Erythropoietin, epoetins, and darbepoetin

Uses

Recombinant human erythropoietin (epoetin and darbepoetin) provides effective therapy with a very favorable risk-benefit ratio in hemodialysis patients with end-stage chronic renal insufficiency, and in patients with progressive renal insufficiency who are not yet being dialysed [ ]. It improves cognitive function and the quality of life of patients with chronic uremia [ ] and is very effective in children with chronic renal graft rejection and anemia [ ]. It also offers new opportunities for treating anemia in non-uremic patients. In patients with chemotherapy-induced anemia, epoetin increases hemoglobin concentration, reduces transfusion requirements, and improves quality of life [ , ]. The response rate to epoetin in patients with multiple myeloma and anemia, which is 55–85% [ ], increases when GM-CSF or G-CSF is co-administered [ ]. Epoetin is also approved for indications such as anemia induced by zidovudine in HIV-infected patients, the prevention of anemia in surgical patients, and anemia of prematurity [ , ]. Treatment with epoetin results in a substantial improvement in the rehabilitation and quality of life of patients with cancer, AIDS, and rheumatoid arthritis [ ].

Anemia due to prematurity can also be treated with epoetin. However, there are still questions to be answered about its efficacy, dosage regimen, and route of administration (subcutaneously or intravenously) [ , ]. A comparison of the efficacy of daily versus less frequent dosing schedules in preterm infants showed that dosage regimens that achieve lower peak serum concentrations over a more prolonged period of time may be more efficacious [ ]. Although growth retardation in children with renal insufficiency does not improve [ , ], well-being, energy, appetite, and cardiac function are enhanced, and by obviating the need for regular blood transfusions, iron overload, allo-immunization to cellular antigens, and transfusion-transmitted viral infections are avoided [ ].

Patients with cancer often develop anemia, and several studies have shown that recombinant human epoetin is a useful alternative to blood transfusion in such patients [ ]. Response rates of up to about 80% have been reported in patients with cancer-related anemia, especially in patients treated with platinum-based chemotherapy [ ]. Epoetin corrects low hemoglobin concentrations, resulting in a better quality of life and probably improving cure rates in cancer patients undergoing radiotherapy [ ]. It also relieves symptoms of fatigue in patients with cancer [ , ], increasing hemoglobin and reducing transfusion requirements [ ]. No acceleration of tumor growth by epoetin has been observed [ ]. Epoetin has also been used in combination with G-CSF and amifostine or G-CSF and IL-3 as adjunctive treatment for cytopenias complicating myelodysplastic syndrome [ , ]. Although these combinations are well tolerated, they promote hemopoiesis only in a subgroup of these patients.

Epoetin combined with parenteral iron is effective and safe for moderate and severe iron deficiency anemia during pregnancy [ ], and iron supplementation is often required [ ]. The use of epoetin in combination with intravenous iron makes collection of larger numbers of autologous erythrocyte units feasible. However, epoetin does not synergize with G-CSF for the mobilization of peripheral blood progenitor cells in healthy donors [ ].

Epoetin has been used to reduce allogeneic transfusion needs by increasing the efficacy of autologous transfusion for elective surgery [ ]. The combination of autologous predonation and epoetin treatment reduces blood requirements during and after orthopedic and cardiac surgery [ ]. In elective open-heart surgery, 26 of 30 patients who received only iron preoperatively needed blood transfusions compared with one of 30 patients who received iron plus epoetin [ ].

While epoetin is not of benefit after autologous bone marrow transplantation, in patients receiving allogeneic bone marrow transplantation epoetin accelerates erythroid engraftment, increases hemoglobin concentrations, reduces requirements for erythrocyte transfusions, and shortens the time to transfusion independence [ ].

The main limiting factor in obtaining an optimal response to epoetin is the adequacy of the patient’s iron stores [ , ]; the response is abated in the presence of iron deficiency, occult blood loss, hemolysis, and other hematological diseases [ , ]. Other causes of an inadequate response to epoetin include concurrent infection or inflammatory disease [ ], aluminium toxicity, vitamin deficiencies, secondary hyperparathyroidism [ , ], and osteitis fibrosa [ , ].

Pharmacokinetics

Subcutaneous epoetin in patients undergoing hemodialysis can maintain the hematocrit at a desired target range using an average weekly dose lower than with intravenous administration [ ]. Intravenous administration leads to higher initial epoetin concentrations compared with subcutaneous administration. However, after intravenous administration the half-life is only 4–5 hours, compared with 19–22 hours after subcutaneous administration [ ].

Darbepoetin

Darbepoetin alfa is a long-acting form of erythropoietin, with additional sialic acid residues, and does not require such frequent administration as epoetin; its long half-life allows administration once every 1 or 2 weeks [ ].

General adverse effects and adverse reactions

Adverse reactions to epoetin and darbepoetin are similar [ ]. Common adverse reactions are infection, hypertension, hypotension, shunt thrombosis, myalgia, nausea, headache, and chest pain [ , ]. After the first few doses of epoetin, flu-like symptoms occur transiently, with an incidence of 5–18% [ , ]. These can be avoided by injecting epoetin subcutaneously rather than intravenously [ , , , ]. It has also been suggested that such symptoms can be avoided by dose escalation, starting with an ultra-low dose [ ]. Subcutaneous injection can cause local reactions, probably due to allergy [ ].

Adverse reactions to darbepoetin include hypertension, injection site pain (generally mild and transient) in the case of subcutaneous administration, cardiovascular events, headache, vascular disorders (vascular access thrombosis), flu-like symptoms, and rashes [ , , ]. Adverse reactions such as hypertension and thrombophlebitis are observed in uremic patients requiring dialysis but not in patients with hematological malignancies [ ].

Observational studies

In a prospective trial in 3012 patients, the clinical benefits and adverse events profiles were similar with once-weekly epoetin compared with historical experience with thrice-weekly dosing [ ].

In 194 patients a low dose of epoetin beta before elective surgery was well tolerated and reduced the need for transfusions [ ].

Effective epoetin treatment has been reported in a transfusion-dependent beta-thalassemia major patient: there were no adverse effects [ ].

In four patients with chronic diffuse gastrointestinal bleeding that was difficult to control, epoetin was successfully used as a hemostatic agent [ ].

Placebo-controlled studies

In a double-blind, randomized, placebo-controlled, multicenter study in 80 critically ill patients, epoetin led to a 45% reduction in the number of erythrocyte units transfused. There were no epoetin-related adverse effects [ ].

Cardiovascular

In a randomized study of 180 patients with anemia due to hormone-refractory prostate cancer, who were treated with epoetin beta 1000 IU or 5000 IU subcutaneously 3 times a week for 12 weeks, cardiovascular events were more frequent with the higher dosage. Four patients had deep vein thrombosis and two had myocardial infarctions; all were taking the higher dosage. However, only one of the patients with deep vein thrombosis had a high hemoglobin concentration [ ].