当前位置： SCI文献检索 > BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY期刊下所有文献 > Chronic pharmacological and safety evaluation of Hematide, a PEGylated peptidic erythropoiesis-stimulating agent, in rodents.

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.

journal_name

Basic Clin Pharmacol Toxicol

journal_title

Basic & clinical pharmacology & toxicology

authors

Woodburn KW,Wilson SD,Fong KL,Schatz PJ,Spainhour CB,Norton D

doi

10.1111/j.1742-7843.2008.00347.x

subject

Has Abstract

pub_date

2009-02-01 00:00:00

pages

155-63

issue

eissn

1742-7835

issn

1742-7843

pii

PTO347

journal_volume

104

pub_type

杂志文章

在线工具

Chronic pharmacological and safety evaluation of Hematide, a PEGylated peptidic erythropoiesis-stimulating agent, in rodents.