Associated with the conference there will be a half-day interactive workshop on "Predictive Toxicology Model Building", taking place on Tuesday 5th of June.
The workshop aims to provide a set of stimulating problem-solving activities used latest advanced modelling and analysis techniques and case studies of relevance to research scientists, modellers, and risk assessors, needing to predict the toxicities of compounds. Workshop participants will study problems with hands-on examples using leading methods and discuss complex issues highlighted by examples presented by the instructor.
Leading this workshop will be Barry Hardy, Director, Douglas Connect To see more information about the workshop, please see the comprehensive workshop page
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Conference agenda
Welcome and Introductions Compounds, Mechanisms & Data
Searching and integrating existing toxicology data
Chemical Categories and Read Across in Risk Assessment
Evaluating the impact of Chemical Modifications on Toxicities
Predicting Metabolites
Mechanism-based use of in vitro assay data
Weight of Evidence approaches
Integration, Validation & Reporting
Creating and Executing Predictive Toxicology Workflows
Building a Validated Predictive Toxicology Model
Regulatory Reporting of in silico-based predictions
Chairman's Opening Remarks Richard Weaver, Associate Principal Scientist, AstraZeneca Cell culture and in vivo model to develop new treatments for renal diseases Frederick W K Tam, Senior Clinical Lecturer (Renal Medicine), Imperial College London West London Renal and Transplant Centre Hammersmith Hospital
Cytokines in pathogenesis of renal diseases
Cell culture model
In vivo model (progression from inflammation to fibrosis and renal failure)
Assessing the effect of small molecule inhibitors in vitro and in vivo
Translation to clinical practice
Applications of humanized mouse models in evaluation of drug-drug interactions, pathways of metabolism and drug safety Mike Piper, Senior Business Development Manager, CXR Biosciences
Current preclinical models can be poorly predictive of DMPK and Safety in humans, due to profound interspecies differences in key pathways of metabolism
We will present data in mice humanised for cytochrome P450s, nuclear receptors and drug transporters, demonstrating that these mice are more predictive of man
Case studies including quantitative prediction of inducers on the AUC of victim substrates in man, production of human disproportionate metabolites in a mouse model, & species-specific inhibition effects
Selection of preclinical species with a focus on the minipig Vibeke Sunesen, Pharmacokineticist, Preclinical Development, Leo Pharma
Can ADMET properties be adequately predicted?
Pros and cons when using the minipig
Case studies: we used the minipig
Using measured physicochemical properties as an aid to early candidate selection John Comer, Co-founder & Technical Director, Sirius Analytical Instruments
Measured values bring increased confidence to ADME studies
Fast methods for pKa and solubility measurement
Small-scale dissolution studies help prepare for effective pre-formulation
Where does PKPD add value in drug discovery? Pablo Morentin-Gutierrez, Associate Principal Scientist , AstraZeneca
Integration of PK/PD in Lead Identification and Lead Optimization phases
Influencing Phase I trials using preclinical PK/PD knowledge
Overcoming major hurdles to implement PK/PD reasoning in Drug Discovery
ADMET and PK/PD modelling in drug discovery and development - New horizons and applications Alan Wilson, Drug Metabolism, Pharmacokinetics, Toxicology and Pathology, Lexicon Pharmaceuticals Inc
Role of ADMET in optimizing drug discovery and development
Strategies, approaches and applications
Incorporating early formulation and PK/PD Modelling
Future directions, opportunities and challenges
Application of in silico methods in the prediction of ADME Alexander Alex, Director, Computational Chemistry, Pfizer
Molecular properties in drug discovery.
Application of in silico ADMET in drug design.
Case study for prediction of drug metabolism.
Rationalisation and prediction of drug absorption
The influence of DMPK & physicochemical science to all key discovery disciplines Richard Weaver, Associate Principal Scientist, AstraZeneca
It’s all in the structure
Prediction of human pharmacokinetics and dose
DMPK is an integral partner in drug discovery
Relationships between physicochemical properties and ADMET Janice Yau Yi Lau, Group Leader, Abbott Laboratories
cLog P/Log D are the top most important physicochemical properties that not only affect ADME properties but also safety outcomes.
Physicochemical properties are important determinant of CNS penetration
Solubility and permeability decrease with increase in MW, cLog P and PSA and is important for absorption and can increase oral bioavailability
Protein binding increases with increase in MW, cLog P, and PSA which affect clearance and efficacy
Brain Tissue Binding of Drugs: evaluation and validation of solid supported porcine brain membrane vesicles (TRANSIL) as a novel high -throughput method Kathleen Boehme, Study Director, Sovicell
Estimating the unbound fraction of drugs in brain as essential for the evaluation and interpretation of the pharmacokinetics and pharmacodynamics of new central nervous system drug candidates.
The low throughput downside of Dialysis-based methods
Combining the TRANSIL brain absorption assay with liquid chromatography mass spectrometry.
Comparing free fractions fu,brain obtained using the TRANSIL brain absorption assay and equilibrium dialysis methods for a test set of 65 drugs (27 marketed and 38 GlaxoSmithKline proprietary drugs).
This not only significantly reduces the biological matrix required but also increases the throughput as compared to the conventional dialysis methods
CNS delivery of antibodies, are we there yet? Saileta Prabhu, Senior Scientist, PKPDS Development Sciences, Genetech Overview of the transport barriers for antibodies in the brain including the blood-brain barrier (BBB)
Disposition of antibodies in the CNS with focus on influx and efflux pathways
BBB physiological parameters in neurodegenerative disease mouse models, and its potential impact on drug delivery
Transporting therapeutic antibodies to the brain by receptor-mediated transcytosis
Challenges in CNS delivery of antibodies to patients Assessment of Human Pharmacokinetics from QSAR Models: Best Model for Humans is Human Vijay Gombar, Research Advisor, Eli Lilly & Co • Presentation will focus on development and performance of QSAR models for human intravenous clearance and volume of distribution
• QSAR predictions are compared with experimental data for a simulated test set of 235 drugs
• When tested on 109 randomly selected drugs, the VDss in silico model predicted 50% and 90% compounds within 1.6-fold and 4.9-fold deviation from VDss measured in clinical studies
• Through an analysis of comparison between experimental data and predictions for proprietary compounds, limits of application of models are identified Chairman’s Closing Remarks and Close of Day One Richard Weaver, Associate Principal Scientist, AstraZeneca Morning Chairman's Opening Remarks Balazs Sarkadi, Head, Membrane Biology Research Group, Hungarian Academy of Sciences Pre-clinical screening of anti-HER2 Nanobodies for molecular imaging of breast cancer Nick Devoogdt, Cellular and Molecular Immunology, Vrije Universiteit Brussel
Evaluating HER2 expression in vivo by radioimmunodetection using Nanobodies and single photon emission computed tomography (SPECT)
The potential of 99mTc-Nanobodies produced against HER2 as tracers for non-invasive imaging of HER2 expression
Study details
One 99mTc-Nanobody identified as the lead compound for a phase I clinical study
Targeted and non-targeted proteomics in biomarker research Dieter Deforce, Professor, Gent University
Targeted and non-targeted proteomics in biomarker research.
Different technological platforms for non-targeted and targeted proteome analysis
Identification of biomarkers
Qualification of biomarkers
Biomarkers in ADMET
Metabolites as perpetrators of drug interactions David Buckley, Principal Scientist, XenoTech
Formation of metabolites that inhibit drug-metabolizing enzymes and drug transporters
Regulatory guidance on metabolites and current in vitro techniques
Clinical significance of metabolites as inhibitors of CYP enzymes and transporters
Is Nrf2 a good biomarker of oxidative stress and reactive metabolites? Helga Gerets, Senior Scientist, In Vitro Toxicology, UCB
Introduction on Nrf2: its role, pathway and activation
Models/experiments used to investigate toxicities related to reactive metabolites/oxidative stress
Experimental approach 1: Cellular toxicogenomic analysis and potential biomarkers
Experimental approach 2: AREc32 cell line: predictivity, advantage and limitations
Relationship between hepatotoxicity and reactive metabolites
The chemoimmunity concept as a framework to understand ADME-Tox Balazs Sarkadi, Head, Membrane Biology Research Group, Hungarian Academy of Sciences
ABC “efflux” transporters involved in the fate of drugs,
“Uptake” transporters involved in the fate of drugs,
Interactions between transporters and enzymes of drug metabolism,
Common regulatory pathways for transporters and metabolic enzymes,
A systems biology approach to analyze drug and xenobiotic interactions within the frame of the chemoimmunity network concept
Afternoon Chair's Opening Remarks Dolo Diaz, Investigative Safety Assessment, Genetech State-of-the-art overview of strategies used for the establishment of liver-based in vitro systems for long-term pharmaco-toxicological testing Mathieu Vinken, Department of Toxicology, Vrije Universiteit Brussel
Increasing importance of in vitro testing platforms for pharmaco-toxicological testing of new chemical entities
Overview of currently available primary hepatocyte culture systems and their shortcomings
Conventional and novel strategies to optimize primary hepatocyte cultures
Future directions
Validation of CellCiphrTM Technology. Building on Experience of In Vitro Liver Cell Toxicity to Predict In Vivo DILI Katya Tsaioun, Chief Scientific Officer , Cyprotex Thomas, Simon1; Metcalfe, Paul1;Tsaioun, Katya1,2
1. Cyprotex, Macclesfield, SK10 2DR, United Kingdom.
2. Apredica, Watertown, MA, United States
Toxicity is a key reason for drug attrition.
High Content Screening (HCS) allows early detection of indicators of cellular toxicity, covering a wide spectrum of cytopathological changes.
CellCiphr™ combines HCS with an proprietary ranking and classifying system for predicting in vivo toxicity.
CellCiphr™ also includes a set of proprietary in silico models for predicting the risk of compound failure in safety studies.
Here relative toxicity rankings of a selection of results for different cell models will be presented and discused.
Case studies of CellCiphr™ use in derisking pharmaceutical programs will be presented.
Toxicogenomics within the pharmaceutical industry Willem Schoonen, Senior Research Scientist, MSD
The focus is on in vivo and in vitro liver toxicogenomics
Prediction scores for in vivo rat liver toxicity with ToxShield
Prediction scores for in vitro rat precision-cut liver slice toxicity with ToxShield
Segregation of gene sets for genotoxicity in human liver HepG2 hepatocytes
Development of luciferase reporter based HepG2 cells for genotoxicity
The Prozac paradox – predicting clinical toxicity from in vitro assays Andrew Brown, Investigator, GlaxoSmithKline
How to interpret in vitro toxicity data in early drug discovery
Relating in vitro toxicity to physicochemical properties and the concept of compound “promiscuity”
New frontiers: Non-functional cardiotoxicity and other non-liver tissue toxicity
Pharmacokinetic drivers of toxicity for small molecules: Evaluating plasma-tissue concentration relationships Dolo Diaz, Investigative Safety Assessment, Genetech
Tissue drug exposures versus drug exposures in the interpretation of toxicity data
Improved In vitro-in vivo correlations and the understanding of in vivo toxicities considering target organ exposures.
Approximate prediction of tissue drug levels using the volume of distribution (Vss) and the clearance (CLp) of a particular molecule
Physicochemical drivers of tissue distribution and how they can affect safety margins
Chairman’s Closing Remarks and Close of Day Two
Workshops
Copthorne Tara Hotel 5 July 2011 London, United Kingdom
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