Genotoxic assessment and toxicity evaluation of peginesatide in CByB6F1 hybrid mice

• Published in: Drug and chemical toxicology (New York, N.Y. 1978) Vol. 34; no. 3; pp. 240 - 249
• Main Authors: Woodburn, Kathryn W., Schatz, Peter J., Wilson, Susan, Fong, Kei-Lai, Wagner, Valentine O., Gudi, Ramadevi, Krsmanovic, Ljubica, Paranjpe, Madhav, Shah, Sudhir A.
• Format: Journal Article
• Language: English
• Published: United States Informa Healthcare 01.07.2011; Taylor & Francis
• Subjects: Animals; Bone Marrow Cells - drug effects; Bone Marrow Cells - pathology; Carcinogenicity Tests; Carcinogens - pharmacokinetics; Carcinogens - toxicity; CHO Cells; Chromosome Aberrations - chemically induced; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Erythropoiesis-stimulating agents; Escherichia coli - drug effects; Escherichia coli - genetics; Female; Genes, ras; genotoxicity; Humans; Injections, Intravenous; Male; Mice; Mice, Inbred ICR; Mice, Transgenic; Mutagenicity Tests; Mutagens - pharmacokinetics; Mutagens - toxicity; Peptides - pharmacokinetics; Peptides - toxicity; pharmacokinetics; safety; Salmonella typhimurium - drug effects; Salmonella typhimurium - genetics; Toxicity Tests, Chronic; toxicology
• ISSN: 0148-0545; 1525-6014
• DOI: 10.3109/01480545.2010.510140

Peginesatide is a PEGylated, investigational, peptide-based erythropoiesis-stimulating agent (ESA) that was designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis. Clinical use of peginesatide is anticipated to result in chronic dosing in chronic kidney disease (CKD) patients, and the nonclinical data to support development should include an evaluation of carcinogenic potential evaluation. Peginesatide was not mutagenic or clastogenic in a standard genotoxicity battery of tests. Doses for a rasH2 transgenic mouse carcinogenicity assay were defined in a 28-day study in the wild-type littermates of the rasH2 transgenic mouse strain, using intravenous doses of 1-25 mg/kg on days 1 and 22. The findings were consistent with exaggerated pharmacology, including polycythemia, with associated increases in hemoglobin level and extramedullary hematopoiesis and bone marrow hypercellularity.