exogenous EPO manufactured by recombinant DNA technology, and it was approved by the Food and Drug Administration (FDA) in 1989. It contains a 165-amino acid sequence with three N-linked and one O-linked carbohydrate changes and has the same biological effects as endogenous EPO.^1,2 It has a molecular weight of 30,400 daltons and is produced by mammalian cells.

Darbepoetin alfa (DA), a hyperglycosylated epoetin alfa analogue, contains five N-linked carbohydrate chains, two more than epoetin alfa, and has the same mechanism of action as rHuEPO.^3,4 Compared with epoetin alfa, darbepoetin alfa has a threefold increased serum half-life and allows extended dosing intervals.^{4, 5, and 6} The additional N-linked carbohydrate chains increased the molecular weight of darbepoetin from 30.4 to 37.1 daltons, and the carbohydrate contribution to the molecule corresponding increased from 40 percent to approximately 52 percent.⁷

Peginesatide is a synthetic pegylated peptide. It stimulates the EPO receptor similar to the endogenous hormone EPO and rHuEPO. Peginesatide is produced using chemistry rather than recombinant DNA technology. Its amino acid sequence is completely different from EPO and yet still able to activate the EPO receptor and stimulates erythropoiesis.⁸ In the summer of 2014, the manufacturer suspended peginesatide production due to post marketing reports of serious hypersensitivity reactions that may be life-threatening or fatal.

The FDA approved ESAs for the treatment of anemia resulting from chronic kidney disease, anemia in certain types of cancer patients receiving myelosuppressive chemotherapy, certain treatments for human immunodeficiency virus (HIV), and also to reduce the number of blood transfusions during and after certain major surgeries.^8,19,20 ESAs are also reportedly being used off-label for various conditions, including myelodysplastic syndrome,⁹ critically ill patients,^10,11 chronic heart failure,¹² anemia of chronic disease,¹³ chronic hepatitis C virus infection,¹⁴ and anemia in low birth weight infants.¹⁵

PHARMACOKINETICS

rHuEPO has a relatively short terminal half-life of 4–8 hours in humans, and it needs to be administered two to three times a week.¹⁶ Compared with rHuEPO, the EPO analogue darbepoetin-alfa carries two additional glycosylation sites that permit a higher degree of glycosylation. Consequently, darbepoetin alfa has a longer half-life of 25.3–48.8 hours in humans,⁵ and greater in vivo biological activity, which allows for less frequent administration.¹⁷ Unlike rHuEPO or darbepoetin alfa, peginesatide comprises a peptide sequence that is dimerized and linked to a two-branched 20-kDa PEG moiety, thus ...