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Epoetin Alfa

A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Use in Nonrenal Applications

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Summary

Synopsis

Epoetin alfa is a recombinant form of the principal hormone responsible for erythrogenesis, erythropoietin. Already an established treatment for anaemia associated with renal failure, epoetin alfa may also be used to correct anaemia in other patient groups. The drug increases the capacity for autologous blood donation in patients scheduled to undergo surgery and attenuates the decrease in haematocrit often seen in untreated autologous donors. However, transfusion requirements did not significantly decrease in many trials. Epoetin alfa also accelerates red blood cell recovery after allogeneic — but not autologous — bone marrow transplant. Limited data in patients with adult rheumatoid arthritis suggest that while epoetin alfa increases haematocrit/haemoglobin levels, overall clinical rheumatological status may not improve. However, the drug did improve quality of life in a small cohort of children with juvenile rheumatoid arthritis in addition to correcting anaemia.

Response rates to treatment with epoetin alfa in patients with anaemia associated with cancer range between 32 and 85%. Anaemia associated with cancer chemotherapy also responds well to treatment with the drug as does anaemia associated with zidovudine therapy in patients with acquired immune deficiency syndrome (AIDS).

Studies evaluating the use of epoetin alfa as treatment for anaemia of prematurity have used different methodologies and dosages, making overall analysis difficult. Nevertheless, it appears that high dosages are necessary for response. Results from 1 study suggest that treatment with epoetin alfa appears to be more costly than transfusional support in this application; the relevance of this finding is questionable, however, given that the aim of treatment with epoetin alfa is elimination of transfusion requirements.

The incidence of many adverse events associated with epoetin alfa treatment in patients with renal failure (hypertension, seizures and thromboembolic events) has been minimal in patients without renal failure. Adverse events occurred at a similar rate in placebo and epoetin alfa recipients in placebo-controlled trials evaluating the use of the drug as treatment for anaemia in patients with cancer receiving chemotherapy or patients with AIDS receiving zidovudine.

In summary, epoetin alfa is an effective alternative to blood transfusion, reducing anaemia and producing consequent improvements in quality of life in many nonrenal applications. It was more effective than placebo in a number of double-blind trials and may be particularly useful as treatment for anaemia associated with other drugs such as cisplatin and zidovudine.

Pharmacodynamic Properties

Epoetin alfa increases reticulocyte counts in healthy individuals and patients with anaemia associated with various pathologies including myelodysplastic syndrome and rheumatoid arthritis. Examination of the myeloid/erythroid ratio in 7 patients with myelodysplastic syndrome receiving epoetin alfa revealed an increased ability to form colony forming unit-erythroid derived colonies in 3 of 4 patients with increased reticulocyte counts.

This increase in reticulocyte count is followed by rises in haematocrit and haemoglobin levels. Platelet and monocyte counts may also increase but remain within the normal range.

Pharmacokinetic Properties

Administration of a single 150 IU/kg dose of epoetin alfa to 6 volunteers produced a peak serum concentration of 144 IU/L after 8 to 24 hours. Peak serum concentrations after subcutaneous administration are low compared with those achieved after intravenous administration but persist for several hours. Bioavailability was approximately 32% in 18 volunteers 72 hours after a single 100 IU/kg dose. The calculated mean volume of distribution of epoetin alfa at steady state was approximately 6-fold lower after subcutaneous than after intravenous administration of a 50 IU/kg dose. Data from animal studies suggest that recombinant human erythropoietin is distributed mainly to the liver and kidneys (although specific uptake occurs mostly in bone marrow); no data are available regarding distribution in humans. In 1 study, serum erythropoietin levels declined monoexponentially over an 18- to 24-hour period after intravenous administration of single or multiple doses of epoetin alfa 150 or 300 IU/kg. Epoetin alfa appears to be eliminated more rapidly after multiple versus single doses.

Therapeutic Use

A number of trials have evaluated the use of epoetin alfa to enhance autologous blood donation in patients scheduled to undergo surgery. Dosage regimens of 12 000 to 24 000IU administered subcutaneously once weekly or 300 to 600 IU/kg administered intravenously twice weekly appear to be most appropriate. Treatment with epoetin alfa enhances autologous blood donation with little effect on haemoglobin/haematocrit levels but the number of patients requiring allogeneic blood transfusions after surgery does not appear to significantly decrease.

The use of epoetin alfa to accelerate red blood cell production after allogeneic bone marrow transplantation has also been evaluated. One study reported a significantly faster rise in haematocrit in human leucocyte antigen-matched, ABO compatible bone marrow transplant recipients treated with epoetin alfa versus an untreated control group. Results from 2 larger controlled trials in this application were also favourable.

Results from 4 small studies, including 2 randomised double-blind placebocontrolled trials, show epoetin alfa to be an effective treatment for anaemia in patients with rheumatoid arthritis. The drug has also demonstrated efficacy as treatment for severe anaemia associated with juvenile rheumatoid arthritis in a small number of patients.

Response rates ≥50% have been reported in preliminary noncomparative studies evaluating the efficacy of epoetin alfa as treatment for cancer chemotherapyinduced anaemia and anaemia associated with various solid and haematological tumours. Several placebo-controlled trials have confirmed these favourable preliminary results.

Studies conducted to evaluate the efficacy of epoetin alfa as treatment for patients with myelodysplastic syndrome have used various definitions of response. However, overall response rates ranged between 0 and 56%.

Controlled studies evaluating the use of epoetin alfa as treatment for anaemia in patients with acquired immune deficiency syndrome (AIDS) have reported significantly reduced transfusion requirements compared with placebo. Results from 2 studies indicate that treatment with epoetin alfa may improve quality of life in patients with AIDS.

Initial pilot studies and some larger more recent trials evaluating the use of epoetin alfa as treatment for anaemia of prematurity indicate that dosages up to 200 IU/kg/week are ineffective but that higher dosages (300 to 600 IU/kg/week) may enhance the rate of erythropoiesis. In a direct comparison, epoetin alfa 200 IU/kg every second day was no more effective than erythrocyte transfusion as treatment for anaemia in 19 preterm infants. A separate cost-benefit analysis suggests that use of epoetin alfa is more costly than blood transfusions.

Very preliminary data suggest that epoetin alfa may be useful in patients with β-thalassaemia or sickle cell anaemia.

Tolerability

Trials evaluating the use of epoetin alfa as treatment for anaemia in patients with AIDS receiving zidovudine or patients with cancer receiving chemotherapy reported a similar incidence of adverse events in epoetin alfa versus placebo recipients. Adverse events that have been troublesome in patients with renal failure treated with epoetin alfa (hypertension, seizures and thromboembolic events) have occurred with a considerably lower incidence in patients with AIDS (treated with zidovudine) or patients with cancer receiving the drug.

Dosage and Administration

In patients with AIDS receiving zidovudine ≤4200 mg/week, the recommended initial dose of epoetin alfa is 100 IU/kg administered intravenously or subcutaneously 3 times a week. If response is unsatisfactory after 8 weeks the dosage can be increased by 50 to 100 IU/kg 3 times per week.

The recommended starting dose of epoetin alfa in patients with cancer undergoing chemotherapy is 150 IU/kg administered subcutaneously 3 times per week. This may be increased to 300 IU/kg 3 times per week after 4 weeks if response is unsatisfactory.

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    Anthony Markham & Harriet M. Bryson

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Various sections of the manuscript reviewed by: W.M. Bennett, Department of Medicine, Division of Nephrology, Hypertension and Clinical Pharmacology, Oregon Health Sciences University, Portland, Oregon, USA; S. Cascinu, Oncologia Medica, University of Ancona, Ancona, Italy; M.A. Fischl, Department of Medicine, Division of General Medicine, University of Miami School of Medicine, Miami, Florida, USA; D.S. Halpérin, Département de Pédiatrie, Hôpital Cantonal Universitaire de Genève, Geneva, Switzerland; J. Hayashi, Second Department of Surgery, Niigata University School of Medicine, Niigata, Japan; R.G. Kendall, Department of Haematology, The General Infirmary at Leeds, Leeds, England; K.M.L. Leunissen, Academisch Ziekenhuis Maastricht, Maastricht, The Netherlands; H. Ludwig, Department of Medicine and Oncology, Wilhelminenspital der Stadt Wien, Vienna, Austria; M. Mittelman, Department of Medicine B, Hasharon Hospital, Petah-Tikva, Israel; J.J. Walshe, Nephro-Urology Division, Beaumont Hospital, Dublin, Ireland

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Markham, A., Bryson, H.M. Epoetin Alfa. Drugs 49, 232–254 (1995). https://doi.org/10.2165/00003495-199549020-00008

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