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



Connie M. Kliwinski*, Dorie Makropoulos, Debora Kwok, Amy L. Volk, Kim Foster, Thomas Nesspor, Chichi Huang, Peter J. Bugelski
Biotechnology Toxicology, RC-1 Centocor R&D 145 King of Prussia Road, Radnor, PA 19087, USA;


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© 2010 Kliwinski et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address Correspondence to this author at the Biotechnology Toxicology, RC-1 Centocor R&D 145 King of Prussia Road, Radnor, PA 19087, USA; Tel: 610-240-8492; Fax: 610 -651-6152; E-mail: Ckliwins@its.jnj.com


Abstract

Renal insufficiency is commonly associated with an erythropoietin (EPO) dependent anemia. CNTO 530 is an EPO-mimetic antibody fusion protein with EPO-receptor agonist activity. The pharmacokinetics and pharmacodynamic activity of CNTO 530 were evaluated in a rat model of chronic renal insufficiency (CRI) induced anemia. Following 5/6 nephrectomy 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 normal range for 44 days. Pharmacokinetic analysis showed that clearance of CNTO 530 increased 1.4 fold and terminal t1/2 and AUC decreased 1.6 fold in CRI rats compared to controls. CNTO 530 is active in a CRI rat model of anemia and widely spaced treatments with CNTO 530 may be sufficient to combat anemia.

Keywords: Partial nephrectomy, recombinant proteins, erythropoietin, rats..