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: Kathryn W Woodburn, Susan D Wilson, Kei-Lai Fong, Peter J Schatz, Charles B Spainhour, Daniel Norton
• Journal: Basic & clinical pharmacology & toxicology (Basic Clin Pharmacol Toxicol) Vol. 104 Issue 2 Pg. 155-63 (Feb 2009) ISSN: 1742-7843 [Electronic] England
• PMID: 19143750 (Publication Type: Journal Article)

Chemical References

• Hematinics
• Hemoglobins
• Peptides
• hematide
• Polyethylene Glycols

Topics

• Animals
• Bone Marrow Cells (cytology, drug effects)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Hematinics (administration & dosage, adverse effects, pharmacokinetics, pharmacology)
• Hematopoiesis, Extramedullary (drug effects)
• Hemoglobins (analysis)
• Injections, Intravenous
• Injections, Subcutaneous
• Male
• Organ Size (drug effects)
• Peptides (administration & dosage, adverse effects, pharmacokinetics, pharmacology)
• Polycythemia (chemically induced)
• Polyethylene Glycols (administration & dosage, adverse effects, pharmacokinetics, pharmacology)
• Rats
• Rats, Sprague-Dawley