AAPS 2001 Annual Meeting and Exposition Pharmaceutical Sciences: Climbing New Heights October 21-25 Colorado Convention Center Denver, CO Headquarters Hotel - Adams Mark

Thursday

Biology Meets Mathematical Modeling: How Advanced PK/PD Analysis Techniques Facilitate the Clinical Drug Development of Biotechnology Products

Symposium
Thursday, October 25, 2001
8:30 am — 12:00 pm
ACPE Program Number: 073-999-01-240-L04

The objective of this symposium is to demonstrate the utility of PK/PD modeling in biotechnology drug development. State of the art modeling approaches are currently being applied to optimize dose and regimen in clinical trials of protein-based therapeutics. For example, PK/PD models have been utilized to validate the hypothesis for mechanism of action and to predict dose-response relationships under various dosing paradigms. These techniques have facilitated clinical trial design and decreased development time by providing a better understanding of possible clinical outcomes. When applied properly, these techniques may also enhance the probability of technical success, and help insure safety and efficacy in the clinic.

Moderators
Yu-Nien “Tom” Sun, Ph.D.
Genentech, Inc.

Lisa Damico, Ph.D.
Genentech, Inc.

Overview of Pharmacodynamic Models Relevant to Biotechnology Products
William J. Jusko, Ph.D.
State University of New York at Buffalo

PK/PD Modeling in the Preclinical Development of Biotechnology Products
Soo Peang Khor, Ph.D.
Genetics Institute, Wyeth-Ayerst Research

PK/PD Modeling for Anti-CD11a Antibody hu1124 in Human Subjects With Psoriasis
Robert J. Bauer, Ph.D.
Xoma LLC

Using PK/PD Modeling to Optimize Dose and Formulation for Hematopoietic Factors
Diane R. Mould, Ph.D.
Georgetown University, Center for Drug Development Sciences

Mechanism-Based PK/PD Modeling for Omalizumab (rhuMAb-E25) Anti-IgE Effects in Patients With Allergic Diseases
Yu-Nien “Tom” Sun, Ph.D.
Genentech, Inc.

Functional Excipients and Novel Delivery Systems

Symposium
Thursday, October 25, 2001
8:30 am — 12:00 pm
ACPE Program Number: 073-999-01-242-L04

Excipients are typically employed to optimize the performance of pharmaceutical products. Excipients are often considered as inert ingredients. But in some cases an excipient can affect the biological processes influencing drug disposition. Key speakers will describe state-of-the-art examples of this more novel use of pharmaceutical excipients in drug delivery systems. The topics will include the development of novel agents for enhancing oral absorption of poorly permeable compounds, the use of excipients to inhibit intestinal metabolism or secretory transport, inhibiting efflux transport to affect organ targeting, and the use of bioadhesives to increase drug retention at the absorption site.

Moderators
Bruce J. Aungst, Ph.D.
DuPont Pharmaceuticals Company

Lawrence Yu, Ph.D.
Food and Drug Administration

Progress in the Oral Delivery of Macromolecules
Andrea Leone-Bay, Ph.D.
Emisphere Technologies, Inc.

Utility of Chitosan and Chitosan Derivatives
Hans E. Junginger, Ph.D.
Leiden University, The Netherlands

Inhibition of Intestinal P-Glycoprotein and cyp3A Metabolism with Excipients
Jeffrey Silverman, Ph.D.
AvMax, Inc.

Pluronic Block Copolymer for Improved Drug Delivery Against Drug Efflux Systems
Alexander Kabanov, Ph.D.
University of Nebraska Medical Center

Bioadhesives and Drug Delivery
Joseph R. Robinson, Ph.D.
University of Wisconsin at Madison

In Vitro Testing Methods for Topicals and Transdermals

Symposium
Thursday, October 25, 2001
8:30 am — 12:00 pm
ACPE Program Number: 073-999-01-243-L04

Several in vitro models that mimic human skin are available to test the skin permeability of drugs formulated in topical and transdermal dosage forms. These models include non-viable human and animal skins, polymer membranes, and organotypic cultures. This symposium will focus exclusively on the organotypic cultures. Most cultures used for this purpose consist of human cells and may be full-thickness or split thickness skin models (epidermal/dermal layers). For each specific research application, it is a significant challenge to select the best model, and once chosen, to judge its capabilities and limitations. Another issue is how to interpret the data obtained in view of the fact that the formulation will be ultimately used on patients, often with compromised skin barrier function.

This symposium is directed towards scientists working with skin permeability testing, drug delivery, and topical/transdermal formulations and would like to learn more about the currently marketed cultured skin models, their advantages and limitations. The speakers are at the forefront of the current science and will provide a forum for stimulating discussion and transfer of information concerning the latest organotypic skin models available, as well as how these models will be further developed in the near future.

Moderator
Bozena B. Michniak, Ph.D.
University of Medicine and Dentistry of New Jersey/NJ Center for Biomaterials, Rutgers

Use of Epiderm Tissue Model for In Vitro Skin Studies
Mitch Klausner, M.S.
MatTek Corporation

Evaluation, Validation and Adoption of Standardized In Vitro Reconstituted Human Tissue Models for Pre-Clinical Safety and Pharmacology Screening of Topical Vehicles
Bart DeWever, M.E.
SkinEthic Laboratories, France

Permeability Characteristics of a Human Skin Alternative: Improvement Using Tissue Culture Modifications
Charles “Scott” Asbill, Ph.D.
McWhorter School of Pharmacy, Samford University

Epidermal Lipid Metabolism and Barrier Function
Philip Wertz, Ph.D.
The University of Iowa

TESTSKIN II: Advancements in Bi-Layered Living Skin In Vitro Testing
Gregory Downing
Organogenesis, Inc.

Microdialysis in Industrial Drug Development

Symposium
Thursday, October 25, 2001
8:30 am — 12:00 pm
ACPE Program Number: 073-999-01-244-L04

This symposium will cover microdialysis-based PK/PD approaches in antimicrobial drug development, characterizing drug disposition in tumors using microdialysis, PK modeling and statistical analysis of microdialysis data and microdialysis as an alternative to skin blister or skin stripping techniques — pros and cons.

Moderators
Ronald J. Sawchuk, Ph.D.
University of Minnesota

Eva Benfeldt, Ph.D.
University of Copenhagen, Denmark

Microdialysis-Based PK/PD Approaches in Antimicrobial Drug Development
Hartmut Derendorf, Ph.D.
University of Florida

Characterizing Drug Disposition in Tumors Using Microdialysis
James M. Gallo, Ph.D.
Fox Chase Cancer Center

Pharmacokinetic Modeling and Statistical Analysis of Microdialysis Data
William F. Elmquist, Pharm.D., Ph.D.
University of Nebraska Medical Center

Microdialysis as an Alternative to Skin Blister or Skin Stripping Techniques — Advantages and Disadvantages
Eva Benfeldt, Ph.D.
University of Copenhagen, Denmark

Predicting Long Term Stability of Drug Products Using Physical Characterization Techniques

Symposium
Thursday, October 25, 2001
8:30 am — 12:00 pm
ACPE Program Number: 073-999-01-245-L04

The ultimate goal of the pharmaceutical scientist is to be able to predict the stability profile of the formulated product that will be marketed and administered to patients. Work is ongoing to understand how to make such predictions without generating real time stability data. In some cases, successes have been reported but often times such approaches have been fraught with problems.

This symposium, co-sponsored by the AAPS Sterile Product Focus Group and the AAPS Preformulation Focus Group, will address how scientists can select a drug molecule or a formulation among various options. Obviously, a better understanding of where and when such predictions can be made and the associated pitfalls are a must. With the growing body of knowledge, it may be possible to make a priority statement about drug stability with increased confidence.

Moderators
Sandeep Nema, Ph.D.
Pharmacia, Inc.

N. Murti Vemuri, Ph.D.
Aventis Pharmaceuticals

The Use of DSC in the Development of Stable Protein Formulations
Wayne Gombotz, Ph.D.
Immunex Corporation

Appropriate Use of Physical and Chemical Based Assays for Formulation Development
Steven Shire, Ph.D.
Genentech, Inc.

Predicting Shelf-Life of Lyophilized Formulations Using Modulated DSC and DEA
Sarma Duddu, Ph.D.
Inhale Therapeutics Systems

Predicting Shelf-Life of Lyophilized Products Using Microcalorimetry
Michael Pikal, Ph.D.
University of Connecticut

Panel Discussion

Validation and Performance of Ligand-Binding Assays — Bioanalytical Issues and Potential Solutions

Symposium
Thursday, October 25, 2001
8:30 am — 12:00 pm
ACPE Program Number: 073-999-01-246-L04

The development of macromolecules as therapeutics has created a niche for ligand-binding based assays in the bioanalytical arena. However, the development, validation and implementation of these assays offer a multitude of analytical challenges. Although the AAPS Workshop on Bioanalytical Method Validation for Macromolecules, March 1-3, 2000, was successful in presenting the complex issues in a public platform, harmonization will require additional discussions to address unresolved issues.

This symposium will focus on the critical issues related to the development and validation of ligand-binding assays for the detection and quantification of therapeutic entities, as well as the qualification of antibodies to these therapeutics, in biological matrices. The presentations will include: (a) assay applications and validation update; (b) assay development: characterization of critical reagents, matrix effects, sample handling, quality controls; (c) data processing for non-linear calibration curves, approaches to define the precision, accuracy, range of quantification, assay control and run acceptability; (d) development and validation of cell based assays: assay selection, validation for activity, serum neutralizing factors and new approaches for assay readouts; and (e) immunogenicity and vaccine potency assessment assays. Approaches to deal with challenging assays that do not meet the pre-established performance criteria will also be discussed.

Moderators
Masood U. Khan, Ph.D.
MEDIMMUNE, Inc.

Russell S. Weiner, Ph.D.
Bristol-Myers Squibb Company

Validation of Ligand Binding Assays — The Unresolved Issues from Then and Now
Masood U. Khan, Ph.D.
MEDIMMUNE, Inc.

Developing Ligand-Binding Assays for Biological Matrices: Emphasis on Pre-Validation Development
Abbie Celniker, Ph.D.
Genetics Institute, Wyeth-Ayerst Research

Statistical Procedures for Determination of Method Accuracy and Precision, Limits of Quantitation and Run Acceptability
Wendell C. Smith, Ph.D.
Eli Lilly and Company

Cell-Based Assays and Their Use for Measuring Activity and Serum Neutralizing Factors: The Problems They Can Solve and Create
Jo Marie Smolec, Ph.D., MBA
ALTA Analytical Laboratories, Inc.

Past, Present and Future — Immunogenicity Assay Strategies for Vaccines Versus Biological Therapeutics
Anthony R. Mire-Sluis, Ph.D.
Genentech, Inc.

Effective Partnering with Contract Laboratories

Roundtable
Thursday, October 25, 2001
9:00 am — 11:00 am

A strong technical agreement between a contract laboratory and a sponsor is a fundamental element for establishing a sound partnership for raw materials testing, clinical testing, for production release or for stability testing. This roundtable will present the essential requirements for setting up an effective technical agreement for utilizing third party testing. The speakers will provide a sponsor view and a contract laboratory view of the services to be performed; reaching agreement on any regulatory registration requirements; setting up protocols for initial and follow-up audits; method transfers and acceptance of transfer, minor and major method changes; change control of methods and references; how data are to be reviewed and accepted, and how exceptions will be handled, who will write final reports, including style and format; how OOS results will be handled, including notifications and timing of notifications; sample management details, including sample tracking; and following the PAC- ATLS (Post Approval Changes — Analytical Testing Laboratory Sites) Guidance for industry.

Moderator
G.W. "Bill" Martin, Ph.D.
Analytical Resources, LLC

Speakers
John Chaber, Ph.D.
Vertex Pharmaceuticals, Inc.

Eric Lindsay
West Coast Analytical Service, Inc.

Grantsmanship for Pharmaceutical Scientists

Education Committee Roundtable
Thursday, October 25, 2001
9:00 am — 11:00 am

This will be an active discussion focusing on writing, submission, and review of grants for work in the pharmaceutical sciences. The roundtable will begin with brief presentations that cover the basics of grant selection, proposal preparation, and the scientific review process. The roundtable will use the procedures of the National Institutes of Health as a model since granting organizations and agencies commonly use a similar mechanism. The goal of the discussion is to inform the participants and provide an opportunity to address questions and concerns about preparing and submitting grants as a pharmaceutical scientist.

Non-Liposomal Lipid Bilayer-Based Systems

Roundtable
Thursday, October 25, 2001
9:00 am — 11:00 am

Although liposomes have been extensively studied due to their structural similiarity to cellular membranes, their instability and limited loading capacity remain as problems. In this roundtable discussion, some alternative lipid systems will be brought to the audience in order to initiate discussions. To address the problems above, two unique lipid bilayer systems, cochleates and hydrogel core anchored lipid bilayer vesicles, will be introduced in the discussion. For cochleates, some promising applications are on the way of development. While the hydrogel anchored vesicle system may still be at the proof-of-principle stage. It is expected that by discussing these alternative ideals, we may refresh our focus on lipid bilayer systems, and have more valuable opinions generated.

Moderator
Jian-xin Li, Ph.D.
FMC Biopolymer

Cochleate System and Its Applications in Drug Delivery
Leila Zarif, Ph.D.
BioDelivery Sciences, Inc.

Hydrogel Core Anchored Lipid Bilayer Vesicles
Tuo Jin, Ph.D.
Long Island University

Validation of Analytical Instruments: A Search for Scientific Rationale

APQ Open Forum
Thursday, October 25, 2001
1:30 pm — 5:00 pm

Current regulations require that the analytical instruments used in today’s laboratories be validated. What are the drivers for these requirements? What is considered a full validation? Can instrument validation be cut into parts and end users and instrument manufacturers be responsible for their parts? Are there uniform requirements for instrument validations? Would a validation performed on one piece of equipment be the same or similar at different laboratories? Would two users give the same answer when asked above questions? And would end user, QA unit, instrument manufacturer and validation consultants agree on the answers to these questions? Such questions go through the minds of most scientists in analytical and bioanalytical laboratories who must perform these validations. Without having scientifically-based consistent practices, can we continue to make progress and benefit from the validation efforts?

It seems we must be at the infancy of instrument validation if so many questions are in the minds of the responsible scientists. It is reminiscent of the days prior to reaching a consensus on analytical or bioanalytical methods validations. With such a variety of instruments in the laboratories, would we ever reach a consensus on how to validate them, or is validation the right terminology for qualifying an instrument for analytical work? The answer is clear — we would never reach a consensus if the users do not find the scientific rationale for performing the validation. Scientific rationale would also increase knowledge in instruments and provide a solid basis for coming to a consensus on meeting the regulatory requirements.

The Open Forum will bring in views from several users on their current scientific basis for performing validations. If truly no scientific basis exists, then we will hear from the users on what basis they perform validations. Prior to the meeting, we will seek the involvement of users at large and get their views and questions through the Internet. During the forum we will discuss everyone’s views and make an effort to find common ground for a scientific basis for instrument validations. The open forum is to start the dialog. The objectives will be met if the dialogs lead to an extended workshop for generation of a consensus on Analytical Instrument Validation.

Moderators
Vinod P. Shah, Ph.D.
Food and Drug Administration

Mario L. Rocci, Jr., Ph.D.
Oneida Research Services, Inc.

In Search for a Scientific Rationale for Instrument Validation
Surendra K. Bansal, Ph.D.
Hoffmann-La Roche, Inc.

Instrument Validation Qualification — An FDA Perspective
Diane T. O'Brien, B.S.
Food and Drug Administration
(Invited)

Appropriate and Inappropriate Uses of Instrument Validation
Alfred G. Childers, Ph.D.
Magellan Laboratories

Performance-Based Validations of LC/MS/MS Systems
Michael J. Avery, M.S.
Pfizer, Inc.

System Validation — A Manufacturer's Perspective
Jeremy D. Batt, B.Sc.
Micromass, United Kingdom

Validation of Analytical Instruments: Is There One Meaning?
Thomas P. Layloff, Ph.D.
United States Pharmacopeia

Current Challenges for Metabolism in Preclinical and Clinical Drug Development

PPDM Open Forum
Thursday, October 25, 2001
1:30 pm — 5:00 pm

Recent regulatory guidelines, including both the International Conference on Harmonization (ICH) as well as national regulatory guidances, have considered the assessment of metabolites during drug development. Advancements in analytical instrumentation, such as liquid chromatography/tandem mass spectrometry (LC/MS/MS), have made it increasingly possible to quantify metabolites in biological matrices. In addition, in vitro techniques have enabled incorporation of metabolism issues earlier in drug development programs, as well as in the design of an appropriate biopharmaceutics strategy for a drug candidate. As a result of these factors, considerable discussion has emerged regarding how metabolites should be evaluated during preclinical and clinical safety assessment. These discussions have revealed significant challenges that remain to be addressed. Examples may include: when is it necessary to conduct pharmacokinetic evaluation of metabolites in animals or in humans, what constitutes a “major” metabolite, are pharmacokinetic studies of pharmacologically inactive metabolites warranted, should pharmacokinetic evaluation of metabolites be conducted in Phase II and/or Phase III clinical trials, what are the critical variables to assess in the clinical pharmacology program for an active metabolite (i.e. gender, age, renal and/or hepatic insufficiency, disease state), should metabolites be evaluated when performing bioequivalence studies for prodrugs or for compounds with active metabolites? Drug metabolism often serves as the key link between preclinical and clinical safety assessment and impacts multiple scientific disciplines. It is the goal of this Open Forum to have a dynamic discussion of the current scientific and regulatory challenges regarding metabolites in the drug development program.

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