ADMET

Donna Dambach, Director, Investigative Safety Assessment, Genentech.

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.

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.

• 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.

• 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.

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.

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.

• 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.

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.

• 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.

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.

• 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.