December 10
Pre-conference Refresher Course:
Principles
of Pharmacokinetic Drug-Drug Interactions
December 11-12
5th International Symposium on Drug-Drug Interactions
Planning Committee
Charles Crespi, GENTEST, Inc.
Gondi Kumar, Amgen, Inc.
Albert P. Li, InVitro Technologies
Juinn Lin, Merck
Suresh V. Ambudkar, NCI, NIH
Jerry Collins, FDA
|
Monday,
December 10, 2001
Pre-Conference
Refresher Course:
Principles
of Pharmacokinetic Drug-Drug Interactions
(Chairs:
Albert P. Li, Juinn Lin) The purpose of this
course is to provide a basic but comprehensive and up-to-date review of the
concepts of drug-drug interaction evaluations as a refresher course for new
comers and veteran practitioners of
the field |
8:00-9:00 AM Continental Breakfast
9:00 AM 10:00 AM
Overview: Mechanism-based Evaluation of
Drug-Drug Interactions
(Albert
P. Li, In Vitro Technologies, Inc., Baltimore, MD) Drug-drug
interaction potential of a new drug candidate can be evaluated with human-based
in vitro experimental systems. In this
lecture, the basic principles of drug-drug interactions and the evaluation of interaction
potential based on the following will be described:
·
Identification of major pathways of
biotransformation
·
Evaluation of inhibitory potential of
drug metabolizing enzymes
·
Evaluation of induction potential of
drug metabolizing enzymes
Special considerations will be given to
the importance of the choice of experimental systems.
10:00 AM 11:00AM
Cytochrome
P450 Inhibition and Drug-Drug Interactions
(Charles L.
Crespi; GENTEST, Woburn, MA) Rapid testing for the inhibition
of drug metabolizing cytochromes P450 is part of the current paradigm for
stopping the development of drugs likely to give clinical pharmacokinetic
drug-drug interactions. An overview of
the mechanisms of cytochrome P450 inhibition and the experimental methods
available to measure cytochrome P450 inhibition will be presented. The
following aspects of the design and implementation of a testing program will be
discussed:
·
Design of a testing program.
·
Operational performance considerations.
·
Special considerations when testing for
inhibition of CYP3A4.
11:00 AM 11:15 AM -
BREAK
11:15AM 12:15 PM
Regulation
of P450 Gene Expression by Nuclear Receptors
(Steven Kliewer,
GlaxoSmithKine, Research Triangle Park, NC) The nuclear receptors
comprise a family of ligand-regulated transcription factors that bind to DNA
sequence elements in the regulatory regions of target genes. The domain
structure, dimerization, ligand binding and DNA binding properties of the
nuclear receptors will be introduced. Nuclear receptors that regulate P450 gene expression and
xenobiotic metabolism, including PXR and CAR, will be discussed.
12:15 PM 1:45 PM LUNCH
1:45 PM 2:45 PM
Principles of In Vitro-In Vivo Extrapolation
(Jiunn Lin, Merck Research Labs, West Point, PA) In vitro experimental systems are used extensively in the
evaluation of drug-drug interaction potential.
In this lecture, the methodology for the prediction of in vivo effects
based on in vitro findings will be described.
2:45 PM 3:45 PM
Transporters and drug-drug interactions (Suresh
V. Ambudkar, National Cancer Institute, NIH, Bethesda, MD) There are
currently eight ABC transporters which are known to transport drugs. Some of these transporters include
P-glycoprotein (Pgp), the multidrug resistance-associated protein (MRPs 1-6),
and the mitoxantrone-resistance protein (MXR1, also known as breast cancer
resistance protein, BCRP, or ABCP).
These transporters which function as an ATP-dependent efflux pumps, play
an important role in the development of multidrug resistance in most cancers. ABC transporters can recognize and transport
a wide variety of amphipathic cytotoxic natural product anticancer drugs. The
basis of substrate selectivity, the pattern of tissue expression as well as
various techniques employed to study these transporters will be reviewed.
3:45 PM 4:00 PM
Round
Table Discussion
6:00 PM 8:00 PM WELCOME RECEPTION
(COCKTAILS AND HORS DOEUVRES, CASUAL ATTIRE, NOT MANDATORY)
Tuesday, December 11, 2001
5TH
International Conference on Drug-Drug Interactions
Session 1:
In Vitro-In Vivo Extrapolation, Computational and Genomic Approaches
(Chairs: Gondi Kumar, Tom Rushmore)
8:00 AM 9:00 AM Continental Breakfast
9:00 AM 9:45 AM
Characterizing Metabolic Drug Interactions with HIV-Protease
Inhibitors: From In Vitro to
In Vivo
(Richard J.
Bertz, Abbott Laboratories, Abbott Park, IL)
Characterizing clinical drug-drug interactions
with the HIV-protease inhibitors offers many challenges. Using in
vitro metabolic data to predict in
vivo drug interactions will be highlighted. The
semi quantitative prediction of metabolic drug-drug interactions will be
discussed, focusing on inhibition and induction of cytochrome P450 isoforms by
the HIV-protease inhibitors, ritonavir and Kaletraδ
(lopinavir/ritonavir). Sources of
uncertainty and inaccuracy of correlations will also be addressed.
9:45 AM 10:30 AM
DrugDrug
Interactions from Preclinical to Clinical: Case Study of Delavirdine
(Richard
Voorman, Pharmacia Corp., Kalamazoo, MI) In vitro and
preclinical animal experiments showed that delavirdine, an NNRTI used in the
treatment of HIV, was a mild mechanism-based inhibitor of CYP3A4 and was also
moderate to weak reversible inhibitor of CYP2D6, CYP2C9 and CYP2C19. Clinical studies showed evidence of
delavirdine-dependent reduction in CYP3A4 activity that resulted in increased
plasma levels of co-administered CYP3A4 substrates, an advantage for certain
HIV therapies. Interestingly, induction
of CYP3A4 activity abolished the apparent inhibitory effects of
delavirdine. These and other drug
interactions will be discussed.
10:30 AM 10:45
AM BREAK
10:45 AM 11:30 AM
Computational
Models for Cytochrome P450 Metabolism and Inhibition (Tim Carlson, Camitro
Corporation, Menlo Park, CA) Computational models are being developed to predict
ADME (absorption, distribution, metabolism, and excretion) characteristics from
compound structure alone. Predictive
models for cytochrome P450 metabolism are based on both steric interactions
with the active site and the electronic characteristics of the substrate. The computational models can accurately
predict the regioselectivity for CYP3A4, CYP2C9, and CYP2D6 oxidations. This session will include a discussion of
predictive models for the cytochrome P450 enzymes, and their application to
lead optimization. Specifically, hear
about:
·
What characteristics distinguish
drug-metabolizing enzymes from other enzymes
·
What determines the binding constants
and regioselectivity of P450 oxidations
·
How predictive models can useful in
lead optimization
11:30 AM 12:15 PM
Monitoring
Expression of Genes Involved in Drug Metabolism and Toxicology Using DNA
Microarrays
(Thomas
Rushmore, Merck Inc.; West Point, PA) Oligonucleotide DNA
microarrays (Affymetrix Inc.) were investigated for utility in measuring global
expression profiles of drug metabolism genes. Induction studies were performed
to investigate the feasibility of using microarray technology to minimize the
long expensive process of testing drug candidates for safety in animals.
Validation of the technology was performed by measuring gene expression
profiles in livers of rats treated with vehicle, 3-methylcholanthrene (3MC),
phenobarbital, dexamethasone, or clofibrate, and by confirming data for six
genes using Q-RT-PCR. Responses of drug metabolism genes including CYPs,
epoxide hydrolases (EHs), UDP-glucuronosyl transferases (UGTs), glutathione
sulfotransferases, (GSTs), sulfotransferases (STs), drug transporter genes, and
peroxisomal genes, to these well studied compounds agreed well with, and in
some cases extended, published observations. Additional gene regulatory
responses were noted which characterize metabolic effects or stress responses
to these compounds. Thus, microarray
technology can provide a facile overview of gene expression responses relevant
to drug metabolism and toxicology.
12:15 PM 1:45 PM LUNCH
Session 2:
New Approaches in the Evaluation of Enzyme Inhibition, Stimulation, and
Induction
(Chairs:
Albert P. Li ,Charles Crespi)
1:45 PM
2:30 PM
New
Developments in Fluorometric Screening Assays for Drug-Drug Interactions (Charles L. Crespi, Stephanie
Turner, Vaughn P. Miller and David M. Stresser,
GENTEST Corp., Woburn, MA) Inhibition of drug
metabolizing enzymes is a principal mechanism for drug-drug interactions. Optimized, multiwell plate-based,
fluorometric assays for the inhibition of the principal drug metabolizing
cytochrome P450s (CYPs) have been available for four years. Screening methodologies now allow rapid
testing of early drug candidates for the specificity and potency of CYP. As with any new technology, there are needs
and opportunities to improve and extend the technology. In this talk we will describe the
characterization of a new, fluorescein-based CYP2C19 substrate and the
extension of this screening technology to the measurement the inhibition of
UGT1A1, the target for drug-endobiotic (bilirubin) interactions. Further extensions to other potential,
non-CYP targets will also be discussed.
2:30 PM
3:15 PM
Regulation
of Xenobiotic Metabolism by Nuclear Receptors
(Steven
Kliewer, GlaxoSmithKline, RTP, NC) The nuclear receptors
PXR and CAR are activated by a variety of exogenous and endogenous chemicals
and regulate a number of genes involved in xenobiotic metabolism. We will
describe our most recent work relating to the structure and function of these
xenobiotic sensors.
3:15 PM 3:30 PM BREAK
3:30 PM
4:15 PM
Evaluation
of Drug-Drug Interactions with Cryopreserved Human Hepatocytes
(Albert P. Li, In Vitro Technologies, Baltimore, MD) Human hepatocytes represent the most physiologically relevant in
vitro experimental system for the evaluation of drug metabolism and
pharmacokinetic drug-drug interactions.
Cryopreservation of human hepatocytes greatly enhanced the utility of
this system. The application of
cryopreserved human hepatocytes in the evaluation of drug-drug interaction
including enzyme inhibition and enzyme induction studies will be described.
4:15 PM 5:00 PM
Multiple
Binding Site-Mediated Drug-Drug Interaction in High Throughput Screening of
Cytochrome P450 3A4 Inhibition (Magang Shou, Merck Research
Laboratories, West Point, PA) CYP 3A4 inhibition in a high
throughput manner (HTS) has been observed to be inconsistent with use of
different probe substrates, thereby leading to the erroneous evaluation of drug
interaction potential. The present
study provides evidence that the multiplicity and complexity of CYP3A4 inhibition are due to the existence
of multiple binding domains at the active site of the enzyme. Therefore, it
forces the choice of investigation more than one CYP3A4 substrate in inhibition
screens.
5:00 PM
Round Table Discussion
Wednesday, December 12, 2001
Session 3:
Transporters and Drug-Drug Interactions
(Chair:
Suresh V. Ambudkar, Jiunn Lin)
8:00 AM 9:00 AM- CONTINENTAL BREAKFAST
9:00 AM
9:45 AM
Evolution and Function of the Human and Drosophila ABC Gene
Superfamily (Michael Dean, National
Cancer Institute, NIH, Frederick, MD) By
systematically searching expressed sequence tag and genomic sequence databases
we have identified 34 human ABC genes bringing the total known genes to
47. With 90% of the genome present in
at least draft sequence form, this represents a nearly complete
characterization. These genes include 12 members in each of the ABCA, and ABCC
subfamilies and 11 in the ABCB. The
genes are dispersed in the genome with 8 genes in clusters of two genes, and
one cluster of 5 ABCA genes on chromosome 17q24. The Drosophila melanogaster
genome contains 55 ABC genes, with 10 ABCA, 10 ABCB and 12 ABCC members. The largest group of Drosophila genes is the ABCG subfamily with 18 members, 8 of which
are found in a 4.1 Mb region of chromosome 2L.
Analysis of the genetic location and expression pattern of human ABC
genes has allowed us to begin to investigate the function of these proteins and
their role in human Mendelian and complex diseases and in drug resistance. An emerging theme in the functional analysis
of ABC genes is their role in the transport of lipids and sterols across
membranes.
9:45
AM 10:30 AM
Mechanism of Action of the Multidrug
Resistance-linked ABC Transporters: Catalytic Cycle of ATP Hydrolysis by
P-glycoprotein (Suresh V. Ambudkar, National Cancer
Institute, NIH, Bethesda, MD) Our studies are
directed toward understanding the mechanism of action of the multidrug
resistance-linked ABC transporters such as Pgp and MRP1.
Our
studies are directed toward understanding the mechanism of action of the
multidrug resistance-linked ABC transporters such as Pgp and MRP1. Our research showed the following:
·
ADP release is the
rate-limiting step in the catalytic cycle and the substrates exert their effect
by modulating ADP release.
·
Two distinct roles for ATP
hydrolysis in a single turnover of Pgp, one in the transport of drug and the
other in effecting con-formational changes to reset the transporter for the
next catalytic cycle.
·
The blocking of ATP binding
to the second site while the first one is in catalytic conformation appears to
be the basis for the alternate catalytic cycle of ATP hydrolysis by Pgp.
10:30 10:45 AM BREAK
10:45
AM 11:30 AM
P-glycoprotein-mediated
Pharmaco-kinetic Drug Interactions (Jiunn Lin, Merck
Research Laboratories, West Point, PA) P-glycoprotein and CYP3A4 has overlapping substrates,
Inhibitors, and inducers. Drug-drug
interactions previously contributed entirely to CYP3A4 may not be entirely
correct, as Pgp may also be involved. Conversely, interactions attributed to
Pgp may also involve CYP3A4. Clinical and mechanistic data on the combined
roles of Pgp and CYP3A4 in pharmacokinetic drug-drug interactions will be
reviewed.
11:30
AM 12:15 PM
Multidrug Resistance Modulation in the
Clinic: A Faded Approach, or a Strategy for the Future? (Susan Bates, National Cancer Institute, NIH, Bethesda, MD) Multidrug resistance due to active outward transport of
anticancer agents was first recognized 3 decades ago, and the identification of
compounds that reverse multidrug resistance almost 2 decades ago. However, multidrug resistance reversal has
not become a clinical reality, and several missteps in our clinical development
strategy can be identified. These include the use of agents that were not
potent, treatment of tumors with non-MDR mechanisms of resistance, reversal
agents with pharmacokinetic interactions resulting in the need to reduce the
dose of the anticancer agent, and the failure to understand that multiple drug
transporters could be present. With
strategies to overcome these problems, and improved ability to target susceptible
tumors, multidrug resistance modulation is a therapeutic idea worthy of renewed
interest.
12:15 PM 1:45 PM Lunch Break
Session 4: Regulatory Update
(Chair:
Jerry Collins, Yasuo Ohno)
1:45 PM
2:30 PM
In
Vitro Evaluation of Drug-Drug Interactions: FDA Perspectives and Experience After
the Publication of the 1997 Guidance to Industry
(Jerry
Collins, US FDA; Rockville, MD)
2:30 PM
3:15 PM
New
Japanese Health Ministry Guidance for Drug-drug Interactions
(Yasuo Ohno,
Japan Health Ministry, Tokyo, Japan)
3:15 PM
3:30 PM BREAK
3:30 PM
4:15 PM
Round Table Discussion: Regulatory Perspectives
4:15 PM
4:30 PM
Concluding Remarks
(Albert P. Li; In Vitro
Technologies, Inc.)
End of Conference
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