Pharmacokinetics and Pharmacodynamics of an EPO-Mimetic Fusion Protein in a Model of Chronic Renal Insufficiency Anemia

摘要

Renal insufficiency is commonly associated with an erythropoietin (EPO) dependent anemia. CNTO 530 is anEPO-mimetic antibody fusion protein with EPO-receptor agonist activity. The pharmacokinetics and pharmacodynamicactivity of CNTO 530 were evaluated in a rat model of chronic renal insufficiency (CRI) induced anemia. Following 5/6nephrectomy and 13 -17 weeks of stabilization, rats received a single subcutaneous (SC) dose of saline or CNTO 530(0.03, 0.1, or 0.3 mg/kg). CNTO 530 caused dose-dependent reticulocytosis and long-lived increases in red blood cells,hemoglobin, and hematocrit. After receiving a dose of 0.1 mg/kg, red cell indices increased and remained within normalrange for 44 days. Pharmacokinetic analysis showed that clearance of CNTO 530 increased 1.4 fold and terminal t1/2 andAUC decreased 1.6 fold in CRI rats compared to controls. CNTO 530 is active in a CRI rat model of anemia and widelyspaced treatments with CNTO 530 may be sufficient to combat anemia.