Toxicity testing safety pharmacology

Some biotechnologically derived pharmaceuticals will cross-react with species that can be evaluated toxicologically, while others cross-react only with nonhuman primates such as the chimpanzee, a protected species. In this case, a well-designed safety, or Phase 0 study at doses higher than the proposed clinical dose may provide valuable safety information. However, a lack of cross-reactivity with any nonhuman species does not necessarily make preclinical safety evaluation impossible, not does it limit toxicity testing to species in which the protein lacks relevant pharmacological activity. Some alternative possibilities are summarized in Table 12.9. 

As a starting place, unlike older pharmacology studies, safety pharmacology studies are normally conducted as GLP studies. At the same time, unlike other safety assessment studies, these do not need to vastly exceed intended therapeutic doses so as to identify signs of toxicity. In this sense, they are closer to hazard tests. 

S Dose levels in vivo It is necessary to define the dose-response relationship of any adverse effects observed. The onset and duration of effects should be measured. Because there are differences in sensitivity between species, the doses chosen need to exceed those used for therapy. The ICH guideline states that the highest dose tested should be a dose that produces moderate adverse effects, for example, dose-limiting pharmacodynamic effects or other toxicities. Such effects should not be so severe that they confoimd the interpretation of the results being sought. Safety pharmacology studies... 

Safety pharmacology In vitro assays can test for hERG potassium channel interaction early in discovery, with ox vivo and in vivo assays being applied later in discovery. HCA assays are being developed for in vitro assessments of cardiac toxicity potential... 

Peptide Class Safety Pharmacology VChronic Toxicity Carcinogenicity Testing Genetic Toxicity Method of Manufacture Approval Date... 

For further description of the method see chapters I.N (Ocular Toxicity Tests) and I.P (Safety Assays in Skin Pharmacology). 

Notifications or applications for clinical trials are supported by summaries or full reports on the preclinical pharmacology and safety assessment. The kind of safety data (e.g. the type and duration of toxicity tests), which are expected at this time, should correspond to the intended route and duration of application. Data on process details and on the quality of the product are not always required. But it must be kept in mind that clinical trials can only render useful results for the later product registration, if the quality characteristics of the tested product and its method of production are the essentially same as for the final product. If available, clinical data from trials in other countries must also be provided. Protocols for the intended clinical trials are an essential part of the application. 

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