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Planning
Committee/Program Chairs
Dr. Alan
G.E. Wilson, Lexicon Genetics
Dr. Albert
P. Li,
Advanced Pharmaceutical Sciences, Inc.
Dr. Dale
Johnson, Chiron Corp.
Dr. Rakesh
Dixit, Merck & Co., Inc.
Dr.
Subrahmanyam Vangala, RW Johnson PRI
Dr. Yuichi
Sugiyama, University of Tokyo
Dr. Tetsuya
Kamataki, Hokkaido University
Dr.
Christopher Lipinski, Pfizer Global R&D (Ret.)
Monday, December 1, 2003
Pre-conference
Workshop 1:
Genomics, Proteomics and
Metabolomics
(Chair: Albert P. Li)
SPONSOR OF THE DAY: 
8:00 AM – 9:00 AM - Continental Breakfast and Registration
8:00 AM – 5:00 PM – Exhibits
9:00 AM – 9:45 AM
Human
Hepatocyte Toxicogenomics Assay
(Albert P. Li;
Advanced Pharmaceutical Sciences, Inc.; Baltimore, MD) Because of species-species
differences in drug metabolism and sensitivity to drug toxicity, laboratory
animal results are not always predictive of human effects. Freshly isolated human hepatocytes
represent a useful experimental system for the evaluation of human drug effects. A human hepatocyte toxicogenomics assay -
an assay quantifying the effects of drugs on gene expression in primary human
hepatocyte cultures – has been developed in our laboratory for the evaluation of
human hepatotoxicity. Results with
model drugs with known hepatotoxicity will be shown and the strengths and
limitation of the assay will be discussed.
9:45 AM – 10:30 AM
Whole Genome Expression Analysis: Comparison of Mice and Men (John Walker, Genomics Institute of
the Novartis Research Foundation (GNF) San Diego, CA) Assembly of the mouse and human genomes will result in better
characterization of genes involved in disease, as well as speed the process of
characterizing gene function. Mouse-Human orthologs likely play important roles
in the function of organisms due to conservation in DNA sequence content.
Conservation in patterns of expression of these genes across tissues also
indicates relative functional importance. We have constructed mouse and human
whole genome expression arrays and have compared patterns of expression across
50 tissues. I will discuss the relevance of the findings, what gene expression
data we have released to the public and what will be available in the near
future.
10:30 AM – 10:45 AM – BREAK
10:45 AM – 11:30 AM
Informatics Methods for Correlating
Molecular Structure with Microarray Expression Data (Paul Blower1, Chihae Yang1, Michael
Fligner2 and Joseph Verducci2 (1) LeadScope Inc.,
Columbus, OH; Department of Statistics, The Ohio
State University) Genomic studies
are producing large databases of molecular information on cancers and other cell
and tissue types. In order to utilize this data for drug discovery, we have
developed a general analytical method for discovering relationships between
compound classes and potential molecular targets. First genes are selected from
statistical considerations or using a gene hierarchy based on the Gene Ontology
Consortium classification. Next, compounds are correlated to gene expression
through GI50 vs. expression level over cell-lines. Finally, a new
method of dynamically generating molecular scaffolds is used to identify the key
structural classes of compounds having common cross-correlations with gene
expression patterns. The links between genes and compound classes provide a
foundation for formulating hypotheses based on molecular mechanisms. The
procedure will be illustrated using the NCI-60 cell lines and microarray-based
gene expression patterns.
11:30 AM – 12:15 PM
Role of Genomics in Drug Discovery and Development (Tom Rushmore, Merck & Co., Inc.) Genomics technology is finally a
practical discipline. The effects of drugs and drug candidates on gene
expression can help define pharmacological and toxicological properties.
The application of genomics in drug development in pharmaceutical industry will
be discussed.
12:15 PM – 1:30 PM – LUNCH BREAK
1:30 PM – 2:15 PM
Metabolomics Application
in Pre-clinical Drug Development (Subrahmanyam Vangala; Johnson & Johnson PRD,
Raritan, NJ) Metabolomics – an evaluation of the
effects of drugs on metabolites found in body fluids such as urine, is an
emerging tool for the evaluation of drug toxicity. An overview of metabolomics and specific
application of this discipline in drug development in J & J will be discussed.
2:15 PM – 3:00 PM
Quantitative Chemical
Proteomics for Identifying Candidate Drug Targets (Yoshiya Oda, Laboratory of Seeds
Finding Technology, Eisai Co., Ltd, Ibaraki, JAPAN) We have developed a
systematic strategy for drug target identification. This consists of the
following sequential steps: (1) enrichment of total binding proteins using two
differential affinity matrices upon which are immobilized positive and negative
chemical structures for drug activity, respectively;(2) covalent labeling of the
proteins with a new cleavable isotope-coded affinity tag (ICAT) reagent,
followed by proteolysis of the combined proteins;(3)isolation, identification,
and relative quantification of the tagged peptides by liquid chromatography-mass
spectrometry;(4)array-based transcription profiling to select candidate
proteins; and (5)confirmation of direct interaction between the
activity-associated structure and the selected proteins by using surface plasmon
resonance. We present atypical application to identify the primary binding
protein of a novel class of anticancer agents exemplified by E7070.
ur results suggest that this approach
provides a new aspect of quantitative proteomics to find specific binding
proteins from protein mixture and should be applicable to a wide variety of
biologically active small molecules with unidentified target proteins.
3:00 PM – 3:15 PM – BREAK
3:15 - 4:00
PM ***NEW SPEAKER***
Proteomics as a Tool to Search for
Biomarkers of Toxicity
(James A. Jersey, Ph.D., Charles River Proteomic Services; Worcester, MA) The
search for biomarkers of toxicity is an area of obvious potential benefit to the
pharmaceutical industry on many fronts. There are many technical
challenges to this search attributable to the primary matrices of investigation,
the common biofluids of plasma and serum. The ten-log dynamic range of
protein abundances in these matrices poses a significant technical challenge to
overcome in accessing the potentially interesting, low abundance species.
Depletion protocols for the highly abundant proteins offer a viable means of
reducing sample complexity, allowing greater proteome penetration, but face the
additional challenge of inter-species applicability. We will describe
methodologies and approaches we have developed for the search for biomarkers
across the common preclinical species. In addition, we will provide a
brief overview of the services offered by Charles River Proteomic Services.
4:00 PM - 5:00 PM
Panel Discussion: Role of Genomics in Drug Development (Chair: Al Li)
END OF DAY
6:00 PM – 8:00 PM - WELCOME RECEPTION
(casual
attire, not mandatory, but encouraged because it’s so much fun!)
Tuesday, December 2, 2003
Pre-conference
Workshop 2:
In silico Prediction of
Drug Properties
(Chairs: Alan GE. Wilson and Dale Johnson)
8:00 AM – 9:00 AM - Continental Breakfast and Registration
8:00 AM – 5:00 PM – Exhibits
9:00 AM – 9:10 AM
Introduction to Workshop and
Objectives (Alan G.E Wilson, Lexicon Genetics;
The Woodlands, TX)
9:10 AM – 9:55 AM
ADME Properties
Prediction: Where are We? (Franco Lombardo; Pfizer Global R&D;
Groton,
CT) A review of very recent work in the
field of in silico ADME prediction, largely focused on the data and outcome of
the predictions rather than on the parameters used, is
presented together with the author’s views on the current state of the field. It
covers primarily work published during the period 2000-2003 and, although
necessarily condensed in scope, it discusses the very slow progress that has
been made in developing robust and predictive models. We submit that the slow
progress is rooted in the lack of accurate data, together with the use of
questionable modeling end-points. The development of general and truly
predictive models for complex phenomena such as absorption and clearance may
still be far away, and possibly beyond reach in the
foreseeable future. The development of local models for use within focused
chemical series may instead be the most appropriate way of utilizing in silico
ADME predictions, once experience and data have been gained on a given project
and/or structural class.
9:55 AM – 10:10 AM – BREAK
10:10 AM –
10:55
Metabolism Prediction (Ken Korzekwa, Camitro Discovery;
Mountain View, CA) We have
developed computational models for the prediction of ADMET properties of
pharmaceutical drug candidates based on chemical structure alone. Our predictive
models for cytochrome P450 metabolism are based on both steric interactions with
the active site of the enzyme and the electronic characteristics of the
substrate. When possible, models are built using data obtained under uniform
experimental conditions in order to eliminate the inter-laboratory variability
that is commonly observed in determining CYP enzyme kinetic parameters. Our
current platform includes models for cytochrome P450s 3A4, 2D6, 2C9. Most of the
models are very high throughput and can be used to screen large virtual
libraries. High-resolution models and series-specific models can be used to
provide details of ADME processes and help in the interpretation of experimental
data. Applications of these predictive models in conjunction with lead
optimization efforts will be discussed.
10:55 AM – 11:40 PM
In Vivo Pharmacokinetic
(PK) and Pharmacodynamic (PD) Modeling and Simulation (Rene A. Braeckman; Ribapharm, Inc.;
Costa Mesa, CA) The application of in vivo modeling and simulation of the PK and
PD of drug candidates in pre-clinical and clinical development will be
presented. There are multiple benefits of PK and PD modeling and simulation for
the success and optimization of drug development programs: A better
understanding of the in vivo behavior can be obtained. The design of future
pre-clinical and clinical trials can be optimized. Through extrapolation of the
PK and/or PD from animal species to other animal species or humans, dosing
regimens for future testing can be optimized. Dose-Exposure-Response
(DER) relationships can be defined.
11:40 AM – 12:25 PM
Role of In Silico Toxicity Prediction
in Drug Discovery
(Alan G.E. Wilson, Lexicon Genetics; The Woodlands, TX)
Toxicity issues are a significant factor affecting new drug candidate failures
and R&D productivity. This has strengthened the importance of
early screening for toxicity properties.
An emerging component of this screening strategy is the use of computer–based
predictive models (in silico).
Global and local (quantitative and qualitative) models are being applied to
library design, to help prioritize synthetic programs, and to identify
structural features which may contribute to undesired effects.
In addition, searchable databases and database engines are marketed for
data storage and retrieval.
Predictive modeling, in conjunction with other screening technologies, has the
potential to transform the drug discovery paradigm.
However, to maximize the potential benefit from in silico technology it
is critical that in silico models be applied judiciously and not over-hyped.
This presentation will discuss the current status of in silico modeling of
toxicity, discuss the current limitations and highlight current gaps and future
needs. Examples will be presented of the application of in silico modeling in
drug discovery and screening strategies.
12:25 PM – 1:45 PM – LUNCH BREAK
1:45 PM – 2:30 PM
Linking with Emerging
Technologies (Dale
Johnson, Chiron Corp.; ) Predicting potential human toxicity during the early
phases of pharmaceutical R&D continues to be only partially successful. The
application of new technologies such as toxicogenomics, proteomics and
metabonomics continue to be in the validation stage; whereas high-content
screening using human cell-based systems and transgenic animal models may emerge
as reasonable alternatives to current approaches.
2:30 PM – 3:15 PM
In Silico Modeling in
Drug Discovery- Future Opportunities and Challenges (Osman F. Güner; Accelrys
Inc.; San Diego,
CA)
Computer-Aided Drug Design (CADD) has become an integral part of drug discovery
and design. Today, almost all new drugs in the market are assisted with these
'in-silico' technologies. During the early days (60s-70s) the primary focus in
CADD was in the lead optimization process, primarily utilizing the quantitative
structure-activity relationship (QSAR) methods. During the 80s and 90s the
focus have shifted from lead optimization to lead identification, also
accommodating the other innovations in the pharmaceutical industry such as
combinatorial chemistry and high-throughput screening. Today, the focus is
increasingly moving into "candidate evaluation": The ability to select
candidates with good anticipated pharmacokinetic behavior, earlier in the
discovery cycle. In this presentation, we will summarize how predictive
ADME/Tox models are being developed and utilized in drug discovery and design.
The presentation will open the floor for discussion on the future directions
and challenges in this field.
3:15 PM – 3:30 PM – BREAK
3:30 PM – 4:15 PM
Panel Discussion: Promising In Silico Approaches for Drug
Development (Chair:
Dale Johnson)
END OF DAY
MAIN CONFERENCE:
Wednesday, December 3, 2003 AM
Physical-Chemical
Properties
(Chairs: Chris Lipinski and Alan GE.
Wilson)
8:00 AM – 9:00 AM - Continental Breakfast and Registration
8:00 AM – 5:00 PM – Exhibits
9:00 AM – 9:45 AM
Physicochemical
Properties in Drug Design/Development
(Chris Lipinski, Pfizer Global R & D;
Groton,
CT) Early discovery technology teams
screening for poor ADME properties can be one of the pharmaceutical scientist’s
best allies in preventing the progression of seriously flawed compounds into
clinical candidate nomination. Poor
aqueous solubility is the single largest physicochemical problem hindering oral
drug absorption and lengthening drug discovery time in the current HTS /
combinatorial chemistry era. Current experimental early discovery stage
solubility screens differ markedly from traditional thermodynamic solubility
assays. The solubility ranking of collections of chemical compounds can be
estimated either from data mining, e.g. using the “rule of five” or from
internal experimental solubility measurements or from calculations from among
the many commercially available solubility programs. Effective communication
between pharmaceutical sciences and medicinal chemists is essential. it is important to appeal to the chemists’ highly developed
pattern recognition skills and to avoid the use of mathematical equations as
much as possible. In terms of technology resource allocation there is no excuse
for not understanding the likely solubility rankings of collections of
compounds.
9:45 AM – 10:30 AM
In Silico Drug Design
Based on Physicochemical Properties Using QSAR ( Quantitative Structure-Activity
Relationship): Advantage, Limitation and Pitfalls (Yukio Tada, Bio-Chem Informatics
Laboratory, Taiho Pharmaceutical Co., Ltd., Saitama, JAPAN) The understanding of
correlation between intrinsic physicochemical properties of chemical compounds
and biological activity is important in a drug discovery. QSAR using several
statistical data modeling techniques provide the basis for prediction of
biological activity including ADME-Tox. However, high-quality and relevant
biological data are required, and relevant chemical descriptors should be
selected among a lot of physicochemical properties for good QSAR analysis. If
there is not information of QSAR, the medicinal chemist
must design compounds only with traditional intuitive experience. This
presentation will encompass drug design of antiallergic agent; Suplatast
Tosilate (launched in 1995 in Japan)
and specific inhibitor of thymidine phosphorylase to potentiate the function of
antitumor 5-trifluoromethyl-2’-deoxyuridine by using QSAR analysis.
10:30 AM – 10:45 – BREAK
10:45 AM – 11:30 AM
Impact of Crystal Close-Packing and
H-bonding Network Formation on Insolubility (Howard Y. Ando; Pfizer Inc.; Ann Arbor, MI) Property-based design starts with biologically active
compounds that have poor solubility and evaluates the molecular mechanisms that
cause this property. Stable crystal formation balances the tendency to
maximize the close-packing of molecules with maximizing the number of H-bonds
that can be formed in the crystal. In this study, we will examine the
results of single crystal x-ray diffraction studies to explore the impact of
conformational restriction, zwitterions of rigid molecules, and H-bonding chain
formation on this balance and on the resulting physical properties of the
crystalline solid. Such insight forms the basis for beginning the
design crystal disrupting strategies to increase solubility.
11:30 AM – 12:15 PM
Permeability and Solubility –
Hits-to-Leads Applications, with Downstream Value (Alex Avdeef; pION Inc.;
Woburn, MA) Modern high-throughput synthesis
methods have generated an enormous number of new molecules for screening
libraries. But many of these
molecules are high molecular weight and high log P (octanol-water partition
coefficient), and consequently posses very low aqueous solubility. A new method for solubility based
on UV detection will be described.
The method requires neither knowledge or measurement of
the molar absorptivity of test compounds, nor a calibration curve relating known
concentrations of test compounds to their spectroscopic properties. The UV method uses 96- and/or 386-well
microtitre plate technology, and can be used for determining either ‘kinetic
solubility’ if executed very rapidly, or ‘thermodynamic solubility’ if run over
a longer period of time (e.g., overnight).
Even though the latter (thermodynamic) technique may require a 15-h
incubation time, several 384-well plates are prepared in parallel and it is
possible to assay 1500-3000 compounds in a 24-h period, if each compound
represents an assay from a single well. Examples of solubility and permeability
measurements will be presented based on assays of standard drugs, as well as
combinatorial molecules. This work
now makes it possible to measure thermodynamic solubility in high throughput.
12:15 PM – 1:30 PM – LUNCH BREAK
1:30 PM – 2:15 PM
Understanding Drug-Serum Protein Interactions and Their
Effects In Vitro and In Vivo (Thomas J. Raub; Eli Lilly & Co.; Indianapolis, IN) One of the
many factors contributing to bioavailability is binding of a compound to blood
components such as serum proteins and red blood cells. The general principle
that only the free or unbound fraction contributes to activity is widely
appreciated and has lead most to approach the issue pragmatically through
intuition. Yet, much confusion and disagreement continue under the many examples
that appear to defy this logic. General concepts of drug-protein interactions
and characteristics of serum proteins and their binding sites will be reviewed.
We will examine the various approaches to screening for this activity, the
virtues and pitfalls of adjusting in vitro assays, and explore the complex
relationship between serum protein binding and pharmacokinetic parameters.
SPECIAL SESSION
Wednesday, December 3, 2003 PM
Drug Development in China:
R&D and Regulatory Update
(Chair: Zhuohan Hu)
2:15 PM – 3:00 PM
Drug Research and
Development in China (Zhuohan Hu; Research Institute for Liver Diseases (Shanghai) Co. LTD.; Shanghai, CHINA) A general picture of Drug
Research and Development in China is presented. The presentation includes 1) The
national strategy for speeding up drug R & D, 2) The government supporting
policy, 3) Achievements and
challenges on bridging academic research with the development in pharmaceutical
industries, integrating the domestic R&D with international cooperation, and
finally outstanding various R & D programs and institutions.
3:00 PM – 3:15 PM – BREAK
3:15 PM – 4:00 PM
Current Regulatory
Requirements for Human Pharmaceutics in China (Cai Cao; Chinese Food and
Drug Administration).; Beijing, CHINA) In this presentation, the major topics will be in
the current status and future development on drug safety evaluation and
inspection. Specific subjects will include the establishment, amendment and
execution of regulations on drug safety evaluation. Detailed description on the
codes and the guidance regarding to Good Laboratory Practice (GLP), Good
Clinical Practice (GCP), and Good Manufactory Practice (GMP) will be provided.
Furthermore, the procedures for filling and approving IND and NDA submission,
inspection and audit clinical centers that conduct clinical trials will also be
outlined. Finally, the programs for training clinical trail auditors will be
specified.
4:00 PM – 5:00 PM
Panel Discussion: Prediction of
Physico-Chemico Properties (Chair:
Chris Lipinski)
END OF DAY
Thursday, December 4, 2003 AM
Drug Metabolism:
Metabolic Stability and Metabolite Identification
(Chairs: Subrahmanyam Vangala and Tetsuya Kamataki)
8:00 AM – 9:00 AM - Continental Breakfast and Registration
8:00 AM – 5:00 PM – Exhibits
9:00 AM – 9:45 AM
Integration of DMPK, Toxicology, and Pharmacology to
Accelerate Drug Discovery (Kanyin E. Zhang, Genomics Institute of Novartis Research Foundation,
San Diego, CA) Drug Metabolism and Pharmacokinetics
(DMPK) issues have been recognized as a major factor for candidate failures
during drug discovery and development. As we increase this awareness and apply
new technologies such as in vitro systems and LC-MS, the DMPK properties
of drug candidates have improved considerably.
Though critical, DMPK is an integral part of a greater effort to
translate
in vitro biological activities of drug candidates into in vivo
pharmacological activities without eliciting toxicity. We therefore, made a conscious effort to
integrate DMPK activities with contemporary in vitro toxicology
screenings and animal pharmacology studies.
This presentation will illustrate this multi-disciplinary approach to
accelerate the drug discovery process.
9:45 AM – 10:30 AM
Frontloading of Drug Discovery: From Physicochemical
Parameters to Metabolism, Pharmacokinetics and Early Tox (Dave Ritchie and Claire Mackie;
Johnson & Johnson PRD; Raritan, NJ and Beerse, BELGIUM) The current
focus in J&JPRD is to reduce the attrition of new chemicals in early
development, namely the period between acceptance into Pre-Clinical Development
and the first in human administration. To address this issue the initiative of
introducing pre-clinical expertise globally into Drug Discovery has been taken.
Using the old paradigm of Drug Discovery (DD), compounds were only screened for
pharmacology concentrating on potency and selectivity, leading often to failure
late in the pre-clinical process. Today in an effort to reduce the fall out, the
pre-clinical expertise has been incorporated earlier into the DD process to
select against drugs with problematic ADME/Tox profiles. We have combined the
determination of pharmacokinetic, tox and safety characteristics at the same
time as biology, chemistry and pharmacology using an iterative process.
The highest return on the investment of early pre-clinical knowledge is the
integration into the actual design phase of new chemicals and not just in the
profiling stage. The ultimate goal is to bring the ADME/Tox and chemistry
together to design better drugs, and here the combination of the powerful
chemoinformatic tools, in silico and in vitro ADME screens in parallel
with the pharmacology are used.
10:30 AM – 10:45 AM – BREAK
10:45 AM – 11:30 AM
Development of HTS and Bacterial System to
Predict Drug Metabolism and Toxicity in Humans (Tetsuya Kamataki; Hokkaido University; Hokkaido, JAPAN) I will spend
major period on the development of genetically engineered E. coli and
Salmonella. Then, I will show new machine for the HTS assay machine, which we
have developed with Hitachi co. in Japan. The new machine is much less expensive and easy to
operate for the assays. The Salmonella system is unique. This is very sensitive
to mutagens and suitable for predicting human mutagenicity of chemicals, because
the bacteria express human P450 together with the reductase inside the cells.
Then, whole story will be 1) Development of E. coli and application to HTS for
drug metabolism. 2) Development of Salmonella system and the advantages of the
system to predict human genotoxicity.
11:30 AM – 12:15 PM
Metabolic Stability and
Metabolite Identification: Optimization for the CYP Inhibitory Potency,
Metabolic Activation, and Preferable
Pharmacokinetics in Humans
(Masato Chiba, Banyu Pharmaceutical CO., LTD.: Ibaraki, JAPAN) It has become
critically important to discover more bio-available drug candidate in many
therapeutic targets where the drug would be preferably given per oral to the
patients. At the early discovery stage in the new drug development, the in vitro metabolic stability is more routinely examined than
pharmacokinetics in experimental animals. The rationale of this strategy is that
the in vitro metabolic stability
reasonably well predicts in vivo
clearance. The structure-activity relationship (SAR) between metabolic
stability, CYP3A4 inhibitory potency and type of substrate-induced P450 binding
spectra in human liver microsomes successfully guided structure modifications to
the metabolically stable candidates for the development. Secondly, metabolite
identification studies have greatly helped medicinal chemist at pre-development
stage to optimize chemical structure which less susceptible to the metabolic
activation, potentially leading to the unfavorable covalent protein bindings.
The presentation will discuss the applications of information on the metabolic
stability and metabolite identification to the optimization of chemical
structures for the CYP inhibition, metabolic activation and pharmacokinetics in
humans at both discovery and pre-development stages.
12:15 PM – 2:00 PM - NETWORKING LUNCH WITH EXHIBITOR PRESENTATIONS
Thursday, December 4, 2003 PM
Drug-Drug Interactions
(Chairs: Yuichi Sugiyama)
2:00 PM – 2:45 PM
******NEW SPEAKER*******
Importance of Assessing Drug-Drug Interactions - The Pharmaceutical Industry
Point of View
(Theodor Guentert, Roche; Basel, SWITZERLAND)
Drug-drug interactions (DDIs) are a major cause for unwanted drug reactions.
Therefore, information on the interaction potential needs to be gathered as
early as possible in drug discovery to aid candidate selection and in
development to allow for proper clinical study design and labeling. In spite of
high expenditure during drug development to clarify the risk posed by DDIs,
withdrawal of drugs from the market due to interactions remains a real threat to
pharmaceutical manufacturers (examples of recent withdrawals: mibefradil,
cerivastatin). Not
all DDIs are unwanted; an interaction can intentionally be provoked to
improve pharmacotherapy. As an example, L-dopa combined with a decarboxylase
inhibitor is used to treat Parkinsonism maximizing its availability in the
brain; enhanced bioavailability of the protease inhibitor saquinavir in HIV
patients is achieved by administering a low dose of the potent CYP3A4 inhibitor
ritonavir. DDI studies can also be used as a research tool to elucidate
mechanistic aspects of drug handling in the body (examples: concomitant oral
administration of ketoconazole to clarify involvement of gastrointestinal
first-pass effect; digoxin or PSC833 coadministration to study role of
P-glycoprotein in absorption).
2:45 PM – 3:30 PM
Clinically Relevant Drug
Interactions Between Statins and Other Drugs: Is Prediction from the In Vitro
Experiments Possible? (Hideki Fujino; Tokyo New Drug Research Laboratories I,
Kowa Company Ltd., Tokyo, JAPAN) The cause of the interaction is
considered to be as follows: the absorption, distribution, excretion and
metabolism of medicines are inhibited via
some mechanisms by the drugs administered concomitantly. In particular, metabolism is the main
factor in drug-drug interaction and CYP plays an important role in drug
metabolism. To gain a better
understanding of the mechanism of the clinically relevant drug interactions
between HMG-CoA reductase inhibitors (statins) and other medicines, several
experiments
in vitro were performed. CYP-mediated metabolism has been
recognized as a major factor for the metabolic fate of statins. Recently, UGTs were principally
responsible for glucuronidation of statins leading to lactonization. Comparing with acid form, a remarkable
increase of the metabolic clearance via
CYP and the metabolic inhibition of CYP-mediated metabolism were noted in its
lactone forms of statins. Our
results indicate that future studies assessing the metabolism and drug-drug
interactions of statins should include the lactone form.
3:30 PM – 3:45 PM – BREAK
3:45 PM - 4:30 PM
Prediction of Clinically
Relevant Transporter-Based Drug Interactions (Yuichi Sugiyama,
University of Tokyo; Tokyo, JAPAN) Due to the broad substrate
specificity of drug transporters, drug-drug interactions involving the
transporters should be always taken into account. Co-administration of an
HMG-CoA inhibitor, cerivastatin (CER) and cyclosporine (CysA) to kidney
transplant recipients results in a significant increase in CE R plasma
concentrations. We have demonstrated that OATP-2/OATP-C mediated CER uptake is
inhibited by CysA with relatively high affinity (Ki = 0.3 uM), and this
inhibition was also confirmed by using isolated human hepatocytes and double
transfected cells (OATP-2/MRP2). We have also developed a rational strategy for
using in vitro data (with the use of isolated hepatocytes and canalicular
membrane vesicles) to predict drug-drug interactions between probenecid and
methotrexate involving hepatic uptake followed by biliary excretion. In
addition, the examples of the transporter mediated drug-drug interactions in the
intestinal absorption and blood brain barrier transport will be shared with you.
4:30 PM – 5:15 PM
Panel Discussion: Prediction of Human Metabolism and
Drug-Drug Interaction Potential of Drug Candidates (Chair:
Yuichi Sugiyama)
END OF DAY
Friday, December 5, 2003 AM
Preclinical Safety
(Chairs: Carl Alden and Albert P. Li)
8:00 AM – 9:00 AM - Continental Breakfast and Registration
8:00 AM – 5:00 PM – Exhibits
9:00 AM – 9:45 AM
The Application of
Molecular Toxicology and Expression Profiling to Drug Discovery and Development
(Jeff Kramer, Global Toxicology, Pharmacia Corporation, Saint Louis, MO)
The primary goals of investigative
toxicology, including the “panomics” technologies, are to predict
development-limiting toxicities early in the discovery/development process, and
to understand, model, and position non development-limiting toxicities. An emerging third goal involves efforts
to predict potential toxicologic liabilities associated with new targets. Molecular toxicology approaches,
including toxicogenomics, are well suited to all three aspects of discovery
toxicology. In this presentation
examples will be given demonstrating the application of expression profiling
technologies to predictive and mechanistic toxicology in support of several
discovery projects. Examples will
include a primary versus secondary target distribution study, the application of
transcription profiling to mechanistic studies with a rodent toxicant, and an
example of the development of molecular markers for screening out toxicity from
a class of discovery candidate lead compounds.
9:45 AM – 10:30 AM
Testing Paradigms to Improve Efficiency in
Safety Pharmacology Screening (Vivek Kadambi; Millennium Pharmaceuticals; Cambridge, MA) In efforts to streamline
assays to identify functional liabilities of lead compounds before the development process, we have designed and implemented a composite safety
pharmacology strategy. This approach is aimed at extracting maximal information
by using combinations of readouts, for e.g., combining the single ascending dose
tolerability study with the Irwin analysis. Several other examples will be presented
wherein such approaches have been successfully utilized for assessment of
functional liabilities
10:30 AM – 10:45 AM – BREAK
10:45 AM – 11:30 AM
Approaches for Evaluating the Druggability
of Novel Targets in Genetically Engineered Mice (Krista M. D. La Perle,
The Rockefeller University; New York, NY)
The decoding of the human and mouse genomes, and advancements in our abilities
to manipulate the mouse genome have resulted in the generation of countless
mouse models of human disease and tools to dissect the functions of specific
genes. Genetically engineered mice (GEMs) carrying transgenes, targeted
mutations, and chemically-induced mutations are increasingly used in the
pharmaceutical industry to validate novel therapeutic targets and to proactively
identify safety issues and toxic liabilities related to these therapeutic
targets. Phenotypic profiling of GEMs involves anatomic and clinical pathology,
behavioral and physiological testing, in vivo
imaging, and new emerging technologies, such as the “omics” technologies. These
phenotypic approaches and specific examples of GEM phenotypes that proved useful
in preclinical settings will be discussed to illustrate the use of GEMs in the
evaluation of the druggability of novel targets.
11:30 AM – 12:15 PM
Preclinical Strategy to Avoid
Idiosyncratic Liver Injury
(Carl L. Alden, Millennium Pharmaceuticals;
Cambridge, MA) Idiosyncratic liver injury accounts for approximately 12% of all cases of
acute liver failure (ALF) in the U.S. The mechanisms are not unique with
the individual susceptibility explained by genetic polymorphisms and
environmental variables, accounting for the low sporadic incidence. Because of
the potential business and individual impact, significant interest exists in
avoidance strategies. A discovery strategy specifically designed to avoid
idiosyncratic response includes in silico, analytic chemistry, in vitro and in
vivo testing, which will be described in depth and which would have enabled
identification of three prototypical idiosyncratic agents.
12:15 PM – 1:30 PM – LUNCH BREAK
Friday, December 5, 2003 PM
Clinical Safety
(Chairs: Rakesh Dixit and Masao Yoneyama)
1:30 PM – 2:15 PM
Development of a
Pharmacogenomics Test for Anti- Cancer Drug, Irinotecan (Masao Yoneyama, Daiichi Pure
Chemicals, Co. Ltd.; Tokyo, JAPAN) An anti-cancer drug called Irinotecan or Camptosar has known to
possess the side effects such as leucopenia and diarrhea, which may sometimes be
fatal. In order to avoid such side
effects and to establish more appropriate Irinotecan regimen for the cancer
treatment, we have initiated the development of a pharmacogenomics test for
Irinotecan based on UGT1A1 polymorphisms.
Such a test will be presented with the clinical data.
