title: A subchronic murine intravenous pharmacokinetic and toxicity study of Hematide™, a PEGylated peptidic erythropoiesis-stimulating agent.
abstract: The subchronic toxicity of Hematide™, a synthetic PEGylated peptidic erythropoiesis-stimulating agent (ESA), was evaluated in CD-1 mice at intravenous doses of 0, 1, 5, 25, and 125 mg/kg administered once every 3 weeks for 3 months. Hematide displayed sustained plasma levels with reduced clearance and prolonged half-lives up to 59.4 hours that translated into sustained, pronounced polycythemia, bone marrow hyperplasia, and splenic and liver extramedullary hematopoiesis. Toxicological findings were considered to be secondary to exaggerated pharmacology, rather than a direct drug effect, and included mortality at ≥25 mg/kg/dose. The no-observed-adverse-effect-level was determined to be 5 mg/kg.
authors.affiliation: Affymax, Inc., Palo Alto, California 94304, USA. Kathryn_woodburn@affymax.com
authors.forename: Kathryn W
authors.initials: KW
authors.lastname: Woodburn
authors.forename: Qing
authors.initials: Q
authors.lastname: Fan
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schatz
authors.forename: Susan D
authors.initials: SD
authors.lastname: Wilson
authors.forename: Kei-Lai
authors.initials: KL
authors.lastname: Fong
authors.forename: Daniel
authors.initials: D
authors.lastname: Norton
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006411:Hematopoiesis, Extramedullary / Q000187:drug effects; D006965:Hyperplasia / Q000139:chemically induced; D008297:Male; D051379:Mice; D019055:No-Observed-Adverse-Effect Level; D010455:Peptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D011086:Polycythemia / Q000139:chemically induced; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D010455:Peptides; C514771:hematide; D011092:Polyethylene Glycols