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Conference Documentation: ADMET (2010)

SMI Publishing, Ltd
July 7, 2010
SKU: SMI2778936

Abstract Table of Contents Related Reports

ADMET screening is crucial to the drug development process and assists the elimination rate of weak drug candidates early in the drug-discovery process, and decreases the proportion of compounds failing in clinical trials for ADMET reasons. SMi's 5th Annual ADMET Conference will bring you up to date with the latest developments, technologies and techniques that are in use across the industry and look towards the future.

By attending this conference, you will learn:

How to effectively integrate ADMET optimisation into drug discovery to reduce attrition rates from AstraZeneca
Strategies for predicting drug-drug interactions arising from CYP450 inhibition from Pfizer
How to develop a mechanism-based PK/PD model from Eli Lilly
The application of High Content Analysis for predictive cytotoxicity testing & preclinical toxicity biomarkers from University College Dublin
Tools and strategies to consider in characterising and investigating hepatotoxicity from Genetech
What the emerging in vitro toxicity assays are and the role of stem cells in assessing human toxicology from Roche
Case studies demonstrating the benefits of evaluating PK in early stage drug development from Merck

The conference will provide a look at how the big names in the pharma industry are approaching ADMET. With a case study focus and presentations from companies including Novartis, AstraZeneca, Pfizer, Eli Lilly, Genentech, MSD, Merck & Co., Roche, Gedeon Richter and more along with distinguished representatives from top academic organisations this conference promises to provide an intimate environment for benchmarking against industry leaders and networking.

Featured Presentations:

Building hypotheses in lead selection and optimisation
Bernard Faller, Director of Metabolism & Pharmacokinetics / in-vitro ADME, Novartis, Switzerland

ADME Optimisation in Early- and Late-Phase Drug Discovery
Gerhard Gross, Global Discipline Leader ADME, AstraZeneca, UK

In Vitro and In Vivo Approaches for Assessing the Potential for Drug Induced Liver Injury
Donna Dambach, Director, Investigative Safety Assessment, Genentech, USA

Emerging In Vitro Toxicity Assays and the Role of Stem Cells in Assessing Human Toxicology
Claudia McGinnis, Group Head, In Vitro Toxicology, Roche, Switzerland

DAY 1
8.30 Registration & Coffee
9.00 Chairman's Opening Remarks: Bernard Faller, Director of Metabolism & Pharmacokinetics / in-vitro ADME, Novartis Pharmaceuticals.
9.05 ADME Optimisation in Early- and Late-Phase Drug Discovery: Integrating ADME into drug discovery in order to reduce the attrition rates; Applicability domain and validity; Decision points; Preclinical strategies; False positive rates; Gerhard Gross, Global Discipline Leader ADME, AstraZeneca.
9.35 Targeting Drugs for the Brain: Innovative high-throughput method for early prediction of brain availability; Fast and reliable prediction of brain disposition and free drug available in brain; Classification of CNS versus non-CNS drugs based on rate and extent; Prediction of CNS side-effects; Hinnerk Boriss, CEO, Sovicell.
10.15 Morning Coffee
10.45 Probabilistic Model of Regioselectivity of Metabolism in Human Liver Microsomes: A ligand-based model of regioselectivity, based on >850 structures; Predicting probability to be a metabolism site for every atom in the molecule using separate models for different reactions; Estimation of the reliability of prediction defining the model applicability domain; Possibility to expand this applicability domain using in-house data; Pranas Japertas, Director of ADMET and PhysChem, Advanced Chemistry Development Labs.
11.25 Vinblastine Treated CaCo-2 Culture as a Drug Penetration Model: An added value model of drug penetration; Characterisation of efflux transporters: function and importance; Experimental approaches to identify P-gp substrates/inhibitors; Comparison of cell culture models of drug penetration; Establishment and characterisation of vinblastine treated Caco-2 culture; Validation of the vinblastine treated Caco-2 penetration assay; Practice of penetrability screening of new chemical entities in our preclinical research; Monika Vastag, Head of In vitro Metabolism Laboratory, Gedeon Richter.
11.55 Integrating Predictive ADMET into Hit to Lead and Optimisation: Getting away from black & white by creating composite ADMET risk scores; Hedging your bets by including ADMET diversity dimensions; Balancing potential ADMET liability against potential potency, selectivity etc.; Accommodating the inherent fuzziness of ADMET exclusion thresholds; Managing interdependence among biological and physical properties; Robert Clark, Director of Life Sciences, Simulations Plus.
12.35 Networking Lunch
1.35 Structure-based ADMET Studies: The challenges and the opportunities; Metabolite prediction of CypP450 reactions; Toxicity from Nuclear Receptors; Understanding P-glycoprotein interactions; Efforts towards predicting hERG liability; Frank Blaney, Director, MemProt Consulting.
2.05 RAPIDD plus: An accelerated programme of integrated drug and biomarker development; Addressing challenges of increasing time-to-market, cost and attrition; Integrated drug and biomarker development in a pre-clinical setting; Helen McKeever, Programme Manager, Almac Group.
2.45 Building Hypotheses in Lead Selection and Optimisation: Linking in-silico, in-vitro and in-vivo data; Translating PK parameters into MedChem actions; When can one use rules derived from the analysis of generic drugs?; Extracting information from the absence of correlation; Bernard Faller, Director of Metabolism & Pharmacokinetics / in-vitro ADME, Novartis Pharmaceuticals.
3.15 Afternoon Tea
3.45 Supersaturation Effects in Solubility-Enhancing Excipients and Biorelevant Media: John Comer, Co-founder & Technical Director, Sirius Analytical Instruments.
4.20 Prediction of DDI's Arising from Cytochrome P450 Inhibition: Importance of understanding CYP inhibition; Extrapolation of in vitro data to predict clinical interactions following CYP inhibition; Factors influencing the extent of a DDI due to CYP inhibition; Future Directions; Kuresh Youdim, Senior Principal Scientist, Pfizer.
4.50 Developing a Mechanism-based PK/PD Model: Influencing early phase development using preclinical models; Connecting the PK with the pharmacology and pre-clinical efficacy of the compound; Providing an improved rationale for selecting the dose rage for Phase I trials; Damien Cronier, Research Scientist, Global PK/PD, Eli Lilly.
5.20 Drug Transporter Assays in Discovery: Available assays; How assays are used in the screening cascades; Utilization of the data (case study); Laurent Salphati, Scientist, Genentech.
5.50 Chairman’s Closing Remarks and Close of Day One
DAY 2
8.30 Registration & Coffee
9.00 Chairman's Opening Remarks: Donna Dambach, Director, Investigative Safety Assessment, Genentech.
9.10 The Utility and Application of TDI Screens in Early Discovery DMPK: In vitro TDI screens for in vivo DDI prediction and Reactive Metabolite potential; Importance of front-loading TDI assays in Discovery; In vitro - in vivo DDI extrapolation; MBI data as a Reactive Metabolite early-warning flag; Richard Weaver, Associate Principal Scientist, AstraZeneca.
9.45 System-dependent inhibition of cytochrome P450 (CYP) enzymes: Common misconceptions and errors; When should cytochrome P450 (CYP) inhibition by drug candidates be evaluated in human hepatocytes and not just human liver microsomes or recombinant CYP enzymes?; Rules to guide the selection of the appropriate test system to evaluate CYP inhibition; Common errors associated with the processing of data from metabolism-dependent inhibition (MDI) studies that incorporate a dilution step.; Why a dilution step - even with correct data processing - should be avoided in evaluating drug candidates MDI of CYP enzymes; Andrew Parkinson, Chief Scientific Officer, XenoTech.
10.25 Morning Coffee
10.55 Integrating Predictive Toxicology Model Development: Data Management, Schema and Integrating Multiple Resources; Predictive Toxicology Application-oriented Ontology Development; Developing combined in silico in vitro Consensus Models; Model Validation and Applicability Domain; Incorporating Pharmacokinetics to Predict Exposure; OpenTox Case Study Example; Barry Hardy, Director, Community of Practice & Research Activities and OpenTox Project Coordinator, Douglas Connect.; Nina Jeliazkova, Technology Director and OpenTox Lead Developer, Ideaconsult.
11.40 Application of High Content Analysis for Predictive Cytotoxicity Testing & Preclinical Toxicity Biomarkers: Criteria for effective cytotoxicity models; Demonstration of predictive cytotoxicity screens and investigations of toxicity mechanisms; Demonstration of toxicity in vivo using high content analysis of peripheral blood lymphocytes; Application strategies for screening for toxicity, identification of mechanisms, and development of translational in vivo biomarkers of toxicity; Peter O'Brien, Veterinary Clinical Pathologist / Toxicologist, University College Dublin.
12.15 Segregation of Genotoxic Compounds: Novel in vitro system approach with human HepG2 liver cell line; Genotoxicity testing in the early phase of the drug development process; Segregation of Genotoxicity scores from Salmonella, Yeast and HepG2 cells; HepG2 cells; - analysis with toxicogenomics for global gene expression profiling of genotoxicants; - validation of promoter based luciferase reporter assays with the promoters of RAD51C, and Cystatin A, and the responsive elements of p53 and Nrf2; - in vitro micronuclei analysis with high content screening, the more traditional way; - advantage of endogenous metabolism by phase I and II enzymes; Willem Schoonen, Senior Research Scientist, Toxicology & Drug Disposition, MSD.
12.50 Networking Lunch
1.50 In Vitro and In Vivo Approaches for Assessing the Potential for Drug Induced Liver Injury: Tools and strategies to consider in characterising and investigating hepatotoxicity; The line between overt toxicity, "outliers" and idiosyncratic toxicity; In vitro-in vivo correlations-consideration of physiochemical and PK drivers of toxicity; Assessing metabolism as the basis for toxicity; Preclinical genomic assessments and their potential clinical application; Clinical trial sampling-leveraging new, 'standard' endpoints; Donna Dambach, Director, Investigative Safety Assessment, Genentech.
2.25 Emerging In Vitro Toxicity Assays and the Role of Stem Cells in Assessing Human Toxicology: Microscale cell culture systems: novel approaches that mimic regulatory tests and allow for higher-throughput testing; Current status of the development of human embryonic stem cell-derived tissue-specific cells and their applications; Stephan Kirchner, Lab Head, In vitro Screening, F. Hoffmann-La Roche.
3.00 Mechanisms of Human (Hepato)Toxicity: Do we benefit from this knowledge?; Business and science arguments for and against early investigation of mechanisms of toxicity; Known mechanisms of human hepatotoxicity; Assays available for prediction of specific mechanisms of toxicity:; HCA, mitochondrial toxicity, phospholipidosis: validation; Case studies: when and which assays are relevant?; Path forward: new cell and tissue models; Katya Tsaioun, President, Apredica.
3.40 Afternoon Tea
4.10 Metabolism-Based Drug Toxicity in Drug Development: Case Study 1 - Assessing the value of reactive metabolite assays; Looking to past failures - could we have predicted toxicity using modern in vitro tools?; Determining the cause(s) of species differentiation in toxicity; Case Study 2 - Exploring the value of "humanised" mice; Looking to past failures - could we have predicted toxicity using modern in vivo tools?; Translation to human toxicity prediction; Timothy Schulz-Utermoehl, Group Manager, In Vitro ADME, Clinical Pharmacology & DMPK, AstraZeneca.
4.45 Evaluation of Microdosing Strategies Utilizing AMS and LC/MS-MS for ADME Studies in Drug Development: Case studies demonstrating the benefits of evaluating PK in early stage drug development; Linear kinetics of test compounds across microdose/sub-pharmacological and pharmacological dose ranges; Analytical tools to measure plasma concentrations over time to define kinetics at micro /sub pharmacological doses; Review of the available information on microdosing approaches and usefulness of such studies; Punam Sandhu, Senior Investigator, Drug Metabolism & Pharmacokinetics, Merck.
5.20 Is There Too Much (Hot) Air in Genetic Toxicity Assessment?: Does in vitro testing in atmospheric oxygen create misleading positive results?; ICH S2 (R1) test guidelines update: what is the appropriate top testing dose?; What is on the horizon for genotoxicity assessment? Maturing new technologies; Richard Walmsley, Professor of Genetics, The University Of Manchester.
5.55 Chairman’s Closing Remarks and Close of Day Two

Conference Documentation: ADMET (2010)

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