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Day One:
Tuesday, November 16
5:00pm Early Registration
6:00-7:00pm Joint Reception with Toxicity Biomarkers attendees
Wednesday, November 17
7:30-8:30am Registration and Coffee
8:30 Chair's Opening Remarks
Dr. Robert Roth, Department of Pharmacology and Toxicology and Associate Director, National Food Safety and Toxicology Center, Michigan State University
8:35 Keynote Presentation
The Many Faces of Idiosyncracy
Dr. John Senior, Associate Director for Science, Office of Pharmacoepidemiology and Statistical Science, Center for Drug Evaluation and Research, U.S. Food & Drug Administration
Efforts to minimize idiosyncratic toxicity in drug development have been frustrated by its appearance postmarketing in patients using approved drug products. Laboratory animals have been bred to genetic uniformity, their environments and experimental conditions controlled carefully, and high risk study participants have been excluded from controlled clinical trials, to avoid generating safety problems during drug development. But it has not been possible to predict or prevent the uncommon or rare, but often serious adverse effects that appear when large numbers of less well selected or observed patients are treated after drug approval. The incredible diversity of human beings, because of both genetic and acquired factors, makes a few of them hypersusceptible to drug-induced injury to various organs or systems. There is no single pathway to, or mechanism of the hypersusceptibility of these individuals to drug-induced injury, but speakers in this conference will address a number of possible mechanisms. We shall discuss both perceived current problems and consider possible solutions, or at least some ways in which improvements may be made. These comments will be offered not as advice or guidance but in the spirit of scientific inquiry, inviting discussion and debate broadly into this problem of general public concern. |
9:15 Understanding of Idiosyncratic Toxicity: The Potential Role of Inflammation in Idiosyncratic Toxicity
Dr. Robert Roth, Department of Pharmacology and Toxicology and Associate Director, National Food Safety and Toxicology Center, Michigan State University
Animal studies have revealed that modest underlying inflammation makes the liver sensitive to otherwise nontoxic doses of some drugs. Results of recent studies that have begun to explore mechanisms of inflammation-drug interaction will be discussed. Since inflammatory episodes are commonplace in people, the results suggest an explanation for certain idiosyncratic drug toxicities and raise the possibility of developing predictive animal models.
9:45 Protective Role of Hepatic Macrophages in Idiosyncratic Drug Reactions
Dr. Cynthia Ju, Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center
Evidence suggest that hepatic macrophages, Kupffer cells, play an important role in inducing T cell hyporesponsiveness to drug-protein adducts, as well as inhibiting drug-induced acute inflammation within the liver. Possible mechanisms involved in Kupffer cell-mediated protection against immune- and non-immune-mediated idiosyncratic drug reactions
(IDR) will be discussed. The results suggest that genetic or environmental factors that impair the protective functions of Kupffer cells may explain why certain individuals are more susceptible to
IDR.
10:15 Exhibit and Poster Viewing and Coffee Break
10:45 The Role of Nitrogen Reduction Pathways in Idiosyncratic Drug Toxicity
Dr. Lauren Trepanier, Department of Medical Sciences, University of Wisconsin-Madison
Arylamine and other nitrogenated drugs generate hydroxylamine and nitroso metabolites that mediate idiosyncratic drug toxicity and
immunogenicity. We have shown that hydroxylamine metabolites are detoxified primarily by enzymatic reduction by NADH cytochrome b5 reductase and cytochrome b5, a pathway which shows pharmacogenetic variability and is decreased in HIV infection. We have also shown that nitroso metabolites are detoxified primarily by non-enzymatic reduction by
ascorbate, and that this pathway is also impaired in HIV infection (in press,
JAIDS). Variability in each of these pathways represents a potential mechanism of increased susceptibility to idiosyncratic drug toxicity, particularly in the setting of HIV infection.
11:15 The Role of Dosing,
Pharmacokinetics, Drug-Drug and Drug-Disease Interactions and Pharmacogenomics in Idiosyncratic Toxicity
Dr. Rakesh Dixit, Ph.D., DABT, Department of Safety Assessment, Merck Research Laboratories, Merck & Company, Inc.
Idiosyncratic adverse effects (IAE) account for at least 3 to 25% of all adverse drug reactions, The presentation will evaluate the impact of total dose,
pharmacokinetics/metabolism, host derived intrinsic factors (e.g., genetic polymorphism in drug metabolism, abnormal receptor sensitivity, variability in immune system, age) and extrinsic factors such as co-exposure to bacterial and viral pathogens, preexisting diseases, drug-drug interaction, drug-nutrients,
drug-disease(s), and drug-drug interactions). The presentation will present case studies on: (1) impact of total dose on
IAEs; (2) impact of individual PK and PD on IAEs outcome; (3) role of preexisting diseases, acquired diseases on drug toxicity; (4) role of nutrition and life style factors on drug toxicity; and (5) role of pharmacogenomics on drug toxicity.\
11:45 Panel Discussion
12:15 Lunch on your own or Technology Workshop (Sponsorship Available)
Reactive Metabolites and Idiosyncratic Toxicity
1:45 Chair's Remarks
Dr. Amit S. Kalgutkar, M.Sc., Ph.D., Senior Principal Scientist,
Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Global Research & Development
1:50 Idiosyncratic Drug
Toxicity: An Examination of Structural and Mechanistic Aspects
Dr. John Erve, Principle Research Scientist, Department of Drug Safety & Metabolism, Wyeth Research
I will focus on a number of drugs associated with idiosyncratic toxicity and focus on the structure toxicity relationships that have been identified. This will include the concepts of toxicophore and bioactivation pathways to reactive intermediates that is receiving much attention today. I will also try to provide a balanced perspective on this issue by examining the mechanisms of toxicity in instances where they are known. A summary of recent work on a drug that was withdrawn from the market will be provided as a case study.
2:20 The Use of Reactive Metabolite Data in Drug Development
Dr. Amit S. Kalgutkar, M.Sc., Ph.D., Senior Principal Scientist,
Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Global Research & Development
Two examples of drugs that form reactive metabolites - one which leads to toxicity and has been withdrawn from the clinic and one which is perfectly safe, will be presented. Underlying
reason(s) for these differences will be highlighted. The chemistry (biochemistry) of the various bioactivation pathways will be emphasized and will be fairly mechanistic in nature. A special emphasis on how best to use reactive metabolite data in a drug development arena will also be provided.
2:50 Detecting and Minimizing Reactive Intermediates
Dr. Ala Nasser, Vion Pharmaceuticals
Toxicity of drug candidates during clinical development accounts for ~20% of attrition while unexpected events during late-stage clinical trials has led to severe restrictions on use or failure to launch. How can we develop better predictive tests for detecting these reactions?
3:20 Exhibit and Poster Viewing and Refreshment Break
4:00 Drug–Protein Adducts: Minimizing the Potential for Reactive Metabolite Formation as a Fundamental Element of Drug Design
Dr. David Evans, Senior Director, Drug Metabolism, Merck & Co.
A perspective on how to address the issue of metabolic activation from an industry viewpoint based on in vitro and in vivo protocols adopted by Merck Research Laboratories will be presented. Examples of efforts made within our laboratories to minimize reactive metabolite formation as a fundamental element of drug design will be discussed.
4:30 High-throughput Screening for Reactive Metabolites in Early Drug Discovery
Dr. John Soglia, Principle Scientist, Pharmacokinetics, Dynamics and Metabolism, ADME Technology Group, Bioanalytical Laboratory, Pfizer, Inc.
Recent efforts in our laboratory have focused on the development of a high sample throughput bioanalytical assay capable of detecting the formation of reactive drug metabolites in vitro to help guide decision-making during early drug discovery. This presentation will provide an overview of the reactive metabolite assay that was developed and the screening approach currently employed in our laboratory.
5:00 Panel Discussion
5:30-6:30 Facilitated Networking with Wine and Cheese
Facilitated Networking Round-Table Topics:
• Role of Inflammation
• Reactive Metabolite Assays
• Designing Metabolic Stability
• Expression Profiling Assessment
• Animal Models for Toxicity Screening
• Computational Prediction of Toxicity Risk |
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