Welcome and Announcements

President’s Keynote Address — Pharmaceutical Climate Change: Have We Anything to Learn from Dinosaurs?
Sir James Black will speak on his experiences in the industry going back 50 years and he will expand upon the successes and failures. He will hint at differences between then and now. Since then, the world has enjoyed 50 years of scientific advances, technological progress and clinical pharmacological experience. He will address the question–“So, has pharmaceutical inventiveness and therapeutic progress advanced in proportion?"

Break

A. Translation Track

Introduction

QT-Understanding the Complexities of Defining the Translation of Animal Data to Humans

This talk will describe the relationship between preclinical QT data (hERG, canine Purkinje fibre and in vivo QT) and the outcome of human thorough QT studies. In particular, the focus will be on defining relevant magnitude of effects and concentration to help understand the translation of preclinical to human data.

B. Emerging Trends Biological

The first-human-dose (FHD) trial in 2006 with TGN1412, an immuno-modulatory monoclonal antibody, had catastrophic consequences. The incident re-emphasised that translating preclinical data into a safe FHD is critical. This talk will describe some TGN1412 learnings and discuss the application of other approaches to optimise the FHD safety assessment of biologics, and try to connect this with the draft “Guideline on Requirements for First-In-Man Clinical Trials for Potential High-Risk Medicinal Products"

Into the Cytokine Storm

The presentation will focus on the physiology/ pathophysiology of Cytokine Storms and their sequelae. It will also cover the key triggers for this pathology, limitations of animal models and discuss potential early markers which may be of use in understanding the liability for new therapies to induce cytokine storms.

A. Translation Track

Introduction

Predicting Nausea and Vomiting in Humans; Understanding the Translation of Animal Models to Man

Nausea and vomiting is one of the most common adverse effects observed in human trials. This talk will describe some of the animal models used to study the emetic/antiemetic effects of new chemical entities and will review efficacy in the ferret compared with humans. In addition learning’s from the effects of NK1 antagonists in animals and humans will be discussed.

Paul Andrews, St. George’s University of London

B. Emerging Trends

While the industry, as a whole, is moving away from developing QT prolonging drugs, evidence is emerging that “QT shorteners” are being identified. The objective of the symposium will be to have an opponent/proponent debate with the aim to stimulate discussion with the audience.

Jean-Pierre Valentin, Session Liaison

Drug-induced Shortening of QT Interval: An Emerging Safety Issue in Drug Development

An increasing number of drugs are found to shorten QT interval. This presentation draws an analogy between congenital forms of long and short QT intervals and proposes that drug-induced shortening interval is an emerging area of cardiac safety that will need to be addressed during drug development.

Drug Induced QTc Shortening: Facts or Fears

At present, links between drug-induced QTc shortening and proarrhythmia are based on hypothetical considerations rather than on solid data-driven experience. While such observations should not be dismissed as irrelevant, substantial body of research is needed before we can truly interpret drug-induced QTc shortening, especially if of modest magnitude.

Marek Malik, St. Paul’s Cardiac Electrophysiology

NOTOCORD Systems are pleased to invite you to their special sponsored presentation:

"The Other 3R's Commitment: Reliability, Rapidity, Results" from 12:30 PM to 1:00 PM. This workshop will cover fundamental concepts for better data acquisition and analysis.

Please stop by our booth # 34 and 35 or RSVP to sps2007@notocord.com

NOTOCORD Systems are pleased to invite you to their special sponsored presentation:

"Innovative Tools Enabling Analysis for Better Predictive Assays" from 1:00 PM to 1:30 PM. This workshop will present advanced tools to build your own specific analysis that matches state of the art predictive.

Please stop by our booth # 34 and 35 or RSVP to sps2007@notocord.com

EMKA Technologies invites you to their sponsored presentation; "Complete
Non-Invasive Telemetry; A Six Year Retrospective: Tox or Safety?"

If you would like to attend please contact Josh Burton via e-mail jburton@emkatech.com or simply give us a ring at (703) 237-9001.

A. Invited Oral Communications 1

1. hERG Potency Estimation and Dose Solution Analysis: What Have We Learned, Hugo M. Vargas, Amgen
   
2. Multiple Mechanisms of QTc Shortening, N. Regan, Pfizer
   
3. AV Block Monkey Can Predict Proarrhythmic Risk of Moxifloxacin: Comparison of the Results with Those From Clinical Study, Atsushi Sugiyama, University of Yamanashi

4. Transgenic LQT1 and LQT2 Rabbits Provide A New Model for Safety Screening for IKr Or IKs Blocking, Katja E. Odening, Brown Medical School
   
   

B. Invited Oral Communications 2

1. Transmural Repolarization Velocity is a Reliable Index Predicting Drug Torsadogenicity in an Isolated Rabbit Heart Model, N. Guérard, Novartis Pharma
   
2. Respiratory Safety Pharmacology: Comparison of Conscious Beagle Dogs and Cynomologus Monkey Models, Simon Authier, LAB Research
   
3. Assessment of Airway Resistance and Compliance in Conscious, K. Norton, Charles River Laboratories
   
4. Continuous Gastric pH Monitoring in Freely Moving Beagle, Stéphane Milano, MDS Pharma Services

Derek Leishman, Session Liaison

Emesis–Mechanism-based PK-PD Modeling: Utility for Prediction of Efficacy-Safety

This presentation will focus on the use of mechanism-based PK-PD modeling concepts for prediction of exposure response of drug efficacy and safety.

Meindert Danhof, Leiden University

Tiffini Brabham & Sarra Laycock, Session Liaisons

Preclinical Physical Dependence Models: Risks and Hurdles

The preclinical models used to evaluate physical dependence will be described. The difficulties related to designing these studies and using these data to support an abuse liability package for scheduling of novel compounds will be discussed.

Mary-Jeanne Kallman, Eli Lilly & Co.

Case Study Examples of Non-Clinical Assessment of Physical Dependence and Withdrawal: Towards a Better Design

The talk will present several physical dependence and withdrawal case studies of marketed CNS active compounds undertaken as part of their non-clinical abuse potential assessment. Learning’s for designing more relevant studies will be discussed.

Paul Butler, Pfizer Ltd.

A. Translation Track

Derek Leishman, Session Liaison

Using PK/PD Modeling for all CV Parameters

Appropriate experimental design and PKPD modeling are key to understand the concentration versus effect versus time relationship; and hence determination of a safety margin and potential mechanism behind any effect. Case studies will be used to show how these considerations have influenced data interpretation and risk management in CV safety.

Off Target Cardiovascular Pharmacology of Torcetrapib and Human Safety Implications

Evaluating the cardiovascular safety of drug development candidates is one of the primary goals of safety pharmacology studies. Torceptrapib (CETP inhibitor) provides an interesting case study of a development candidate with known cardiovascular effects (tachycardia) and recently demonstrated increase cardiovascular events in a large outcomes study

Peter Siegl, Merck & Co.

Animal Welfare Considerations and Safety Pharmacology

A discussion on the current trends in animal welfare and their impact on designing and conducting safety pharmacology studies.

Respiratory Safety Pharmacology Studies: A Re-evaluation of ICHS7A

The ICH S7A guideline states that the method for assessing drug effects on respiratory function should involve “respiratory rate and other measures of respiratory function (e.g., tidal volume or hemoglobin oxygen saturation)”. This presentation will provide arguments and data to support the belief that an assessment of respiratory function must include measures of both ventilatory function and lung mechanics, that the assessment of ventilatory function must include both respiratory rate and tidal volume, and that the use of hemoglobin oxygen saturation is not an appropriate method for detecting drug-induced ventilatory change.

8:30 AM

Potential Effects of Anesthesia on Hemodynamic Parameters

This presentation will discuss the potential effects that common anesthetics could have on studies designed to investigate the hemodynamic effects of drugs.

Historical Comparison of Drug Induced Hemodynamic Effects in Anesthetized and Conscious Animals

This presentation will discuss the historical data comparing drug effects in conscious and anesthetized models. this presentation will look at the reasons for those differences which have been observed.

B. Emerging Trends

Jean-Pierre Valentin & Alan Bass, Session Liaisons

Overview of Current and Emerging
Methods/Assays for Safety Pharmacology: Stem Cells as Enabling Tools for
Screening

There is a crying need to reduce attrition due to safety (incl. Safety Pharmacology) reasons during the discovery and development phases. One way of achieving this is to introduce early in the discovery phases screens that are predictive of a clinical safety outcome and that are amenable to the early discovery phases (ie., high throughput, low compound requirement; rapid turn around time etc.). The objective will be to review existing and emerging in vitro safety & secondary pharmacology screens and associated in silico tools.

Anthony Behinski, Pfizer Ltd.

Computational Methods for Predicting Secondary Pharmacology: How Far Have We Really Come?

Potentially useful pharmacology datasets are now becoming available. These will impact on our ability to predict the potential pharmacological class of molecules from chemical structure. This talk will address both the datasets and the current methods with the aim to give a realistic view of the potential of this area.

Break

Derek Leishman, Session Liaison

Translation of Convulsive Risk from Preclinical Models to the Clinic

This presentation emphasizes the prediction of convulsive risk across species to the clinic using different types of data. The profiles of specific compounds will be presented to illustrate issues and pitfalls for risk assessment and specific approaches that support clinical progression.

Brainstem Auditery Evoked Potential in Non-Rodent with Lint to Human Relevance

To evaluate auditory function in dogs most often brainstem auditory evoked potentials are used. With this method it is possible to investigate degenerative lesions in the inner ear, the VIII cranial nerve or in the central auditory pathways. BAEPs are measured in the awake dog under general anesthesia. Monaural clicks are delivered through earplugs and recorded waves are analyzed. Abnormal waves could be caused by lesions or by axonal conduction disturbances to the supposed generations. A correlation between severity of lesions and the formation of BAEP exists.

B. Emerging Trends

Application of Translation Imaging in Drug Discovery: Safety and Efficacy Perspectives

This presentation will discuss the utilization of imaging techniques as part of the drug development process.

ELSEVIER is pleased to invite you to their luncheon presentation.

The presentation topic is "Lessons Learned: See how Documentation of side effects across the life cycle (Preclinical; Clinical & Post-Marketing) of marketed drugs can bring you a missing piece of your puzzle".

This luncheon will be located in the Ochil Room of the Galloway Suite on Level 1 in the Edinburgh International Convention Center (EICC).

If you would like to attend, please contact Pascal Hua at Elsevier via e-mail: p.hua@elsevier.com, or by phone: +33-(0)6-08-72-67-36 (Cell) or simply stop by our booth (#104).

A. Invited Oral Communications 3

1. Validation of an OptoMotry System for Measurement of Visual Acuity in Han Wistar Rats, Khine Phu Maung, AstraZeneca, Student Travel Award
2. Application of the Probablistic Method for QT rate-correction in telemetered beagles: Effects of moxifloxacin, Andrea Greiter-Wilke, F. Hoffmann-La Roche
3. Central Nervous System Effects of Psychoactive Reference Compounds in Baby, Juvenile, and Adult Rats, Herbert M. Himmel, Bayer HealthCare
4. Comparison of a Hippocampal Brain Slice and Zebra Fish Assay for Assessment of Seizure Liability, A. Easter, AstraZeneca

B. Invited Oral Communications 4

1. Effects if JNJ-17333030, Naratriptan and Sumatriptan on Human Isolated Coronary Artery, Sandra Williams, Asterand
2. Gastrointestinal Telemetry: A Tool for Studying the Migrating Motor Complexes in the Dog, Stéphane Milano, MDS Pharma Services
3. Zebrafish: The Future on In Vivo Safety Pharmacology Screening, S. Berghmans, VASTox
4. Blood Pressure and Cardiac Structure and Function Evaluation Following Treatment with Sunitinib (SU11248, SUTENT®), Eileen R. Blasi, Pfizer Global R&D

NMR-Based Urine Analysis in Rats: Prediction of Proximal Tubule Kidney Toxicity and Phospholipidosis

The use of 1H-NMR spectroscopy for analyzing biological samples including urine, serum and organ preparations (metabonomics) offers the potential of detecting toxicities with a relatively high throughput. This presentation describes a non-invasive approach using urine collected from rats after single administration of a variety of compounds with proven toxicities. Models for either phospholipidosis or kidney proximal tubule toxicity were developed and tested for their predictivity. The data presented support the contention that this experimental approach provides good predictivity for detecting these two toxicities and, as such, offers the safety pharmacologist a new tool for the early detection of drug-induced toxicities even after single administration.

Two Companies’ Experience ‘Liability Assays in Zebra Fish'

Both AstraZeneca and Pfizer will share data generated in zebra fish ‘liability assays’ with standard agents. This will be an opportunity to compare, contrast and combine the data from these studies.

Current Status and Perspective of GLP and Safety Pharmacology in China

China obtained a great achievement in the field of GLP in the past 10 years. More than 25 GLP laboratories have emerged and some multinational pharmaceutical companies have set up R&D centers. In addition, the laws related to the animal protection and intellectual property protection have been enforced.

Bridging Preclinical to Clinical Development: A Clinical Perspective on Safety Pharmacology

Progressing a NCE to clinical trials represents a milestone in drug development. Non-clinical safety information influences design of first in human studies and helps understanding of the emerging safety profile. This presentation describes how non-clinical safety is used in managing risks in clinical development.

Konrad Tomaszewski, Pfizer Ltd.

Adjourn