Safety profiling assay

The first requirement of an in vitro safety profiling assay is to be as predictive as possible of an adverse event, given all the limitations of in vitro assays and the other important parameters to consider in combination, such as physicochemical... 

Certainly, most in vitro assays cannot predict (a) metabolite effects, (b) adverse effects associated by accumulation, and (c) drug actions at targets with mutations. Nevertheless, early safety-profiling assays have the power to detect trends toward certain adverse reactions and organ toxicity and to navigate drug discovery teams away from them. The major difficulty is estimating the impact of the data on the clinical performance determined by the human therapeutic index. 

Preclinical in vitro safety-profiling assays have to be used in an integrated environment, considering various elements of compound performance. There are few examples (e.g., the Ames test and broad-scale cytotoxicity assays) that, when applied appropriately, can support yes-no decision making during early phases of drug discovery. Most of the profiling assays, however, rely on results from other parallel-run assays and on the confirmation in downstream tests. 

Compile a comprehensive list of all compounds tested in safety profiling assays where a dose-response curve was valid (actives) or no response occurred (inactives). 

The general safety profile from CEREP including 155 in vitro assays specifically designed to identify potential side effects of drug candidates (not in a specific pathology). 

Meyer, T, Sartipy P., Blind, F., Leisgen, C. and Guenther, E. (2007) New cell models and assays in cardiac safety profiling. Expert Opinion on Drug Metabolism and Toxicology, 3 (4), 507—517. 

Because the safety profiles defined by safety pharmacology studies can have a significant impact on the successful development of new therapeutic agents, it is important that the techniques and assays used in safety pharmacology studies minimize the occurrence of false negative and false positive results. For this reason, techniques that provide direct measures of respiratory parameters should be used. A direct measure is one that provides the endpoint of interest, in contrast to an indirect measure that provides a surrogate endpoint,... 

Figure 10-1 Alignment of safety profiling, discovery toxicology, and pathology with the pre-clinical drug discovery process8. Profiling assays are implemented according to requirement of the phase, compound availability, and capacity. The complexity is increasing as projects progress toward clinical candidate selection.

Several areas of in vitro safety profiling underwent rapid development during the past couple of years. Dedicated chapters of the present book will discuss in detail organ- and system-specific toxicity/safety strategies, assays, and their implications. Here we will use two examples to demonstrate the development and application of early safety profiling capabilities. 

As a first important result, these trials confirmed the excellent safety profile of completely synthetic peptides in general, and poly-L-arginine in particular. Furthermore, several important lessons regarding the activation of human T cells were learned in both studies, T cell responses were assessed using [ H]-thymidine prohf-eration and IFN-y ELIspot assays, and fluorescence-activated cell sorting (FACS). 

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