The Institute
for Scientific Exchange, Inc. Presents:
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DDI-2004 7th International Conference
on Drug-Drug Interactions: Mechanism, Prediction, Accuracy, Clinical Approaches
and Novel DDI Events Conference Venue: San Diego Marriott Hotel &
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Featuring experts from the following institutions: Advanced Pharmaceutical Sciences, Inc.; Astex
Technologies; Merck Research Labs; Millennium Pharmaceuticals, Inc.;
Northeastern University; Pfizer Global R&D; RTI International; Louisiana
State University; Tufts University; University of North Carolina; University of
Washington; Washington State University; XenoTech LLC; The Scripps Institute
Now Open www.ISEbooks.com Your online Science book solution
Planning
Committee Chairs:
Albert P. Li, Advanced Pharmaceutical Sciences, Inc.
Magang Shou,
Merck Research Labs
Session I:
DDI Evaluation in Drug Development
Chair: Albert P. Li
Overview: Current Status of
Drug-Drug interactions (Albert P.
Li, Advanced Pharmaceutical Sciences, Inc.;
Use of In Vitro
Approaches to Evaluate Potential Clinical Drug-Drug Interactions (Lawrence
L. Gan, Millennium Pharmaceuticals, Inc.; Cambridge, MA) Adverse drug reaction (ADR) as a
result of inhibition and/or induction of drug metabolizing enzymes (e.g.
CYP3A4) and/or drug transporters (Pgp and MRP2) by co-administered drugs is a
key safety and efficacy concern in the health care community. Various in vitro systems have been developed
during recent years to evaluate the potential of drug candidates to inhibition
and/or induce drug metabolizing enzymes or transporters prior to clinical
development. Computer modeling of in
vitro data to project/predict clinical drug drug
interactions (DDI) has also been attempted lately. Examples of these approaches as well as the
limitations will be discussed.
Strategies to Reduce
Propensity of Toxicological Drug-Drug Interaction in Drug Discovery (Weichao Chen, Ph.D., Merck &
Co., Inc. San Diego, CA) Toxicity of drug candidates is one of the major
problems facing the pharmaceutical industry. In some cases, metabolic drug-drug
interactions can lead to serious toxicological consequences in humans by
increasing the formation of toxic metabolites. For example, CYP2E1 inducers
would increase the risk of hepatotoxicity of acetaminophen and halothane
through increased metabolic bioactivation. Strategies to avoid propensity of
toxicological drug-drug interaction in drug discovery will be presented.
In vivo Probes and
Clinical Assessment of CYP3A Drug Interactions (Evan Kharasch,
Role of
Regulatory Affairs in Drug-Drug Interactions Studies (Romi Singh, Merck Research
Labs; Blue Bell, PA) Drug-drug interactions of NCEs are closely scrutinized by
the regulatory agencies as part of drug approval/registration process. Various regulatory guidances
from key regulatory bodies (e.g., FDA, EMEA) will be presented and
discussed. Timing and implications of
conducting such studies will be considered and evaluated.
CYP Induction-Mediated Drug Interactions:
Clinical Implications (Jiunn H. Lin,
Merck Research Laboratories;
Industry Perspective on
the Conduct of In Vitro Drug-Drug Interaction Studies (Gondi Kumar, Amgen, Inc.; Thousand Oaks, CA) Pharmaceutical industry has recently
published a perspective describing a minimal best practice for in vitro
and in vivo pharmacokinetic drug-drug interaction studies targeted to drug
development, and to define a data package that can be expected by regulatory
agencies in compound registration dossiers.
The goal was also to achieve consistency in quality and predictability
of drug-drug interaction studies but not to limit innovation and experimental
approaches. This talk will focus on
the conduct of in vitro drug-drug interactions.
PANEL DISCUSSION: DDI and Drug Development Successes and
Challenges (Chair:
Session II:
New Tools for DDI
Evaluation
Chair: Scott Obach
Drug-Drug Interactions
Involving Membrane Transporters in the Kidney (Joanne Wang,
P450 Crystal Structure for the
Modeling of P450-Drug Interactions (Pamela Williams, Astex Technology;
5:15 PM 6:00 PM **NEWLY ADDED SPEAKER**
Monoclonal Antibodies (Mabs) Define Cytochrome P450 Drug Metabolism (HV Gelboin, K Krausz, National Cancer Institute, Bethesda, MD) Specific inhibitory Mabs quantify the role of each human cytochrome P450 in the metabolism of a drug or NCE (new chemical entity) or xenobiotic. We have isolated hybridoma clones that produce Mabs uniquely specific to human P450s 1A1, 1A2, 2A6, 2C8, 2C9, 2C19, 2C family (8, 9, 18, 19), 2D6, 3A4/5 and 2E1. The Mabs are highly inhibitory (80-90%) to the enzyme activity of the target P450 and thus the amount of inhibition of the metabolism of the substrate drug incubated with human liver microsomes defines the maximum contribution of the target P450 to the metabolism of the drug. In stark contrast to the other complex analytic systems that are selective, the Mab system is precise and specific to the target P450 and is extraordinarily simple methodology. The in vitro microsome Mab system defines the contribution of the target P450 to the metabolism of the substrate and identifies substrates metabolized by a single or multiple P450s and P450s catalyzing alternate metabolic pathways. Substrates metabolized by a single P450 or thru a specific metabolic route can be used as in vivo probes. The system can be applied to the study of polymorphic P450s, and identify the metabolic consequences of the absence of a polymorphic P450 in individual microsomes.
END OF DAY
(casual attire, not mandatory, but
encouraged because its so much fun!)
Session II: Continued
New Tools for DDI
Evaluation
Chair: Scott Obach
Predicting Drug Interactions in CYP 2C9 and
2C19 Mediated Reactions with Computational Models (Jeffrey P. Jones,
PXR Modeling Toward
Dialing out PXR Agonist Activity (Ying-Duo Gao; Merck Research Laboratories; Rahway, NJ)
Using the recently published PXR crystal structures, compounds that showed
activities on a transactivation assay were docked
into the ligand binding site in the hope of developing a strategy to dial out
the PXR activity. Docking of some classic CYP3A inducers, such as Rifampicin, will be discussed as well.
Development and Validation of
Research Tools for Evaluation of Drug-Drug Interactions (DDIs) Involving the
Human UDP-Glucuronosyltransferase Enzymes (UGTs) (Michael Court, Tufts University;
Boston, MA) Although in vitro methodologies for the evaluation of DDI potential
are routinely applied to drugs that are metabolized by the P450s, such methods
are less well developed for drugs that are cleared primarily by
glucuronidation. A focus of our laboratory has been to develop and
validate the research tools essential to this process, including UGT
isoform-selective substrate probes, chemical and antibody inhibitors, and cell-based
models for the evaluation of UGT induction. An overview of current
progress will be provided.
Immortalized and Fresh Human Hepatocytes: Use and Performance in
Metabolism, Induction and Toxicity Screening (Andrew Parkinson, XenoTech,
Predicting Clinical DDI Arising from
CYP3A4 Induction Using In Vitro Data: Studies with the Fa2N-4 Immortalized
Hepatocyte Line
(Sharon L. Ripp, Pfizer Global Research & Development; Groton, CT) The Fa2N-4 human hepatocyte line, when treated with
prototypical inducers, shows a robust induction of CYP3A4 mRNA and enzymatic
activity. We are examining ways to use this in vitro induction data to predict
clinical DDI due to CYP3A4. One possibility is to combine potency and efficacy
data from Fa2N-4 cells with efficacious plasma concentrations to assess in vivo
induction potential. Studies assessing the validity of this approach using
prototypical inducers will be discussed.
Session
III:
Metabolic & Mechanistic DDI
Chair: Magang Shou
Metabolism-Based Drug-Drug
Interactions: Utility of In Vitro Information (Ronald S. Obach, Pfizer, Inc.; Groton, CT) Over the
past several years, our knowledge of mechanisms underlying drug-drug
interactions has increased to the extent that we now routinely incorporate in
vitro drug interaction data into drug discovery and development
strategies. Furthermore, such data can
be used in drug labeling even in the absence of clinical pharmacokinetic
data. Specific details regarding the gathering
and utilization of vitro drug interaction data will be discussed. Approaches used to predict the magnitude of
interactions will be described. The
relevance of seemingly unimportant experimental details in accurately
predicting drug-drug interactions will be highlighted. Furthermore, considerations of the
application of good laboratory practices to in vitro drug-drug interaction
studies will be presented.
In Vitro-In Vivo Correlation of Metabolism-based Drug Interaction (Magang Shou, Merck Research Laboratories,
Mechanism-Based Inactivation of CYP 3A4 by 4-Ipomeanol (Jiang Zheng,
Evidence for the Direct
Interaction of Cytochrome P450 Enzymes: How Do These Interactions Affect P450
Function (Wayne L. Backes; Louisiana State University Health Sciences Center; New
Orleans, LA) P450
enzymes do not act independently, but require a 1:1 interaction with the
NADPH-P450 reductase. In microsomes, P450 is in a 20:1 excess over
reductase. Therefore, particular forms
of P450 must effectively compete with others for the reductase or be
metabolically silent. This raises questions regarding how these enzymes are
organized in the endoplasmic reticulum.
We will present evidence that one P450 can influence the metabolic behavior
of another P450, and plan to discuss the potential effect on drug
disposition.
Structural Determinants
of Substrate Binding to Human Drug Metabolizing P450s (Eric F. Johnson, The
Scripps Research Institute;
Panel
Discussion: Sessions 2 and 3
END OF DAY
Session IV:
Food & Herbal Medicine Drug-Drug
Interactions
Chair: James Mathews
Drug-Drug Interactions with Herbal
Products: In Vitro Investigations with Kava and Other Herbs (James Mathews; RTI International;
Drug Interactions with
Herbal Medications (Carol Collins;
The Grapefruit Juice Effect: Are Furanocoumarins
Responsible? (Mary Paine,
Grapefruit juice (GFJ) elevates blood levels of numerous
drugs, primarily by inhibiting intestinal CYP3A4 during absorption. In vitro evidence indicates that furanocoumarins are the major CYP3A4 inhibitors. To test this hypothesis in vivo, the effects
of a furanocoumarin-free GFJ were compared with orange juice (control) and
GFJ on the oral pharmacokinetics of felodipine. Results indicate that furanocoumarins
are indeed the major inhibitors responsible for elevating blood levels of felodipine and probably other CYP3A4 substrates that
undergo extensive intestinal first-pass metabolism.
Panel Discussion: Session 4
END OF CONFERENCE
About the Institute for
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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
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 (Phone: 1 619-234-1500; Fax: 1-619-234-8678; International
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