Single-and repeat-dose toxicity of HM10760A, a long-acting erythropoietin, in rats and monkeys

This paper presents some results of a joint research project conducted by FRAME and Liverpool John Moores University, and sponsored by Defra, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity end-points associated with REACH. This paper focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for repeat dose (sub-acute, sub-chronic and chronic) toxicity testing. It reviews the limited number of in silico and in vitro tests available for this endpoint, and outlines new technologies which could be used in the future, e.g. the use of biomarkers and the ‘omics’ technologies. An integrated testing strategy is proposed, which makes use of as much non-animal data as possible, before any essential in vivo studies are performed. Although none of the non-animal tests are currently undergoing validation, their results could help to reduce the number of animals required for testing for repeat dose toxicity.

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Rodent big brother: Development and validation of a home cage automated behavioural monitoring system for use in repeat-dose toxicity studies in rats

Toxicology Letters ◽

10.1016/j.toxlet.2014.06.206 ◽

2014 ◽

Vol 229 ◽

pp. S47-S48 ◽

Cited By ~ 2

Author(s):

Will S. Redfern ◽

J. Douglas Armstrong ◽

James Heward ◽

Ben Allison ◽

Tim Lukins ◽

...

Keyword(s):

Monitoring System ◽

Home Cage ◽

Repeat Dose ◽

Repeat Dose Toxicity ◽

Toxicity Studies ◽

Big Brother ◽

Development And Validation

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Prospects for reducing and refining the use of dogs in the regulatory toxicity testing of pharmaceuticals

Human & Experimental Toxicology ◽

10.1191/096032700682694242 ◽

2000 ◽

Vol 19 (8) ◽

pp. 440-447 ◽

Cited By ~ 26

Author(s):

C L Broadhead ◽

G Betton ◽

R Combes ◽

S Damment ◽

D Everett ◽

...

Keyword(s):

Life Sciences ◽

Toxicity Testing ◽

Assessment Process ◽

Preliminary Evaluation ◽

Repeat Dose ◽

Human Toxicity ◽

Risk Assessment Process ◽

Repeat Dose Toxicity ◽

Data Collation

A workshop was held to critically discuss the need for a non-rodent species and the role of the dog in regulatory toxicity testing of pharmaceuticals; to discuss opportunities to reduce and refine the use of dogs in preclinical toxicology; and to identify a number of specific recommendations which could be feasibly achieved to move the process forward. To facilitate a preliminary evaluation of the contribution of dog studies to the risk assessment process, anonymised, unpublished data were provided from fully evaluated, repeat dose toxicity studies in the rat and dog. Results ofthe International Life Sciences Institute (ILSI) Human Toxicity Project were also presented and discussed. Analysis of the data demonstrated that the dog can provide additional toxicity information, which, in some cases, was shown to be predictive for humans. Discussions indicated that there is potential for achieving a reduction in dog use and several possible approaches were identified. To further the progress of this initiative, there is a need to collate the results of pharmacology, toxicology, and clinical studies to address some of the proposed approaches. One of the outcomes of the workshop will be the establishment of a steering group to co-ordinate data collation for further analysis.

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Recommended Tissue List for Histopathologic Examination in Repeat-Dose Toxicity and Carcinogenicity Studies: A Proposal of the Society of Toxicologic Pathology (STP)

Toxicologic Pathology ◽

10.1080/01926230309809 ◽

2003 ◽

Vol 31 (2) ◽

pp. 252-253 ◽

Cited By ~ 2

Author(s):

Carla L. Bregman ◽

Rick R. Adler ◽

Daniel G. Morton ◽

Karen S. Regan ◽

Barry L. Yano

Keyword(s):

Repeat Dose ◽

Histopathologic Examination ◽

Repeat Dose Toxicity

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Nonclinical Safety Assessment of a Synthetic Peptide Thrombopoietin Agonist

International Journal of Toxicology ◽

10.1177/1091581811404708 ◽

2011 ◽

Vol 30 (4) ◽

pp. 385-404 ◽

Cited By ~ 5

Author(s):

Elaine Knight ◽

Gary Eichenbaum ◽

Verna Hillsamer ◽

Tony Greway ◽

Alfred Tonelli ◽

...

Keyword(s):

Antibody Formation ◽

Safety Assessment ◽

Chemical Nature ◽

Osseous Metaplasia ◽

Repeat Dose ◽

Stopping Criterion ◽

Platelet Volume ◽

Repeat Dose Toxicity ◽

Pharmacologic Effect ◽

Pharmacologic Activity

RWJ-800088 is a novel, potent polyethylene glycol (PEG)-conjugated thrombopoietin (TPO) mimetic that increases platelet levels and protects against thrombocytopenia. A nonclinical safety program was customized for this peptide that takes into account its protein-like structure, synthetic chemical nature, agonist pharmacologic activity, and mode of administration. In repeat-dose toxicity studies, the salient findings were dose-related increases in circulating platelet counts, mean platelet volume, and megakaryocytes in the bone marrow with no antibody formation. Reversible myelofibrosis and hyperostosis were observed in rats, but not dogs, when the circulating platelet levels exceeded 3× those of vehicle controls. The bone effects were due to the exaggerated pharmacologic effect and excessive stimulation and elevation of megakaryocytes by TPO, which results in intramedullary proliferation of fibroblasts and mesenchymal cells followed by osseous metaplasia. These findings support the use of platelet elevations of >3× as a stopping criterion to prevent potential adverse bone-related effects in humans.

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