2010 Archived Content

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Recommended Short Courses*

Monday, June 149:00 am – 12:00 pm
(SC3) Translating Safety Biomarkers from the Lab to the Clinic
(SC4) Use of Stem Cells for Safety Screening

2:00 pm – 5:00 pm
(SC6) Addressing Safety Concerns for Biological Drugs
(SC8) Mechanistic Insights into Cardiotoxicity

Wednesday, June 16
6:00 pm – 9:00 pm (Dinner will be served)
(SC9) Mechanistic Insights into Hepatotoxicity



*Separate Registration Required. 




12:30 pm Registration


Tackling Idiosyncratic Hepatotoxicity 

1:55 Chairperson's Opening Remarks 

Moderator: Arie Regev, M.D., Hepatology Consultant and Chair, Liver and GI Safety Committee, Global Patient Safety, Eli Lilly & Co.

2:00 Early Prediction of Drug-Induced Hepatotoxicity: Where are We Now and Where are We Going?

Arie Regev, M.D., Hepatology Consultant and Chair, Liver Safety Committee, Global Patient Safety, Eli Lilly & Co.

Drug induced liver injury (DILI) is the most common drug-safety issue leading to regulatory action including withdrawal of drugs from the market, restrictions in indications, and warnings to health care providers and patients. In the vast majority of these cases the hepatotoxicity is of the idiosyncratic type and is typically missed in the preclinical stages of drug development. This presentation will review the current knowledge on early prediction of idiosyncratic DILI, and will focus on future endeavors to address unmet needs in this field.

2:30 Better Prediction of Idiosyncratic Hepatotoxicity in Pre-Clinical Species Using a Multiple -Omics Approach

Xi Yang, Ph.D., ORISE Post Doctoral Fellow of the Center for Hepatotoxicity, Division of Systems Biology, U.S. FDA National Center for Toxicological Research

Idiosyncratic hepatoxicity can not be predicted using traditional preclinical animal models and is a major cause of post-marketing drug removal. This presentation will provide an overview of a multiple -omics (genomics, proteomics, and metabolomics) approach being applied at the US FDA NCTR to better predict idiosyncratic hepatotoxicity in preclinical animal models. A unique aspect of this study is the use of mutliple genomics samples(blood and liver mRNA and blood microRNA) combined with proteomics and metabolomics analyses. The results from this study will be published in the public domain to facilitate the identification of biomarkers that will allow better predicition of idiosyncratic hepatotoxicity.

3:00 Sponsored byEMD NovagenMultiplex Evaluation of Mitochondrial ToxicityWei Zheng, M.S. Ph.D, Immunoassay Team Lead, Research & Development, Merck KGaA, EMD Chemicals (North America)Oxidative phosphorylation produces more than 95% of the conserved cellular energy in the form of ATP under normal conditions. This process involves 5 different protein complexes (Complexes I-V) and is tightly controlled by transcriptional regulation at the level of DNA and RNA, by substrate feedback inhibition and by post-translational modifications including phosphorylation and acetylation. Inefficient electron transfer through complexes I-IV causes human disease. Diseases thought to involve compromised oxidative phosphorylation include diabetes, Parkinson's disease, Alzheimer's, cancer and the aging process itself. Many diverse classes of drugs inhibit oxidative phosphorylation.  Not surprisingly, the ability to monitor the levels of the 5 oxidative phosphorylation complexes need to be a key part of drug development and drug toxicity studies.  However suitable  high throughput approaches do not exist. Here we describe a high throughput, multiplex approach to monitoring oxidative phosphorylation as a part of our WideScreen BeadPlex assays, using the Luminex technology. We establish the accuracy, reproducibility and insights provided by using this assay in studies of the effects of 4 different drugs on HepG2 cells, i.e. ddC an antiviral, chloramphenicol an antibiotic, rosiglitazone and troglitazone, two anti-diabetes compounds, one in widespread use, the other taken off the market because of unexpected toxicity.

3:15 Sponsored Presentation (Opportunity Available) 

3:30 Networking Refreshment Break, Poster and Exhibit Viewing


New Approaches to Understand and Predict Idiosyncratic Hepatotoxicity

Paul WatkinsPaul B. Watkins, M.D., Director, Hamner-UNC Institute for Drug Safety Sciences, Verne S. Caviness Distinguished Professor of Medicine, University of North Carolina at Chapel Hill

Our institute is collaborating with the FDA and Entelos to develop computer models that will explain idiosyncratic hepatotoxicity (IH). The knowledge required to complete these models is being obtained though multiple avenues, including analyses of DNA banks obtained from patients who have experienced IH and, in partnership with industry, studies of many proprietary compounds that have failed in clinical trials due to hepatoxicity. These studies involve a new panel of inbred mice, the Collaborative Cross, that mimics the genetic heterogeneity observed in man.


Early Prediction of Idiosyncratic DILI: What is the Forecast for This Decade and What Should Drug Makers Do Today?

Moderator: Arie Regev, M.D., Hepatology Consultant and Chair, Liver and GI Safety Committee, Global Patient Safety, Eli Lilly & Co.

5:30 End of Day

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