Toxicogenomic and pharmacogenomic biomarkers for drug discovery and personalized medicine

Abstract

Safety is the main cause for failure of novel drug candidates, underscoring the needs for improvement. The emergence of toxicity during the late stages of drug development may necessitate a return to seed compound screening, because toxicity is often inherent to the basic structure and is thus difficult to be eliminated by minor modification. An urgent need therefore exists for safety biomarkers that enable prediction of potential toxicity and prioritization of candidate compounds during the early stages of drug discovery and development. The use of biomarkers in the early stages of drug development will ensure that drug candidates are safe before they are administered to humans. Toxicogenomics is a promising approach to identify genomic biomarkers associated with specific mechanisms of toxicity induced by drug treatment. Toxicogenomic biomarkers are applicable for efficient screening of drug candidates at an early stage of drug development, resulting in a significant reduction in the time and cost associated with development of new molecular entities. A more detailed appreciation of the molecular mechanisms associated with a given toxicity potentially facilitates an enhanced ability to translate the finding from animals to human in the context of safety evaluation. The advent of toxicogenomic technologies had also accelerated the understanding of individual differences in genetic susceptibility to therapeutic agents in the clinical setting. Such efforts on toxicogenomics and pharmacogenomics have facilitated identification of new genetic biomarkers that can provide predictive tools for improved drug response and fewer adverse drug reactions. This chapter provides the current scientific state-ofthe- art and future perspectives on toxicogenomic and pharmacogenomic biomarkers in drug discovery. Advent in toxicogenomic and pharmacogenomic strategies could have significant impacts in shifting unpredictable, mechanistically unclear events to predictable, manageable risks, providing the drug with a clear value.