Toxicology and Efficacy Study

Adverse drug events such as cardiotoxicity, hepatotoxicity, and other organ toxicities keep surfacing in the clinic and idiosyncratic drug toxicity continues to haunt the drug development process. New screening technologies, in vitro assays, in vivo models, and computational tools continue to be developed. While in silico and in vitro models will continually be developed and refined, in vivo preclinical safety models remain the gold standard for assessing human risk.

Role of Early In Vivo Testing

The primary objectives of early in vivo preclinical toxicity testing of drug candidates are to characterize potential adverse effects and to provide initial estimates of safety margins to determine if a compound is likely to be safe for use in humans, or whether to eliminate such molecules from further development. Traditionally, toxicity testing in vivo occurs once a drug candidate has acquired substantial ancillary information. These prerequisites include knowledge of the desired efficacious properties based on in vitro and/or in vivo efficacy models, and acceptable pharmacokinetic properties in the relevant species based on in vitro and single-dose in vivo studies in rodents and non-rodents.

Fig.1 Toxicology profiling in discovery. (Kramer, 2007)

Prospective In Vitro Toxicology Assays

Prospective in vitro toxicology assays are those assays that are conducted before the first in vivo toxicology studies, and attempt to predict toxicities that are development-limiting or those that may be commonly missed in early in vivo toxicity assays. These include assays for general or cell-type-specific cytotoxicity, genotoxicity, hERG (human ether-a-go-go-related; also known as KCNH2) channel block, drug-drug interactions, and metabolite mediated toxicity. Of these, cytotoxicity assays are often among the earliest toxicity assays to be conducted. The predictive ability of in vitro cytotoxicity assays for in vivo target organ toxicity is often questionable at times owing to the limitations of in vitro models. However, in vitro cytotoxicity assays can be valuable for interpreting the results of in vitro safety and efficacy assays.

Molecular Imaging (MI) Biological Assessment (MIBA) Strategies in Toxicology/Safety

The early identification of drug candidates that have the potential for adverse effects on kidney or liver function is an important priority in the drug discovery and development process for both safety and financial reasons. Near-infrared (NIR) fluorescence MI offers a useful approach to non-invasively assess drug effects in preclinical testing, and there are opportunities for MIBA strategies, in particular, that may help to understand in situ dynamic biological changes in tissue. MI and MIBA approaches are more likely to be of use in very early screening/triaging of compounds early in the drug discovery process rather than in the late stages of development and formal toxicology. The publications in drug-induced liver and kidney injury, as well as non-drug-induced models of liver/kidney injury, support the potential for MIBA approaches in toxicology testing in vivo.

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Reference

1. Kramer, J.A.; et al. The application of discovery toxicology and pathology towards the design of safer pharmaceutical lead candidates. Nat Rev Drug Discov. 2007 Aug;6(8):636-49.