Abstract:
:We conducted a retrospective analysis of publicly available preclinical toxicology studies with erythropoiesis-stimulating agents (ESAs) to examine common adverse events in rats, Beagle dogs, and cynomolgus monkeys. Mortality and/or thrombotic events were reported sporadically in a subset of studies and attributed to the high hematocrit (HCT) achieved in the animals. However, similarly high HCT was achieved in both high-dose and low-dose groups, but there were no reported adverse events in the low-dose group suggesting HCT was not the sole contributing factor leading to toxicity. Our analysis indicated that increased dose, dose frequency, and dosing duration in addition to high HCT contributed to mortality and thrombosis. To further evaluate this relationship, the incidence of toxicities was compared in rats administered an experimental hyperglycosylated analog of recombinant human erythropoietin (AMG 114) at varying dosing schedules in 1-month toxicity studies. The incidence of mortality and thrombotic events increased in higher dose groups and when dosed more frequently, despite a similarly high HCT in all animals. The results from the investigative study and retrospective analysis demonstrate that ESA-related toxicities in preclinical species are associated with dose level, dose frequency, and dosing duration, and not solely dependent upon a high HCT.
journal_name
Toxicol Patholjournal_title
Toxicologic pathologyauthors
Andrews DA,Pyrah IT,Boren BM,Tannehill-Gregg SH,Lightfoot-Dunn RMdoi
10.1177/0192623313486317subject
Has Abstractpub_date
2014-01-01 00:00:00pages
510-23issue
3eissn
0192-6233issn
1533-1601pii
0192623313486317journal_volume
42pub_type
杂志文章,评审abstract::A variety of phenotypic cellular changes emerge in the liver of different species prior to the appearance of hepatocellular adenomas and carcinomas induced by carcinogenic agents (chemicals, radiation, hepadna viruses) or develop "spontaneously." Foci of altered hepatocytes have been studied most extensively in rats t...
journal_title:Toxicologic pathology
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journal_title:Toxicologic pathology
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abstract::In the Federal Register of January 10, 2000 (65 FR 1399), FDA published a draft guidance entitled "Photosafety Testing." The notice gave interested persons an opportunity to submit comments. As a result of the comments, certain sections of the guidance were reworded to improve clarity. A final guidance was published i...
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journal_title:Toxicologic pathology
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abstract::Laser scanning cytometry (LSC) is a powerful tool for qualitative and quantitative analysis of tissue sections in preclinical drug development. LSC combines the strengths of flow cytometry with tissue architecture retention. This technology has been used predominantly with immunofluorescent techniques on cell culture ...
journal_title:Toxicologic pathology
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abstract::The histologic effect of 400 mg/M2/day of hydrocortisone, given alternatively from day 7 to day 19 after birth, was studied on the spleen of the immunologically immature rat. Two days after the cessation of treatment, the periarteriolar lymphatic sheaths were found to be largely depleted of small lymphocytes. Immunope...
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journal_title:Toxicologic pathology
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journal_title:Toxicologic pathology
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journal_title:Toxicologic pathology
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journal_title:Toxicologic pathology
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journal_title:Toxicologic pathology
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journal_title:Toxicologic pathology
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journal_title:Toxicologic pathology
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