title: Subchronic safety evaluation of EPO-018B, a pegylated peptidic erythropoiesis stimulating agent, after 5-week subcutaneous injection in Cynomolgus monkeys and Sprague-Dawley rats.
abstract: EPO-018B, a synthetic peptide-based erythropoiesis stimulating agent (ESA), is coupled to polyethylene glycol (PEG) and designed to specifically bind and activate the erythropoietin (EPO) receptor to result in production of red blood cells. This study was designed to evaluate the potential subchronic toxicity of EPO-018B for Cynomolgus monkeys and Sprague-Dawley rats both at 0, 0.5, 5 and 50 mg/kg every week for 5 weeks, followed by 6-week recovery for rats and 12-week recovery for monkeys. The No Observed Adverse Effect Level (NOAEL) for rats and monkeys were both considered to be at least 0.5 mg/kg/day, the minimum toxic dose to be 5.0 mg/kg/day and the severe toxic dose to be more than 50.0 mg/kg/day. The toxicological effects included the exaggerated pharmacology and secondary sequelae that resulted from an erythropoiesis-stimulating agent treatment to healthy animals. Most treatment induced effects were reversible or showed ongoing recovery upon discontinuation of treatment. The anticipated patient population for EPO-018B treatment is targeted to be the anemia patients caused by chronic renal failure or chemotherapy against to cancer and is expected to have an ideal clinical application prospect.
authors.affiliation: Department of Hygiene and Toxicology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xue-Lian
authors.initials: XL
authors.lastname: Gong
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zong
authors.forename: Guo-Cai
authors.initials: GC
authors.lastname: Lu
authors.forename: Bo-Jun
authors.initials: BJ
authors.lastname: Yuan
mesh_terms: D000818:Animals; D001794:Blood Pressure; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004920:Erythropoiesis / Q000187:drug effects; D005260:Female; D006397:Hematinics / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size; D010455:Peptides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D059550:Toxicity Tests, Subchronic; D016482:Urinalysis
chemical_list: D006397:Hematinics; D010455:Peptides; C514771:hematide; D011092:Polyethylene Glycols
keywords: Cynomolgus monkeys; EPO-018B; Sprague–Dawley rats; Subchronic toxicity