Toxicity transgenic animal studies

The ICH S6 guidance states that toxicity studies in nonrelevant species may be misleading and so are discouraged. When no relevant species exists, the use of relevant transgenic animals expressing the human receptor or the use of homologous proteins should be considered. 

Modifications of the standard battery may be necessary for some classes, e.g., antibiotics which are toxic to bacteria or e.g., for compounds like topoisomerase inhibitors which interfere with the mammalian cell replication system. A selection of additional assays is being proposed, further modifications may be acceptable via discussion in the ICH Maintenance Process. Alternative strategies may consider assays like the in vivo Comet assay (single cell gel electrophoresis measuring DNA strand breaks) or gene mutation tests with transgenic animals or in vivo DNA adduct studies. 

In vivo tests should be chosen carefully to avoid an uninformative outcome. ThCTefore, toxicokinetics, metabolism, chemical reactivity, and mode of action have to be considCTcd carefully. T3rpicaUy, a bone marrow micronucleus or clastogenicity test is conducted. However, if thrae are indications that point to a more appropriate assay, then this assay shoitld be conducted instead (e.g., mutagenicity study with transgenic animals comet assay in stomach/smaU intestine/colon, if there is no uptake via gastrointestinal tract comet assay in the liver if there is metabolism to toxic species) (see Chapter 12). 

Most of the studies with these alternative models were conducted in discovery research. However, several respondents had conducted pivotal regulatory toxicity studies with homologous proteins and animal disease models, either to allow products such as MAbs and cytokines to be tested in man, or in support of regulatory toxicity studies by clarifying a finding. Only one respondent had conducted pivotal regulatory toxicity studies with transgenic animals in order to take a MAb into man. 

A relatively recent twist in studying SE toxicity has employed transgenic mice. As an example, animals expressing both human HEA-DQ6 and duster of differentiation antigen (CD)4-positive T cells readily succumb to normally sublethal amounts of SEB (versus nontransgenic controls) without any potentiating... 

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