Pharmaceutica Analytica Acta

Abstract

Differential Effects of Long-lived Erythropoietin Receptor Agonists in Rats

Peter J. Bugelski, Dorie Makropoulos, Tracey Spinka-Doms, Ed Eirikis, Amy Volk, Qun Jiao and Chichi Huang

Erythropoietin (EPO) regulates proliferation and differentiation of erythroid precursor cells into erythrocytes. Here, we report on experiments designed to study how the pharmacokinetic profiles of EPO receptor agonists, ranging from the short-lived epoetin-? to the long-lived EPO-MIMETIBODYTM constructs CNTO 530 and CNTO 531, influence the pharmacodynamic response in rats. Rats received a single dose of an EPO-R agonist and the effects on reticulocytes, red blood cells and hemoglobin were measured over time. The increase in red blood cells and hemoglobin were negatively correlated with clearance. At doses that cause a similar effect on reticulocytes, very long-lived EPO-R agonists caused prolonged production of red blood cells. In conclusion, we have shown that very long-lived EPO-R agonists cause prolonged production of red blood cells and increase in hemoglobin that is independent of their in vitro potency or the peak release of reticulocytes. These data suggest that EPO may be a survival factor for reticulocytes.