AASLD-FDA-NIH-PhRMA Hepatotoxicity Steering Group Meeting, 2006 Presentations: Integrating liver toxicogenomics with clinical pathology, histopathology and drug metabolism data in preclinical studies
Patrick J. Wier, PhD
Vice President for Safety Assessment,
Integrating liver toxicogenomics with clinical pathology, histopathology and drug metabolism data in preclinical studies – GSK perspective [PDF]
From a study of over 170 known compounds in rats, a relational database of individual animal treatment (compound, dose, duration), liver micro array, toxicology, clinical pathology and histopathology data was created. A combination of statistical analyses and biological perspectives identified liver expression changes correlating with 9 different liver toxicity manifestations and 7 different liver toxicity modes of action. These were configured into a rat liver TaqMan panel for application to sub-acute rat toxicology studies as part of first tier drug development. Interpretation of these gene expression data is made by reference to previously studied known compounds. These gene expression data are considered to be “exploratory” and not used for human safety decision making. Instead, these data are used in conjunction with traditional endpoints, drug metabolism, and other properties to aid in the selection of drug development candidates. Hepatic gene expression changes that corroborate clinical or histopathology findings help distinguish “background” (spontaneous or vehicle-related) from drug-related effects in preliminary toxicology studies with small group sizes. Hepatic gene expression changes can suggest potential modes of action (e.g., GSH depletion,) not evident from traditional endpoints, and mode of action information can help guide subsequent compound “screening” or further preclinical studies. In addition, predicted compound properties (e.g., P450 interaction) can be confirmed or refuted in vivo with rat liver gene expression data. In summary, we have practically integrated liver toxicogenonics into a “routine” toxicology testing protocol by creating a facile data generation/reporting process, providing sufficient reference knowledge (and processes to grow the knowledge base as new compounds are tested) to all scientists (not just genomic specialists), and positioning gene expression results in the context of traditional endpoints.
Dr. Patrick Wier received his PhD from the University of Rochester in 1985. He has been active as a councilor for the Teratology Society 2001-4, and as a lecturer for the Society of Toxicology (2004: Interpreting female reproductive toxicity data). He has worked and published in the field of toxicology, focusing especially on reproductive tract of primate animals. He is now the Vice President for Safety Assessment of the GlaxoSmithKline Company.