Erythropoietin therapy is one of the greatest inventions in Nephrology and it changed the way we treat anemic patients, which we were only dependent on blood transfusions in the past. Erythropoietin is a glycoprotein. Recombinant erythropoietin is produced by recombinant DNA technology in mammalian cell culture. Erythropoietin is available in many forms but α-epoetin and β-epoetin and Darbepoetin a longer acting erythropoietin with the half-life approximately three folds longer than recombinant erythropoietin is used regularly.
1µg darbepoetin is equal to 200 IU OF erythropoietin. This has been achieved by adding two extra N – linked carbohydrate side – chains to the erythropoietin molecule. As a result, darbepoetin requires less frequent dosage, usually once a week or once in every two weeks and sometimes only once a month in stable hemodialysis patients.
Recombinant human erythropoietin was introduced when it was realized that the major factor causing renal anemia is the deficiency of erythropoietin hormone by the diseased kidneys. The theory came in to practice in 1977 when human erythropoietin was isolated from the urine of patients with aplastic anemia. This allowed cloning of genes for human erythropoietin which was expressed in suitable mammalian cell line and large-scale synthesis of genetically engineered hormone began.
Animal studies were successful with greater efficacy and relative safety and clinical trials began in Seattle and London towards the end of 1985. Recombinant human erythropoietin got its license to use in renal anemia in 1990.
ERYTHROPOIETIN: STUDY OF THE DRUG
Recombinant human erythropoietin is like therapeutic protein hormones such as insulin which gets inactivated by acid in the stomach, therefore need to be given parenterally. Erythropoietin is available in vials, pre-filled syringes, and multidose injecting pen. Erythropoietin is relatively unstable at room temperature and must be kept in a fridge at 4°C.
Early clinical trials in hemodialysis patients used intravenous erythropoietin administered thrice weekly. After intravenous administration, serum erythropoietin concentrations decrease exponentially, with an elimination half-life of approximately 4–11 hours. Few authors said that half-life shortened with the repeated administration but there is no proper explanation for this.
When the intraperitoneal route was researched as a potential means of administering erythropoietin to patients on peritoneal dialysis, following intraperitoneal administration, serum erythropoietin concentrations starts to increase after 1–2 hours and reach a peak at around 18 hours. Peak concentrations are only 2–5% of those obtained with the same intravenous dose and the bioavailability of intraperitoneal erythropoietin is disappointingly low at 3–8%. A daily dose of erythropoietin is no better and should not be used, weekly dosing may be sufficient in renal failure patients.
With subcutaneous administration, peak serum concentrations of about 4–10% of an equivalent intravenous dose are obtained at around 12 hours, and thereafter they decay slowly such that concentrations greater than baseline are still present at 4 days. The bioavailability of subcutaneous erythropoietin is about seven times that of intraperitoneal administration, at around 20–25%.
ERYTHROPOIETIN: EFFECT OF THE DRUG
Based on drug studies, initial dosage regimens for erythropoietin employed thrice-weekly administration. This has remained the most popular dosage frequency for both intravenous and subcutaneous administration, although once-weekly, twice-weekly, and seven-times-weekly (once-daily) dosing have all been used successfully in treating patients with subcutaneous erythropoietin. With intravenous erythropoietin, the once-weekly administration is inadequate, and twice- or thrice-weekly dosing is required. Lower doses will be needed if the subcutaneous route is used.
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