Successful Drug Development Despite Adverse Preclinical Findings Part 2: Examples
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- Ettlin Robert A.
- Ettlin Consulting Ltd.
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- Kuroda Junji
- KISSEI Pharmaceutical Co., Ltd.
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- Plassmann Stephanie
- PreClinical Safety (PCS) Consultants Ltd.
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- Hayashi Makoto
- Biosafety Research Center, Foods, Drugs, and Pesticides (BSRC)
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- Prentice David E.
- PreClinical Safety (PCS) Consultants Ltd.
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Abstract
To illustrate the process of addressing adverse preclinical findings (APFs) as outlined in the first part of this review, a number of cases with unexpected APF in toxicity studies with drug candidates is discussed in this second part. The emphasis is on risk characterization, especially regarding the mode of action (MoA), and risk evaluation regarding relevance for man. While severe APFs such as retinal toxicity may turn out to be of little human relevance, minor findings particularly in early toxicity studies, such as vasculitis, may later pose a real problem. Rodents are imperfect models for endocrine APFs, non-rodents for human cardiac effects. Liver and kidney toxicities are frequent, but they can often be monitored in man and do not necessarily result in early termination of drug candidates. Novel findings such as the unusual lesions in the gastrointestinal tract and the bones presented in this review can be difficult to explain. It will be shown that well known issues such as phospholipidosis and carcinogenicity by agonists of peroxisome proliferator-activated receptors (PPAR) need to be evaluated on a case-by-case basis. The latter is of particular interest because the new PPAR α and dual α/γ agonists resulted in a change of the safety paradigm established with the older PPAR α agonists. General toxicologists and pathologists need some understanding of the principles of genotoxicity and reproductive toxicity testing. Both types of preclinical toxicities are major APF and clinical monitoring is difficult, generally leading to permanent use restrictions. <br>
Journal
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- Journal of Toxicologic Pathology
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Journal of Toxicologic Pathology 23 (4), 213-234, 2010
JAPANESE SOCIETY OF TOXICOLOGIC PATHOLOGY
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Keywords
Details 詳細情報について
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- CRID
- 1390282679392869632
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- NII Article ID
- 130000450747
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- NII Book ID
- AN10232280
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- ISSN
- 1881915X
- 09149198
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- NDL BIB ID
- 10966129
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- Text Lang
- en
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- Data Source
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- JaLC
- NDL
- Crossref
- CiNii Articles
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- Abstract License Flag
- Disallowed