TITLE:
Pharmacodynamics of CNTO 530 and Darbepoetin-α in Human TNF-α Transgenic Mice, a Murine Model of Anemia of Chronic Disease
AUTHORS:
Ram Achuthanandam, Dorie Makropoulos, Laura Johns, Amy Volk, Kerry Brosnan, Jin Lu, Wojciech Krzyzanski, Peter J. Bugelski
KEYWORDS:
Fusion Protein, Recombinant, Flow Cytometry, Erythropoiesis
JOURNAL NAME:
Pharmacology & Pharmacy,
Vol.2 No.1,
January
19,
2011
ABSTRACT: CNTO 530 and darbepoetin-a are long lived erythropoietin receptor agonists (ERAs). Clinically, anemia of chronic disease (ACD) is associated with increased expression of tumor necrosis factor-a (TNF-a) and mice transgenic for human TNF-a develop ACD. The purpose of this investigation was to compare the effects of these agents in a murine model of ACD. Human TNF-a expressing (Tg 197) mice were administered a single subcutaneous dose of CNTO 530 or darbepoetin-a and the pharmacodynamic response in bone marrow spleen and peripheral blood evaluated. RBC life span and reticulocyte age distribution were also evaluated. CNTO 530 induced a dose responsive increase in reticulocytes, RBCs and Hgb in both wild type and Tg197 mice. Although the reticulocyte response was similar to wild types, the RBC and Hgb response to CNTO 530 in Tg197 mice was blunted. There was no statistically significant difference in RBC life span with either compound. Darbepoetin-α caused a greater peak in % dead Pro/basophilic erythroblasts, greater peak EMH in the spleen and a greater increase in reticulocyte maturation time. In contrast, despite a similar peak increase, CNTO 530 caused a more sustained response of reticulocyte, EMH, RBC and Hgb, consistent with increased exposure. In conclusion, CNTO 530 and darbepoetin-a increased RBC and hemoglobin in a murine model of ACD. Compared to darbepoetin-a, CNTO 530 had a more sustained effect, consistent with increased exposure.