title: Genotoxic assessment and toxicity evaluation of peginesatide in CByB6F1 hybrid mice.
abstract: 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.
authors.affiliation: Affymax, Inc., Palo Alto, California, USA. Kathryn_woodburn@affymax.com
authors.forename: Kathryn W
authors.initials: KW
authors.lastname: Woodburn
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schatz
authors.forename: Susan
authors.initials: S
authors.lastname: Wilson
authors.forename: Kei-Lai
authors.initials: KL
authors.lastname: Fong
authors.forename: Valentine O
authors.initials: VO
authors.lastname: Wagner
authors.forename: Ramadevi
authors.initials: R
authors.lastname: Gudi
authors.forename: Ljubica
authors.initials: L
authors.lastname: Krsmanovic
authors.forename: Madhav
authors.initials: M
authors.lastname: Paranjpe
authors.forename: Sudhir A
authors.initials: SA
authors.lastname: Shah
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D016466:CHO Cells; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity*; D002869:Chromosome Aberrations / Q000139:chemically induced; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D005260:Female; D011905:Genes, ras; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009152:Mutagenicity Tests; D009153:Mutagens / Q000493:pharmacokinetics / Q000633:toxicity*; D010455:Peptides / Q000493:pharmacokinetics / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D036401:Toxicity Tests, Chronic
chemical_list: D002273:Carcinogens; D009153:Mutagens; D010455:Peptides; C556270:peginesatide