title: Chronic pharmacological and safety evaluation of Hematide, a PEGylated peptidic erythropoiesis-stimulating agent, in rodents.
abstract: Hematide is a synthetic peptide-based, PEGylated erythropoiesis-stimulating agent, which is being developed for the chronic treatment of anaemia associated with chronic renal failure. To support the safety of long-term dosing of chronic renal failure patients, a comprehensive toxicology programme was implemented including rat subchronic and chronic studies. Rats were administered 0, 0.1, 1 and 10 mg/kg of Hematide every 3 weeks for 3 months via subcutaneous injection or for 6 months via intravenous injection. The dosing period was followed by a 6-week follow-up period. The primary pharmacology of Hematide resulted in erythroid polycythemia as measured by elevated haemoglobin levels that were time- and dose-dependent. The pharmacology profiles were similar regardless of administration route. For example, for male rats at Day 90, subcutaneous dosing resulted in haemoglobin increases of 2.7, 4.5 and 6.9 g/dl for 0.1, 1 and 10 mg Hematide/kg respectively, compared to 2.8, 5.7 and 7.4 g/dl increases for intravenous dosing. Histopathological changes were related to the prolonged severe polycythemia induced in normocythemic animals administered an erythropoiesis-stimulating agent. The findings included extramedullary haematopoiesis in the spleen and liver, bone marrow hypercellularity and organ congestion. Microscopic findings were reversible, demonstrating a return towards control findings within 6 weeks following cessation of dosing. Systemic exposures, based on both area under the curve (AUC) and maximum concentration (C(max)), were substantially greater for intravenous than subcutaneous administration. No Hematide-specific antibodies were detected. In conclusion, Hematide is a potent erythropoiesis-stimulating agent, and the studies provide support for the safety of clinical development, including chronic dosing, for the treatment of anaemia associated with chronic renal failure.
authors.affiliation: Affymax Inc, Palo Alto, CA, USA. kathryn_woodburn@affymax.com
authors.forename: Kathryn W
authors.initials: KW
authors.lastname: Woodburn
authors.forename: Susan D
authors.initials: SD
authors.lastname: Wilson
authors.forename: Kei-Lai
authors.initials: KL
authors.lastname: Fong
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schatz
authors.forename: Charles B
authors.initials: CB
authors.lastname: Spainhour
authors.forename: Daniel
authors.initials: D
authors.lastname: Norton
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006397:Hematinics / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006411:Hematopoiesis, Extramedullary / Q000187:drug effects; D006454:Hemoglobins / Q000032:analysis; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010455:Peptides / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011086:Polycythemia / Q000139:chemically induced; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D006397:Hematinics; D006454:Hemoglobins; D010455:Peptides; C514771:hematide; D011092:Polyethylene Glycols