Erythropoietin - Hematopoietic Growth Factors

ERYTHROPOIETIN

Chemistry & Pharmacokinetics

Erythropoietin, a 34–39 kDa glycoprotein, was the first human hematopoietic growth factor to be isolated. It was originally puri-fied from the urine of patients with severe anemia. Recombinant human erythropoietin (rHuEPO, epoetin alfa) is produced in a mammalian cell expression system. After intravenous administra-tion, erythropoietin has a serum half-life of 4–13 hours in patients with chronic renal failure. It is not cleared by dialysis. It is mea-sured in international units (IU). Darbepoetin alfa is a modified form of erythropoietin that is more heavily glycosylated as a result of changes in amino acids. Darbepoetin alfa has a twofold to threefold longer half-life than epoetin alfa. Methoxy polyethylene glycol-epoetin beta is an isoform of erythropoietin covalently attached to a long polyethylene glycol polymer. This long-lived recombinant product is administered as a single intravenous or subcutaneous dose at 2-week or monthly intervals, whereas epoe-tin alfa is generally administered three times a week and darbepo-etin is administered weekly.

Pharmacodynamics

Erythropoietin stimulates erythroid proliferation and differentia-tion by interacting with erythropoietin receptors on red cell pro-genitors. The erythropoietin receptor is a member of the JAK/ STAT superfamily of cytokine receptors that use protein phospho-rylation and transcription factor activation to regulate cellular function . Erythropoietin also induces release of reticulocytes from the bone marrow. Endogenous erythropoietin is primarily produced in the kidney. In response to tissue hypoxia, more erythropoietin is produced through an increased rate of transcription of the erythropoietin gene. This results in correction of the anemia, provided that the bone marrow response is not impaired by red cell nutritional deficiency (especially iron defi-ciency), primary bone marrow disorders , or bone marrow suppression from drugs or chronic diseases.Normally, an inverse relationship exists between the hematocrit or hemoglobin level and the serum erythropoietin level. Nonanemic individuals have serum erythropoietin levels of less than 20 IU/L. As the hematocrit and hemoglobin levels fall and anemia becomes more severe, the serum erythropoietin level rises exponentially. Patients with moderately severe anemia usually have erythropoie-tin levels in the 100–500 IU/L range, and patients with severe anemia may have levels of thousands of IU/L. The most important exception to this inverse relationship is in the anemia of chronic renal failure. In patients with renal disease, erythropoietin levels are usually low because the kidneys cannot produce the growth factor. These are the patients most likely to respond to treatment with exogenous erythropoietin. In most primary bone marrow disorders (aplastic anemia, leukemias, myeloproliferative and myelodysplastic disorders, etc) and most nutritional and second-ary anemias, endogenous erythropoietin levels are high, so there is less likelihood of a response to exogenous erythropoietin .

Clinical Pharmacology

The availability of erythropoiesis-stimulating agents (ESAs) has had a significant positive impact for patients with several types of anemia (Table 33–4). 

The ESAs consistently improve the hematocrit and hemoglobin level, often eliminate the need for transfusions, and reliably improve quality of life indices. The ESAs are used routinely in patients with anemia secondary to chronic kidney disease. In patients treated with an ESA, an increase in reticulocyte count is usually observed in about 10 days and an increase in hematocrit and hemoglobin levels in 2–6 weeks. Dosages of ESAs are adjusted to maintain a target hemoglobin up to, but not exceeding, 10–12 g/dL. To support the increased erythropoiesis, nearly all patients with chronic kidney disease require oral or parenteral iron supplementation. Folate supplementation may also be necessary in some patients.

In selected patients, erythropoietin is also used to reduce the need for red blood cell transfusion in patients undergoing myelo-suppressive cancer chemotherapy who have a hemoglobin level <10 mg/dL, and for selected patients with low-risk myelodysplas-tic syndromes and anemia requiring red blood cell transfusion. Patients who have disproportionately low serum erythropoietin levels for their degree of anemia are most likely to respond to treat-ment. Patients with endogenous erythropoietin levels of less than 100 IU/L have the best chance of response, although patients with erythropoietin levels between 100 and 500 IU/L respond occa-sionally. Methoxy polyethylene glycol-epoetin beta should not be used for treatment of anemia caused by cancer chemotherapy because a clinical trial found significantly more deaths among patients receiving this form of erythropoietin.hemoglobin levels are <10 g/dL) and with the lowest dose needed to avoid transfusion.

Allergic reactions to ESAs have been infrequent. There have been a small number of cases of pure red cell aplasia (PRCA) accompanied by neutralizing antibodies to erythropoietin. PRCA was most commonly seen in dialysis patients treated subcutane-ously for a long period with a particular form of epoetin alfa (Eprex with a polysorbate 80 stabilizer rather than human serum albumin) that is not available in the United States. After regula-tory agencies required that Eprex be administered intravenously rather than subcutaneously, the rate of ESA-associated PRCA diminished. However, rare cases have still been seen with all ESAs administered subcutaneously for long periods to patients with chronic kidney disease.