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Advancing Drug Safety Assessment Using Mouse Population-Based Approaches

Alison Harrill

Several recent studies have indicated a role of genetic variation in the predisposition to serious adverse drug reactions (ADRs) and the introduction of low cost genotyping technologies has provided an unprecedented opportunity to define the genetic basis for ADR susceptibility in the clinic. However, the small cohort sizes that are available for genomic association studies may preclude detection of rare allelic variants in the clinic. The ideal model to study these effects would not only improve clinical prediction, but also improve detection of the ADR during preclinical testing. One approach is to use rationally designed populations of genetically diverse as a toxicity screening strategy to mimic the genetic diversity of the human population. We have previously shown the utility of the model to predict quantitative trait loci that underlie susceptibility to acetaminophen-induced liver injury in humans. Recently, we conducted a study using novel anti-trypanosomal drug DB289, for which clinical development was halted due to liver toxicity and renal failure. Using the population-based approach, we detected the potential for kidney stress using sensitive renal biomarker KIM-1. In addition, we have recently shown that a population-based approach could have detected the hepatic liability that caused a novel antibiotic to fail in a Phase I trial. Data will be presented that indicate the potential for a mouse population-based approach to predict the potential for an ADR, to generate hypotheses regarding the toxicity mechanisms, and to determine the genetic basis of ADR susceptibility in man.

Alison Harrill is an Assistant Professor at the University of Arkansas for Medical Sciences in the Department of Occupational & Environmental Health. She is currently a member and project team leader on major pharmaceutical consortia efforts to advance the science of preclinical safety testing, including the Predictive Safety Testing Consortium Hepatic Working Group, the Health and Environmental Sciences Institute’s (HESI) Application of Genomics to Mechanism-Based Risk Assessment Technical Committee, and the HESI Committee on Biomarkers of Nephrotoxicity. Dr. Harrill received her Ph.D. in Toxicology from the University of North Carolina at Chapel Hill. Dr. Harrill has received several awards for her translational research that include the Outstanding Published Paper in Advancing the Science of Risk Assessment Award (2009) and Top 10 Abstract Award (2013) from the Risk Assessment Specialty Section of the Society of Toxicology.

Tue, October 29, 2013
01:00 PM - 02:00 PM

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