Institute for Scientific Exchange, Inc. Presents:
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IDT-2004:
3rd International Conference on
Idiosyncratic Drug Toxicity: Identification
of Susceptible Individuals and Early Determination of Idiosyncratic Drug Toxicity
Potential San Diego Marriott Hotel & Downtown The following institutions are represented: Abbott Laboratories; Advanced Pharmaceutical Sciences, Inc.; Althea Technologies, Inc.; AstraZeneca; Chinese University of Hong Kong; F.
Hoffmann-La Roche Pharmaceuticals; Humboldt University of Berlin; Johnson & Johnson PRD; Merck
Research Laboratories; Michigan State University; Millennium Pharmaceuticals, Inc.; Naval Surface Warfare Center; NIH; Pfizer Global
R&D; Rutgers University; Taipei Veterans General Hospital; The University
of British Columbia; The University of Liverpool; University of Arizona; University of Toronto
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Planning Committee/Program Chairs
Albert P. Li, Advanced Pharmaceutical Sciences, Inc.
Wednesday, June 16, 2004
12:00 PM – 1:00 PM Registration
1:00 PM – 6:00 PM Exhibits
Session 1: Mechanistic Evaluations
(Chair: Albert P. Li)
1:00 PM – 1:45 PM
Overview: Idiosyncratic Drug Toxicity: A Need to Revise the Current Paradigm of Toxicology (Albert P. Li, Advanced Pharmaceutical Sciences, Inc., Baltimore, MD) The current practice of toxicology is based on Paracelsus’s principle of “dose makes the poison” developed in the 15th century. Based on this principle, drugs are developed and administered to patient at an established efficacious but “safe” dose. The occurrence of IDT illustrate that dose alone is not the determinant factor – host factors such as genetic differences, age, sex, disease conditions, and environmental factors such as co-administered drugs and foods, may play key roles in drug toxicity. Drug safety evaluation therefore should also include host and environmental variables. Such a comprehensive approach may minimize the occurrence of IDT.
1:45 PM - 2:30 PM
Inflammation and Hepatotoxicity: Is There a Connection to Drug Idiosyncrasy? (Robert A. Roth, DABT; Michigan State University; East Lansing, MI) Recent results of animal studies indicate that modest underlying inflammation renders the liver sensitive to otherwise nontoxic doses of some drugs. Inasmuch as modest inflammatory episodes are commonplace in people, the results suggest a novel hypothesis about the etiology of drug idiosyncrasy. Moreover, they raise the possibility of developing animal models and/or in vitro models that might predict idiosyncratic potential of drug candidates.
2:30 PM –2:45 PM –BREAK
2:45 PM – 3:30 PM
Mechanisms Related to Quinolone Induced Idiosyncratic Toxicity (Jeffrey Waring; Abbott Laboratories; Abbott Park, IL) 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 analysing human hepatocytes treated with various quinolone agents. Our results suggest possible mechanisms underlying the toxicity associated with some quinolones.
3:30 PM – 4:15 PM
Cytokines in Drug-Induced Liver Injury (Debra L. Laskin; Rutgers University, Piscataway, NJ) Macrophages and inflammatory cytokines have been implicated in hepatotoxicity induced by a number of different drugs and chemicals including acetaminophen (APAP), alcohol and carbon tetrachloride (CCl4). With each of these agents, increased numbers of macrophages are observed in the liver after exposure of mice to hepatotoxic doses. These cells exhibit characteristics of activated macrophages, including altered morphology and increased generation of inflammatory cytokines such as TNFa and cytotoxic mediators like nitric oxide. The findings that hepatotoxicity is prevented by agents that block macrophages strongly implicates these cells in toxicity. However, the specific role of inflammatory mediators in toxicity depends on the toxicant and the mechanisms underlying tissue injury.
4:15 PM – 4:30 PM – BREAK
4:30 PM – 5:15 PM
Role of Immune and Non-Immune Mediators in Drug-Induced Liver Idiosyncratic Toxicity (Mohammed Bourdi, Laboratory of Molecular Immunology, NIH; DHHS, Bethesda, MD) Drug-induced liver idiosyncratic toxicity (DILIT) is often life threatening and is one of the major reasons new drugs never reach the market or are withdrawn post marketing. Unfortunately, it remains impossible to predict accurately which new drugs will cause DILIT and who will be at risk of developing DILIT. This is due in large part to a lack of animal models. Studies in our laboratory have indicated that the hepatotoxic potential of drugs can be amplified when deficiencies exist in the formation of one or more hepatoprotective factors such as interleukins (IL) -4, -6, and -10. These findings suggest that certain polymorphisms of these and other factors and/or polymorphisms in their receptors may contribute to the incidence of immune and non-immune mediated DILIT in patients.
5:15 PM – 6:00 PM– Panel Discussion
END OF DAY
7:00 PM – 9:00 PM - WELCOME RECEPTION (casual attire, attendance not mandatory, but encouraged because it’s so much fun!)
Thursday, June 17, 2004
Session 2: Reactive Metabolites
(Chair: Amit Kalgutkar)
7:00 AM – 8:00 AM - Continental Breakfast and Registration
7:00 AM – 5:00 PM – Exhibits
8:00 AM – 8:45 AM
Addressing Reactive Metabolite Formation in Early Drug Discovery (Amit Kalgutkar Pfizer Global Research and Development; Groton, CT) There are myriad examples of drugs that are hepatotoxic or cause idiosyncratic toxicity for which bioactivation mechanisms have been described. These examples provide guidance in that chemical substituents that are known to undergo bioactivation to a reactive intermediate should be avoided in early drug discovery efforts. However, when considering bioactivation and reactive metabolite formation within a new chemical entity, several factors must be accounted for before making a judgment based solely on structure. For instance, not all compounds possessing "structural alerts" are bioactivated and not all compounds that are bioactivated cause toxicity. The presentation will highlight literature and in-house examples of such compounds with experimental approaches designed to assess the risk of adverse drug reactions.
8:45 AM – 9:30 AM
The Metabolism of Diclofenac - Enzymology and Toxicology Perspectives (Wei Tang; Merck Research Laboratories, Rahway, NJ) Bioactivation of diclofenac entails two pathways, one of which is glucuronidation catalyzed primarily by UGT2B7. Covalent binding of the resulting acyl glucuronide to hepatic proteins is dependent on the activity of Mrp2 transporter. The second pathway involves oxidation of diclofenac to benzoquinone imines. This is catalyzed by CYP2C9 and 3A4, with the activity of latter being enhanced by quinidine. It is conceivable that either of the bioactivation pathways may lead to idiosyncratic hepatotoxicity of the drug in susceptible patients.
9:30 AM – 9:45 AM –BREAK
9:45 AM – 10:30 AM
Remoxipride and Aplastic Anemia: Are Reactive Metabolites Responsible? (John C. L. Erve, AstraZeneca R&D; Sodertalje, SWEDEN) Remoxipride is an atypical antipsychotic, binding to the dopamine receptor. Several cases of aplastic anemia led to withdrawal of remoxipride from market in 1993. The remoxipride metabolite NCQ-344 is a hydroquinone while the structural isomer NCQ-436 is a catechol, both of which might form reactive quinones. These metabolites were shown to induce apoptosis in bone marrow cells. Furthermore, NCQ-344 also caused necrosis. Three glutathione conjugates of NCQ-344 were characterized by MS; NCQ-436 did not form conjugates. Hypochlorous acid oxidized NCQ-344 to the para-quinone while NCQ-436 resisted oxidation. Stimulated neutrophils produced from 2 to 5 fold greater amounts of glutathione conjugates from NCQ-344 than unstimulated neutrophils. Ab initio calculations indicate that the reaction leading to the respective quinone was spontaneous for the para-quinone while ortho-quinone formation was not.
10:30 AM – 11:15 AM
Methods for the Characterization of Reactive Metabolites and Risk Factors for Idiosyncratic Hepatotoxicity in Non-Clinical Drug Development (Axel Paehler, F. Hoffmann-La Roche Ltd. Pharmaceuticals; Basel, SWITZERLAND) Persuasive evidence suggests a causal link between neoantigens formed by covalent binding of reactive metabolites and some idiosyncratic drug reactions. Although remaining asymptomatic in most individuals, immune response may lead to severe pathological manifestations in a few cases. Cellular stress factors like hepatocellular cholestasis, oxidative stress, inflammation or cytotoxicity might trigger idiosyncratic drug reactions in conjunction with covalent adducts formed from reactive metabolites. Non-clinical approaches to address such risk factors in conjunction with methods for reactive metabolite detection will be discussed.
11:15 AM – 12:00 PM
Reactive Acylating Metabolites of Acidic Drugs (Mark P. Grillo, Merck & Co., Inc.; West Point, PA) Many carboxylic acid-containing drugs have been shown to covalently bind to protein in exposed patients. Such covalent drug-protein adducts have been proposed to act as immunogens leading to idiosyncratic immunotoxic side-effects. One type of covalent modification occurs when acidic drugs become irreversibly bound to protein via acyl-linkages with protein nucleophiles. The purpose of this presentation will be to review recent studies on the chemical reactivity, and hence potential toxicity, of acyl glucuronide and S-acyl-CoA thioester intermediates of acidic drugs. Mechanistic in vitro and in vivo studies on the formation of S-acyl-glutathione conjugates of acidic drugs will be presented.
12:00 PM – 1:30 PM– ISE, Inc. Sponsored Networking Lunch
Session 3: Experimental Approaches
(Chair: Robert Roth)
1:30PM – 2:15 PM
Diclofenac Activates T cells in the Direct Popliteal Lmph Node Assay and Selectively Induces IgG(1) and IgE Against Co-injected TNP-OVA (Bradford W. Gutting, MS, PhD; Naval Surface Warfare Center, Dahlgren Division; Dahlgren, VA) This work examined the immunostimulating potential of diclofenac in the PLNA. Diclofenac caused a dose-dependent reaction that led to an accumulation of PLN T cells with an activated phenotype. The reaction was attenuated in T-cell-deficient mice. When administered with TNP-OVA, diclofenac caused significant increases in IgG1 and IgE antibody, and increased intracellular levels of IL-4 in CD4+ T cells. Collectively, these data suggest that diclofenac activates T-helper 2-like cells leading to IL-4 production and IgG1/IgE antibody synthesis.
2:15 PM – 3:00 PM
Successful Nonclinical Prediction for Idiosyncratic Drug Liver Injury (Carl L. Alden; Millennium Pharmaceuticals, Inc.; Cambridge, MA) Idiosyncratic liver injury is generally considered to be non-dose responsive, of low incidence, and not predicted in nonclinical testing. Review of the summary basis of approval for three drugs (zileuton, troglitazone, bromfenac) causing idiosyncratic injury indicates the belief that preclinical testing does not predict idiosyncratic responses is not true, in these cases. These three drugs caused liver alterations in preclinical testing without a therapeutic margin. Nonclinical testing strategies sufficient to detect molecules inducing idiosyncratic injury will be described.
3:00 PM – 3:15 PM – BREAK
3:15 PM – 4:00 PM
Inhibition of Bile Acid Transport as Endpoint for Hepatotoxicity (Vsevolod Kostrubsky; Pfizer Global Research & Development, Ann Arbor, MI) Hepatic toxicity is a major factor for discontinuing the development of compounds in preclinical development or Phase I clinical trials. Some compounds demonstrate only minor or no signs of liver toxicity in experimental species yet cause unexpected clinical hepatotoxicity. Using these compounds, we investigated the role of drug-bile acids interaction both in vitro and in vivo and association between inhibition of bile acid transport and clinical hepatotoxicity.
4:00 PM – 4:45 PM
Drug-Induced Autoimmunity in the Brown Norway (BN) Rat as an Experimental Model for Idiosyncratic Drug Reactions (IDRs) (Jack P. Uetrecht; University of Toronto, Ontario, CANADA) In order to deal with IDRs it is necessary to understand the mechanisms involved. It is virtually impossible to perform mechanistic studies in humans or in vitro. Penicillamine causes an autoimmune syndrome in BN rats that is similar to the adverse reactions that occur in humans. Nevirapine causes an immune-mediated rash in BN rats and susceptibility can be transferred to naïve animals with CD4+ T cells. These models can be used to gain a better understanding of IDRs.
4:45 PM – 5:30 PM
Could Hepatocytes Become the Gold Standard for Predicting Acute Hepatotoxicity In Vivo? (Peter J. O'Brien, Katie Chan and Arno G. Siraki, University of Toronto, Toronto, Ontario, CANADA) Perhaps the largest chemical class of compounds that causes hepatotoxicity in vivo in rodents is the halobenzenes. Their Phase 1 metabolites include epoxides, phenols, hydroquinones, catechols and quinones. Using "Accelerated Cytotoxic Mechanism Screening” (ACMS) techniques, the order of cytotoxic effectiveness of the 20 halobenzenes tested with isolated rat hepatocytes in vitro at 2h were found to be similar to liver toxicity reported in rats in vivo at 24-48h. Furthermore, although the ACMS techniques revealed differences in molecular cytotoxic mechanisms between the halobenzenes, the same mechanism for a particular halobenzene was the same in vitro as in vivo. A structure-toxicity relationship was also found using ELUMO, EHOMO, and m (dipole moment) that predicted toxicity. Halobenzene induced hepatocyte cytotoxicity was markedly increased by H2O2/peroxidase (an activated neutrophil model) suggesting that inflammation could increase halobenzene hepatotoxicity. This was shown to result from an increase in intracellular toxic phenoxyl radical formation. ACMS techniques with hepatocytes were also used to screen idiosyncratic hepatotoxic drugs (containing phenol, aniline and halobenzene moieties) that were withdrawn.
5:30 PM – 6:15 PM
Screening Idiosyncratic Drug Toxicity Potential with Gene Expression Analysis (Gordon Vansant, Althea Technologies, Inc.; San Diego, CA) Improvement in preclinical idiosyncratic liver toxicity screening could have a very positive impact on the drug screening and development process. 2 of 11 drugs withdrawn from the market post approval between 1996 and 2001 were due to idiosyncratic liver injury. Based on known toxic mechanisms, a panel of genes can be selected for monitoring of responses that would suggest a compound would be toxic in the clinic. It would be extremely cost effective if an in vitro platform could be used for monitoring a compounds impact on a selected gene set. We have developed a multiplex PCR assay that can monitor the expression of 30 genes in one reaction. Based on numerous toxicity studies we have selected 20 genes that are relevant to many of the physiological mechanisms related to toxicity. We have also utilized an immortalized cell line as our in vitro platform for this particular assay. Rezulin (troglitazone) is a drug for treatment of type II diabetes that was withdrawn from the market due to idiosyncratic drug toxicity. Two other very similar drugs, Avandia (rosiglitazone) and Actos (pioglitazone) are still on the market for the same indication as Rezulin. We present data from a gene expression screen that compares the impact these three compounds have in the liver cell line C9. This expression data implicates that Rezulin would be toxic as compared to the other two drugs and predicts possible mechanisms of action of its toxicity.
6:15 PM - Panel Discussion
END OF DAY
Friday, June 18, 2004
7:00 AM – 8:00 AM - Continental Breakfast and Registration
7:00 AM – 5:00 PM – Exhibits
Session 4: Genetic and Environmental Factors
(Chair: Michael Kelley)
8:00 AM – 8:45 AM
Predicting the Unpredictable: Nonclinical Approaches to Anti-Epileptic Drug Development (Michael F. Kelley, Johnson & Johnson Pharmaceutical R&D, L.L.C.; Spring House, PA) Many anti-epileptic drugs (AEDs) are associated with idiosyncratic drug reactions (IDRs). Factors thought to contribute to this association are the high daily doses required for AED efficacy and the potential for metabolism to reactive intermediates. Drug development strategies are needed to identify AEDs with less potential for IDRs. This presentation will review IDRs associated with select AEDs, their putative mechanisms, and experimental approaches to screen new AED candidates for IDR potential.
8:45 AM – 9:30 AM
CYP2C9 Polymorphism and Idiosyncratic Drug Toxicity (Jürgen Brockmöller, Department of Clinical Pharmacology, Georg August University University, Göttingen, GERMANY) Pharmacogenomic research aims to make primary idiosyncratic adverse drug reactions better predictable and thus preventable. The drug metabolizing enzyme cytochrome P450 (CYP) 2C9 metabolizes about 10 to 20% of all drugs. In most populations there are three allelic variants, *1, *2, and *3, with extensive differences in metabolic capacity. Several severe adverse dug effects may be related to the CYP2C9 polymorphism: bleeding complications in oral anticoagulant drug treatment, CNS toxicity and severe allergic reactions after phenytoin treatment, severe hypoglycemia after oral antidiabetics and hepatotoxicity of nonsteroidal anti-inflammatory drugs. CYP2C9 may also play a role in endogenous eicosanoid and prostanoid biotransformation which makes the impact of CYP2C9 polymorphisms for individual disease susceptibility and adverse drugs even more complex.
9:30 AM – 9:45 AM –BREAK
9:45 AM – 10:30 AM
Genetic Polymorphisms of Drug-Metabolizing Enzymes and the Susceptibility to Antituberculosis Drug-Induced Hepatitis (Yi-Shin Huang, MD, Taipei Veterans General Hospital, Taipei, TAIWAN) Antituberculosis drug-induced hepatitis is the most prevalent drug-related hepatotoxicity in Taiwan, India and many other countries. The associated drug-metabolizing enzymes are phase 1 toxification enzymes, including N-acetyltransferase (NAT) and cytochrome P450 2E1 (CYP2E1), and phase 2 detoxification enzymes including glutathione S-transferase (GST) and NAT. Genetic polymorphisms of these enzymes may affect the disposition of hepatotoxic intermediaries. Our recent studies revealed that NAT2 slow acetylators, CYP2E1 c1/c1 and null GST M1 genotype might increase the susceptibility to antituberculosis drug-induced hepatitis. This pharmacogenomic survey may help identify the susceptible populations and prevent this potentially grave hepatotoxicity.
10:30 AM – 11:15 AM
Gender Differences in Susceptibility and Metabolic Activation of Hepatotoxic Clivorine in Rat (Ge Lin, The Chinese University of Hong Kong; Hong Kong, CHINA) Clivorine is a natural pyrrolizidine alkaloid present in various herbal plants. It has been shown to cause hepatotoxicity and liver tumors in laboratory animals. In our recent studies, a gender difference in susceptibility of SD rats to clivorine intoxication was observed. This difference was found to be related to the gender difference in the liver metabolic activation of clivorine mediated by CYP3A isoforms.
11:15 AM – 12:00 PM
12:00 PM – 1:30 PM – LUNCH BREAK
The Role of Oxidant Stress and Reactive Nitrogen Species in Acetaminophen Hepatotoxicity (Hartmut Jaeschke, University of Arizona; Tucson, AZ) Recent findings suggest a role for inflammatory cells including Kupffer cells, neutrophils, NK and NKT cells as sources for cytokine and reactive oxygen formation in the pathophysiology of acetaminophen hepatotoxicity. In addition, mitochondria emerged as critical intracellular source of reactive oxygen and reactive nitrogen species affecting not only the injury mechanism but also the capacity to activate regeneration in hepatocytes and sinusoidal endothelial cells. These intracellular events together with the capacity to mount an inflammatory response determine an individual’s susceptibility to acetaminophen.
1:30 PM – 2:15 PM
Is There a Role for CYP2C9 Genetic Polymorphism in Valproic Acid-Associated Hepatotoxicity? (Thomas K. H. Chang; The University of British Columbia; Vancouver, British Columbia, CANADA) The mechanism of valproic acid (VPA)-induced hepatotoxicity is still not known, but it has been postulated that 4-ene-VPA, which is an oxidative metabolite, may be biotransformed to an electrophile diene that inhibits mitochondrial β-oxidation enzymes and depletes cellular glutathione. The biotransformation of VPA to form 4-ene-VPA is catalyzed by cytochrome P450 2C9 (CYP2C9), which is subject to genetic polymorphism. This presentation will focus on the influence of CYP2C9 genotypes on the formation of 4-ene-VPA in human liver microsomes.
2:15 PM – 3:00 PM
Summation of the Conference: Where Are We in the Understanding of Idiosyncratic Drug Toxicity (Albert P. Li, Advanced Pharmaceutical Sciences, Inc.; Baltimore, MD) The key findings and their relevance on idiosyncratic drug toxicity presented in this conference with be summarized.
3:00 PM – 3:15 PM – BREAK
3:15 PM – 4:00 PM - Panel Discussion
END OF CONFERENCE
POSTER
PRESENTATIONS:
Poster
Presentations are always encouraged. Please submit your poster abstract for
approval by the organizing board by April 30th. Poster size should be no larger than 4
feet high by 7 feet long. Abstracts
of posters will be included in the participant binder and in the ISE
website. There is no formal poster
presentation scheduled. All posters will
remain displayed throughout the conference.
Please be prepared to display your poster during registration on Sunday
June 13th or before the first session begins on Monday, June 14th. Poster presenters will have ample time for
discussion during breaks and the Welcome reception.
Submit
posters abstracts for approval to Nola Mahaney, VP, Operations; ISE, Inc.; 5707
Calverton Street, Suite 2C; Baltimore, MD 21228 or fax at (410) 869-9560 or
email file attachment to nola@isciencex.com. Approved poster presenters are responsible
for completing a conference attendance registration form (visit www.isciencex.com/register.htm) and for the shipping of
the poster itself. Please contact Nola
Mahaney for any questions or concerns.
Please refer to “Travel Information” for hotel address and shipping
information.
Travel Information
San Diego 333 West Harbor
Drive , San Diego ,
CA USA San Diego International Airport
San Diego Bay and marina.
Hotel Information
A
limited number of rooms have been reserved at the San Diego Marriott Hotel
& Marina in Beautiful downtown San Diego at a reduced conference rate of
$189.00 per single room. There is an additional
charge for extra persons.
Please make your hotel reservation directly by
telephone at (609) 449-1000 or (800) 825-8888.
Please ask for the “IDT-2004” block.
Payment
Payment
may be made by check or credit card.
Checks should be made in US $, payable to Institute for Scientific
Exchange, Inc. Mail to: ISE, Inc.,
IDT-2004 Conference: US
$1500.00 ______________
SPECIAL DISCOUNT: Both **DDI-2004
& IDT-2004: US$2500.00___________
Exhibitors: US $2000.00________________________
Academic/Government participants will receive a 50% discount.
Cancellation Policy
All
cancellations are subjected to a $250.00 cancellation fee. Longer than 30 days,
100% refund (less $250.00). Less than 30 days, no refund but registration may
be transferred to another person. All
refund requests must be in writing. All refunds
will be issued after the meeting has occurred. No refunds requests will be
accepted after
Fax: 410-869-9560
E-mail: nola@isciencex.com
Deadline:
Email to nola@isciencex.com
or mail/fax completed form with remittance to: ISE, Inc. 5707 Calverton Street, Suite 2C,
Contact
Nola Mahaney for Exhibitor or Sponsorship Opportunities at nola@isciencex.com, or phone (410) 869-9166);
or visit www.isciencex.com/exhibitors