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Characterization of Gene Expression Profiles from Drug-Induced Liver Injury Ching-Wei Chang and James J. Chen NCTR

Background: Drug-induced liver injury (Hepatotoxicity) Liver Toxicity Biomarkers Study: Drug pair, tolcapone and entacapone Methods: Design and marker identification strategy Results: Validation (statistics)Susceptible Animals: Clinical variablesSummary. Outline . Background. Hepatotoxicity accounts for ~27% of drugs withdrawn from the market in the period 1960-2002.Hepatotoxicity accounts for over 40% of drug candidate terminations in the clinical phase.An estimate cost due to hepa1140

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Characterization of Gene Expression Profiles from Drug-Induced Liver Injury Ching-Wei Chang and James J. Chen NCTR

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    1. Characterization of Gene Expression Profiles from Drug-Induced Liver Injury Ching-Wei Chang and James J. Chen* NCTR/FDA 2009 Non-Clinical Biostatistics Conference October 22, 2009 Boston, MA

    4. Idiosyncratic Liver Toxicity In preclinical development, the animal species studied exhibit clear signs of liver toxicity, e.g., liver enzyme elevations, histopathological alterations, or both. In clinical phase I, II, or III trials, the subjects/patients exhibit signs of liver toxicity, despite the absence of liver toxicity in animal species. After the drug is on the market, there are incidences of liver toxicity in the target patient population.

    6. Treatment of Parkinson's disease Tolcapone (Tasmar®) implicated in 3 female deaths due to drug-induced liver injury 5% incidence of elevated ALT (>3xULN) in females Tolcapone withdrawn from market; Tolcapone reintroduced with black box warning Entacapone shows no signs of liver toxicity

    17. ATP binding, kinase activity, and catalysis of the diphosphomevalonate decarboxylase activity

    18. Catalysis of the phosphates activity In conjunction with protein kinases, it provides an important mechanism for regulating cellular activity

    24. Vars2 identified in both animals A member of Valyl-tRNA synthetase protein Vars2 is in one of the top 3 most significant tolcapone-specific pathways Vars2 involves in nucleotide binding and tRNA aminoacylation for protein translation related to acetaminophen-induced liver disease

    25. The genomic markers were classified into four ideal categories based on the statistical testing: T, E, C, D. 695 genes were identified, of which 238 genes were ideal markers, T, E, C, or D; 138 of the 238 were classified consistently by a 5x5 SOM. 69 pathways were identified from the 695 genes, 5 of 8 associated with a tolcapone-specific (t) pathway were significant.

    26. 2 animals in the tolcapone high dose group were found to have extremely high ALT, AST, or TBIL levels. Six T genes were identified in one animal and 3 T genes were identified in another animal. The Vars2 gene was in common in both animals; this gene is in one of the top 3 most significant tolcapone-specific pathways. Future Work: Integrating proteomic, metabolomic, and microarray data

    27. NCTR Dr. Frederick A. Beland – Principal Investigator Dr. James C. Fuscoe – Genomics team Dr. Richard D. Beger – Metabolomic team Dr. Weida Tong – Bioinformatics team BGMedicine Dr. Wade Hines; Dr. Thomas Plasterer Proteomics team

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