Pharmacokinetics and Application of Erythropoietin Therapy: Overview of Epoetin Alfa Studies in Japan

Erythropoietin (EPO) is a glycoprotein that has 3 N-link sugar chains. EPO was purified by Miyake and Goldwasser from the urine of aplastic anemia patients in 1977.' The EPO gene was cloned by Lin et al. from a genomic library in 1983,2 and recombinant human EPO, Epoetin Alfa, became available for therapeutic use in 1985. Epoetin Alfa is produced by Chinese hamster ovary (CHO) cells because of the importance of N-linked sugar chains for biological activities and is widely used for the treatment of anemia associated with chronic renal failure, cancer, HIV infection, and for boosting hemoglobin for the donation of autologous blood. Epoetin Alfa is a 34 kDa glycoprotein with 40% carbohydrate moieties and is identical with human natural EPO. The benefit of Epoetin Alfa for the anemia associated with chronic renal failure was studied and reported by Eschbach et al. in 1987.j The application of Epoetin Alfa for surgical settings and oncology was reported by Goodnough in 1991 .4 Epoetin Alfa is approved in more than 70 countries and widely used for chronic renal failure patients. At the beginning of the clinical development of Epoetin Alfa, intravenous administration was the route investigated, because Epoetin Alfa is a large glycoprotein and was not thought to be effective given subcutaneously or orally. Patients on hernodialysis have to visit dialysis centers two or three times per week and receive Epoetin Alfa intravenously at the center. Anemia patients on continuous ambulatory peritoneal dialysis (CAPD) or with predialysis chronic renal failure did not visit those centers or hospitals so often, and the need for frequent administration of Epoetin Alfa to maintain hematocrit created an inconvenience. Experiences through the development of other cytokines such as G-CSF and GM-CSF made the benefit of subcutaneous administration of those cytokines known to the public, and trials for Epoetin Alfa subcutaneous dosage have been reported. The most convenient Epoetin Alfa treatment is the least frequent, probably subcutaneous (sc) administration or sustained release. Formulation of Epoetin Alfa is also important for sc administration when you need higher dosage Epoetin Alfa treatment. The recommended dosage of Epoetin Alfa and available drugs in Japan are listed in TABLES 1 and 2. Intravenous (iv) administration two or three times per week at 25 or 50 IU/kg is recommended for anemia associated with chronic renal failure. Frequency required for iv administration is quite inconvenient for patients not on hemodialysis.