Target-related toxicity

Use of tissue distribution to evaluate target-related toxicity... 

Key decisions relating to toxicity Are there any target-related toxicity issues Which lead library to focus on Which lead series to focus on Which development candidate to nominate Toxicity occurred, how to find a safer back up Toxicity occurred, why ... 

Use RNAi, transgenic mice to identify target-related toxicity Rank order based on therapeutic index of well-characterized in vitro test Rank order based on therapeutic index of better-characterized in vitro test Check therapeutic index based on plasma concentration prediction Develop plausible hypothesis that fits existing data Develop plausible hypothesis that fits existing data... 

Biology related includes target-disease linkage, clinical efficacy, and target-based toxicity (exaggerated pharmacology)... 

One of the roles of a toxicologist involved in early discovery as a project team representative can be to generate a list of potential and likely toxicities deduced from target-related information such as tissue expression, similarity to other targets, precedent described in literature and sometimes chemical structure similarity. When... 

Stochastic responses under conditions of the experiment should be reviewed carefully with respect to the relevance of the evidence to humans (e.g., the occurrence of bladder tumors in the presence of bladder stones and implantation site sarcomas). Interpretation of animal studies is aided by the review of target organ toxicity and other effects (e.g., changes in the immune and endocrine systems) that may be noted in pre-chronic or other toxicologic studies. Time- and dose-related incidence of pre-neoplastic lesions may also be helpful in interpreting animal studies. 

Extensive evidence suggests that the immune system is a sensitive target for toxicity of 2,3,7,8-TCDD and structurally related halogenated aromatic hydrocarbons (Kerkvliet 1995). Exposure to 2,3,7,8-TCDD can increase susceptibility to bacterial (Thigpen et al. 1975 Thomas and Hinsdill 1979 White et al. 1986), viral (Clark et al. 1983 House et al. 1990), parasitic (Tucker et al. 1986), and neoplastic disease (Luster et al. 1980). However, the specific immunological functions affected by 2,3,7,8-TCDD in most of the host-resistance models have not been fully defined. Thymic involution is characteristic of exposure to 2,3,7,8-TCDD and structurally related chemicals in all species examined. There is experimental evidence showing that immune suppression in rodents occurs at lower doses of... 

Reproductive toxicity studies with PS ODNs have been performed with both human-specific sequences as well as species-specific sequences. Like chronic studies, this combination of human drug and surrogate provides insight into whether any effects observed are class related or target related. 

---