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Thursday, June 17
8:20 am Chairperson's Remarks
Yvonne Will, Ph.D., Associate Research Fellow, Compound Safety Prediction, Pfizer Global R&D
8:30 Transcriptional and Signaling Regulation of Hepatic ABCC Genes by Hepatotoxicant Treatment
José E. Manautou, Ph.D., Associate Professor of Toxicology, Department of Pharmaceutical Sciences, University of Connecticut
Drug transporters are responsible for the transport of drugs and endogenous compounds in various organs. Changes in the expression and function of drug transporters contribute to drug resistance. This talk will focus on the changes in expression of hepatic multi-drug resistance-associated proteins during liver injury induced by toxic acetaminophen treatment and its relationship to acquire resistance to acetaminophen hepatotoxicity. The role of oxidative stress signaling and other cellular mediators in regulating drug transporters will be also discussed.
9:00 Probing Mechanisms of Inter-Individual Susceptibility to Toxicants with Population-Based Experimental Approaches
Ivan Rusyn, M.D., Ph.D., Associate Professor of Environmental Science and Engineering, University of North Carolina
Genetic polymorphisms have a profound effect on differences between individuals in response to drugs and toxicants, yet are not fully considered in safety evaluation. A variety of in vivo and in vitro approaches are now available to elucidate the genetic determinants for inter-individual differences in toxicity. In addition, toxicity phenotypes may be combined with genetics and gene expression datasets and offer insights into the molecular mechanisms and provide necessary science-based underpinnings and tools for improved toxicity testing and risk assessment.
9:30 Mitochondrial Toxicity in Drug-Induced Liver Injury: Pre-Clinical Screening Strategy
Yvonne Will, Ph.D., Associate Research Fellow, Compound Safety Prediction, Pfizer Global R&D
Attrition of drugs due to hepatotoxicity remains a large concern for many pharmaceutical companies. Between 38 and 51% of compound-induced liver effects reported in humans are not detected in non-clinical test species. The evidence is compelling that mitochondrial dysfunction contributes to drug-induced liver injury (DILI). Early identification of new chemical entities (NCE) that perturb mitochondrial function is therefore of significant importance in drug discovery if attrition due to toxicity is to be avoided. Within the past three years, we have developed screening assays to assess mitochondrial function at the organelle and cellular level. We will show examples of NSAIDs, anti-virals and anti-diabetics, as we have profiled them utilizing these assays. We will demonstrate how these screens can detect mitochondrial toxicity and subsequent hepatotoxicity.
10:00 Networking Coffee Break, Poster and Exhibit Viewing
10:45 Metabolism-Mediated Hepatotoxicity: Mechanisms and Predictions
Jan Wahlstrom, Ph.D., Senior Scientist, Pharmacokinetics and Drug Metabolism, Amgen, Inc.
Metabolism plays a central role in candidate selection, as the formation of reactive intermediates may suggest the potential for dermatological sensitization, genotoxicity or liver injury. While results from in vitro assays such as covalent microsomal binding are often used in candidate selection, further mechanistic information such as site of metabolism or site of protein adduction may underwrite toxicological risk more appropriately. This talk will focus on integrating in silico modeling with in vitro assays to predict metabolism-mediated hepatotoxicity in the drug discovery setting using the candidate selection process for AMG 458, a potent inhibitor of the receptor tyrosine kinase c-MET, as a case study.
11:15 In vitro-in vivo Correlations and Pharmacokinetic Drivers of Hepatotoxicity with Small Molecule Kinase Inhibitors
Dolo Diaz, Ph.D., DABT, Scientist, Investigative Safety Assessment, Genentech, Inc.
Improving the predictivity of in vitro hepatotoxicity systems relies on the demonstration of robust in vitro-in vivo correlations. Disconnects between in vitro IC50 values and in vivo plasma exposures have hampered the translational utility of in vitro systems. One important in vivo variable often missing from the interpretation is the actual hepatic drug level, which can vary largely from systemic plasma exposures. Examples will be presented in which in vitro-in vivo correlations and differences in species sensitivity can be better understood by considering target organ exposures, as well as approaches for using pharmacokinetic parameters to anticipate differences between hepatic and systemic drug levels.
11:45 Luncheon Presentations (Sponsorship opportunity available)
1:15 pm Chairperson's Remarks
Eric Blomme, D.V.M, Ph.D., D.A.C.V.P., Senior Project Leader, Abbott Laboratories
1:25 Quantitative Liver-Specific Blood Protein Fingerprint: A Signature for Hepatotoxicity
Zhiyuan Hu, Ph.D., Research Scientist, Institute for Systems Biology
We have employed a targeted proteomics approach to identify liver-specific blood proteins that reflect the activities of their cognate biological networks. We report a panel of twelve liver-specific blood proteins responsive to the mouse model of acetaminophen hepatotoxicity. We observed a striking dynamic correlation between the changes in liver-specific blood protein concentrations and the histopathology over time. The panel has the potential to effectively detect liver toxicity-in cases of poisoning-or in clinical trials to detect toxic liver responses.
1:55 In vitroPrediction of Hepatotoxicity
Stefan Platz, Ph.D., D.V.M., Head of Toxicology/Pathology, F. Hoffmann-La Roche Ltd.
Liver toxicity is a major safety concern and frequently results in discontinuation of development of drug candidates. Hence, there is a significant interest to select compounds deprived of hepatic liability early during the development process. Currently, a number of different cell systems are used, including immortalized cell lines, transfected cell lines or primary cells that can be grown in simple monolayer or in organotypical 3D cell culture models. These systems all differ in throughput, complexity and, their ability to mimic the (patho)physiology of the liver. The impact of the exposure to test compounds on these systems is usually evaluated using a wide range of technologies. Hepatotoxic risk can thus be evaluated based on cellular imaging, biochemistry endpoints or –omics technologies. During the evaluation phase of these systems and before implementing a sophisticated screening strategy, it is of utmost importance to assess the accuracy of the predictions. For this purpose, in vitro test systems are compared to in vivo results regarding response to a well defined reference compound set.
2:25 Ice Cream Refreshment Break in the Exhibit Hall
3:05 Sandwich-Cultured Hepatocytes: An in vitro Tool to Predict Hepatic Exposure of Drugs/Generated Metabolites and Hepatotoxicity
Kim L.R. Brouwer, Pharm.D., Ph.D., Chair, Division of Pharmacotherapy and Experimental Therapeutics, The University of North Carolina at Chapel Hill
The ability to accurately predict the metabolism, hepatic accumulation/exposure and excretory routes (canalicular excretion to bile vs. basolateral efflux to blood) of drug candidates and generated metabolites in vivo using in vitro systems is of great interest in drug discovery and development. Several applications of sandwich-cultured hepatocytes using B-CLEAR® technology will be discussed and several drug/metabolite pairs will be used as examples [terfenadine/fexofenadine; morphine/morphine 3-glucuronide; troglitazone/troglitazone sulfate and glucuronide. The use of the technology for determination of cellular exposure to hepatotoxic compounds generated in hepatocytes from the species of interest and as a screening tool to assess impaired hepatic bile acid transport as a potential mechanism of drug-induced hepatotoxicity, will also be discussed.
3:35 Strategic Use of High-Content Technologies to Predict and Characterize Hepatotoxicity
Eric Blomme, D.V.M, Ph.D., D.A.C.V.P., Senior Project Leader, Abbott Laboratories
Hepatotoxicity represents an important cause of failure in drug discovery and development, and improved approaches to predict and characterize this toxicity could significantly impact pharmaceutical R&D. Several relatively novel high-content technologies can help de-risk compounds for hepatotoxicity by improving the predictive value of preclinical in vivo and in vitro models. Here, we present several strategies that leverage carefully selected methodologies to improve hepatotoxicity prediction.
4:05 PANEL DISCUSSION
Effective Evaluation and Utilization of Tools for Predicting Hepatotoxicity
Moderator: Eric Blomme, D.V.M, Ph.D., D.A.C.V.P., Senior Project Leader, Abbott Laboratories
4:35 End of Conference
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