Day Two: 

Thursday, November 18

8:00   Morning Coffee

8:30   Summaries from Round-table Discussions

Prediction of Idiosyncratic Potential

8:50   Chair's Remarks
Dr. Rakesh Dixit, Ph.D., DABT, Department of Safety Assessment, Merck Research Laboratories, Merck and Company, Inc.

8:55   Mechanisms Related to Quinolone Induced Idiosyncratic Toxicity
Dr. Yi Yang, Senior Researcher, Department of Cellular and Molecular Biology, Abbott Laboratories
Idiosyncratic drug toxicity, defined as toxicity that is dose-independent, host-dependent, and usually cannot be predicted during early phases of clinical trials, is a particularly confounding complication of drug development. Some quinolone antibacterial compounds have been associated with this type of toxicity. We have applied microarray analysis towards analzying human hepatocytes treated with various quinolone agents. Our results suggest possible mechanisms underlying the toxicity associated with some quinolones.

9:25   In Vitro Oxidative Stress and ACMS Screening for Idiosyncratic Toxicity Potential 
Dr. Peter O'Brien, Faculty of Pharmacy, University of Toronto
Whilst drug or NCEs metabolic activation to hepatotoxic reactive species has focussed on microsomal P450 studies it is clear that hepatotoxicity in vivo is promoted by inflammation. Inflammatory cell peroxidase/hydrogen peroxide can metabolically activate drug/NCEs or their P450 metabolites to radicals that cause toxic hepatic oxidative stress. The toxicity of non hepatic tissues induced by drugs/NCEs likely can also be attributed to the metabolic activation of drugs/NCEs by peroxidases. “Accelerated Molecular Cytotoxic Mechanism Screening” techniques using peroxidase/hepatocytes will be described for screening drugs/NCEs.

9:55   Poster and Exhibit Viewing and Coffee Break

10:15   Comparison of Metabonomic Analysis Techniques in Idiosyncrasy-like Liver Injury in Rats Co-treated with Lipopolysaccharide and Ranitidine 
Dr. Jane Maddox, Department of Pharmacology and Toxicology, Michigan State University
Biofluid metabonomics is a method of evaluating the biochemical status of an animal and has the potential to provide information on the status of live animals. Small amounts of urine can be collected during the course of a study, and various techniques can be used to detect these xenobiotic-induced changes. Recently, liver injury resembling human ranitidine (RAN) idiosyncrasy was created in RAN-treated rats by cotreating them with a nonhepatotoxic dose of lipopolysaccharide. Metabonomics has not previously been used to segregate animals treated with a single drug from those coexposed to another agent. Therefore, urine was collected for nuclear magnetic resonance-, direct infusion electrospray ionization mass spectrometry-, and Fourier-transform infrared spectroscopy-based metabonomic analyses. Results will be discussed and techniques compared.

10:45   Idiosyncratic Toxicity Potential from a Toxicogenomics Perspective
Dr. Michael McMillian, Principal Scientist, Mechanistic Toxicology, PreClinical Drug Evaluation Johnson & Johnson PRI
Compounds with reactive metabolites are viewed as high risk for idiosyncratic reactions since antigens are formed by covalent binding of these haptens to endogenous proteins. These reactive compounds and metabolites tend to be robust inducers of Nrf2-regulated oxidative stress-responsive genes. Using cDNA microarrays we have determined a gene signature pattern for oxidative stressors/ reactive metabolites. Although the most robust inducers of these genes tend to be directly hepatotoxic, moderate inducers such as felbamate are not usually acutely toxic in rats. These compounds are of interest as possible inducers of idiosyncratic reactions in people.

Technology Showcase

11:15   PharmGenix™ Rat Panels: a New Approach for Detecting Idiosyncratic Toxicity in Preclinical Safety Testing 
Dr. Steven Nye, Director, Genomics Research & Development, PhysioGenix, Inc.
Recent drug failures attributed to idiosyncratic toxicity may result from a failure of the pharmaceutical industry to address the lack of genetic diversity in animal models and cell-based assays used in preclinical efficacy and safety testing. A robust combinatorial breeding strategy has been developed with specially selected rat strains to create PharmGenix™ panels, which are the first genetically diverse, yet reproducible, in vivo animal model for preclinical efficacy and safety testing. We have demonstrated that such panels have enhanced power to detect drug toxicity compared to standard models using either single inbred or outbred rats. In addition, the combinatorial nature of the approach rapid identifies sensitive and resistant genomes and accounts for the influence of genome background. Drug testing with the PharmGenix™ panel can be used to identify the genetic basis for an adverse drug response as a start point for drug optimization, rescue and mechanistic studies.

11:45   Computational Approaches to Prediction of Idiosyncratic Toxicity 
Dr. Sean Ekins, Vice President, Computational Biology, GeneGo, Inc.
The development of computational methods for the early assessment of metabolism and toxicity may allow the removal of potentially undesirable compounds from early drug discovery, including those involved in idiosyncratic toxicity. I will describe the development of MetaDrugTM, a tool for the prediction of human drug metabolism and toxicity using predictive models and a database of annotated metabolic, and regulatory networks onto which gene expression, proteomic and metabonomic data can be overlaid. I will provide relevant applications of this technology and describe how this approach represents a step towards merging computational models for predicting human metabolism, toxicity and systems biology. This approach will be useful in assisting in the improvement of the quality of drug discovery candidates and avoiding toxicity.

12:15   Close of Conference