title: A 9-Month Toxicity and Toxicokinetic Assessment of Subcutaneous Pegylated Human C-peptide (CBX129801) in Cynomolgus Monkeys.
abstract: C-peptide is formed in the biosynthesis of insulin and is therefore deficient in patients with type 1 diabetes mellitus. A pegylated form of human synthetic C-peptide (CBX129801) has been developed to extend the half-life of the native peptide and is undergoing clinical investigation as replacement therapy to treat diabetic peripheral neuropathy. This monkey study was conducted to evaluate the toxicity of CBX129801 with weekly subcutaneous dosing for 39 weeks at dose levels of 0 (vehicle), 0.4, 1.33, and 4.0 mg/kg/wk. No systemic adverse effects were observed at any dose with maximal CBX129801 plasma concentrations of 735 to 1050 nmol/L during the dosing period (physiological range is 1-3 nmol/L). CBX129801-related effects were limited to minimal macrophagic vacuolization at the injection sites and in the associated draining (axillary) lymph nodes; these local effects largely resolved by the end of a 7-week recovery period. No systemic macrophagic vacuolization was observed. Additionally, there was no histological evidence for plaque formation in the major arteries of these nondiabetic animals.
authors.affiliation: ProDev Consulting Services, Ltd, Poway, CA, USA dennisnaas@cox.net.
authors.forename: Dennis
authors.initials: D
authors.lastname: Naas
authors.affiliation: General Toxicology Department, WIL Research, Ashland, OH, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Morris
authors.affiliation: Department of Pharmacokinetics, MicroConstants, Inc, San Diego, CA, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kousba
authors.affiliation: Vice President, Regulatory Affairs and Quality, Cebix Incorporated, San Diego, CA, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Mazzoni
mesh_terms: D000818:Animals; D002096:C-Peptide / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D003929:Diabetic Neuropathies / Q000188:drug therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D006207:Half-Life; D006801:Humans; D007279:Injections, Subcutaneous; D008252:Macaca fascicularis; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000139:chemically induced; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D066007:Toxicokinetics
chemical_list: D002096:C-Peptide; C000608079:CBX129801; D011092:Polyethylene Glycols
keywords: C-peptide; ICH M3; PEG; atherogenic; dose selection; pegylation; type 1 diabetes mellitus; type 2 diabetes mellitus; vacuolization