Proof-of-concept study on improved efficacy of rHuEPO administered as a long-term infusion in rats

Abstract

Background Human recombinant erythropoietin (rHuEPO) is often used in the treatment of diseases associated with a decreased production of red blood cells (RBC), such as chronic renal failure. rHuEPO is typically administered as an intravenous or subcutaneous (SC) injection every few days. The low minimum effective concentration (MEC) of rHuEPO, compared to the concentrations observed after standard doses, suggests that a low dose of the drug administered as a long-term infusion should be efficacious. This study aimed to compare the efficacy observed after a single subcutaneous administration of rHuEPO with that observed after a long-term infusion of rHuEPO via implanted osmotic pumps at a similar or lower dose. Materials and methods In this study three rats received rHuEPO as a single SC injection at a dose of 1350 IU/kg, nine via osmotic pumps at a rate of 0.25, 0.5 and 1 IU/kg and at a total dose of 333 IU/kg, 667 IU/kg, 1333 IU/kg. Three rats served as a control group. The erythropoietin concentrations, RBC count and hemoglobin were measured. Results An increase in RBC count and hemoglobin was observed after SC infusion of rHuEPO. The baseline corrected area under the effect curve for hemoglobin and RBC count was more than 10-times higher for the SC infusion than for a single SC administration with a comparable dose. Conclusions This study demonstrates that administration of rHuEPO as a long-term infusion at a rate ensuring MEC allows to achieve a high efficacy of therapy using relatively small doses of the drug.

A new role for erythropoietin in the homeostasis of red blood cells

“…The current paradigm of RBC homeostasis is based on two main assumptions: EPO regulates the production of new cells in the bone marrow 12 , 54 , and sinusoidal macrophages remove RBCs from the blood when they attain a certain species-specific age 55 . Qualitatively, these elements seem to provide a sound explanation for the control of RBC populations.…”

Killing them softly with EPO: a new role for erythropoietin in the homeostasis of red blood cells

“…The current paradigm of RBC homeostasis is based on two main assumptions: EPO regulates the production of new cells in the bone marrow [15, 53], and sinusoidal macrophages remove RBCs from the blood when they attain a certain species-specific age [54]. Qualitatively, these elements seem to provide a sound explanation for the control of RBC populations.…”