Predictive Toxicology The application of toxicogenomics, toxicology with genomics tools, is becoming a generally accepted approach in the pharmaceutical industry to identify compounds with potential safety problems before they are evaluated in regulatory toxicology studies. The approach is useful because the profile of a known toxicant in a particular tissue can be derived using a toxicogenomics approach. Most of the investigations for toxicogenomics involve in vivo studies in rodents, especially rats, since this species is commonly employed as the primary model by the pharmaceutical industry. The presence of a signature of toxicity can alert investigators to potential overt toxicity (such as necrosis), or organ pathology (such as peroxisomal proliferation). By comparing an investigational compound’s toxicogenomic profile with known signatures of toxicity derived from DrugMatrix, it is possible to:

1. Match candidate profiles against known toxicity profiles
2. Compare compounds by degree of toxicity
3. Anticipate compound-induced pathology
4. Elucidate the mechanism of toxicity in target organs

 Understanding Mechanism of Action While a large amount of literature has focused on the toxicological profiling of compounds to identify mechanisms and markers for adverse physiological events, toxicogenomics can equally provide an enormous range of information about other activities of drugs. Some of these alternative activities may not be adverse effects, but may actually provide alternative or additional therapeutic applications for drugs. This might prove useful rescuing failing candidates (e.g. conversion of Viagra from a failing angina candidate to a successful erectile dysfunction therapeutic). Specific programs exist that are directed to identifying new therapeutic applications for ‘old’ drugs. Studies performed at Iconix and MDS Pharma Services using DrugMatrix have demonstrated the predictive power of this approach. By comparing the genomic profile for Gemfibrozil to those of the class of fibrates to which it belongs, it has been possible to identify the genomic responses uncommon to the class, but specific to Gemfibrozil. This approach identifies a pathway up-regulated by Gemfibrozil but not by other members of the fibrate class,and may account for the clinical effects of Gemfibrozil that differentiate it from other fibrates.

DrugMatrix can be applied to understanding the broad spectrum of effects of chemical compounds on a living system to characterize, evaluate, and prioritize compounds for further optimization or, if necessary, elimination from further consideration. Future directions include extending our reach to develop surrogate genomic and proteomic markers for drug optimization and design.