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Chronic Pharmacological and Safety Evaluation of Hematide™, a PEGylated Peptidic Erythropoiesis-Stimulating Agent, in Rodents

Authors
  • Woodburn, Kathryn W1
  • Wilson, Susan D2
  • Fong, Kei-Lai3
  • Schatz, Peter J1
  • Spainhour, Charles B4
  • Norton, Daniel4
  • 1 Affymax Inc., Palo Alto, CA USA
  • 2 Aclairo Pharmaceutical Development Group Inc., Vienna, VA, USA
  • 3 Pennsylvania Biolab Inc., Radnor, PA, USA
  • 4 Calvert Laboratories, Olyphant, PA, USA
Type
Published Article
Journal
Basic & Clinical Pharmacology & Toxicology
Publisher
Wiley (Blackwell Publishing)
Publication Date
Feb 01, 2009
Volume
104
Issue
2
Pages
155–163
Identifiers
DOI: 10.1111/j.1742-7843.2008.00347.x
PMID: 19143750
PMCID: PMC2667308
Source
PubMed Central
License
Unknown

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 (Cmax), 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.

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