Optimizing Lead Selection (3 Volumes)

Optimizing Lead Selection
(Volume 1)

1. Executive Summary
2. Introduction
3. High Throughput Metabolism Screening
   • High Throughput Screening In Vitro and In Silico
   • Metabolizing Enzyme Systems for In Vitro Analysis
   • The Use of Expressed Recombinant Human Enzymes
   • Automated In Vitro Enzyme Metabolizing Assays
   • Correlation between Enzyme Distribution in the Liver and Their Importance in Drug Metabolism
   • Use of Metabolic Assays in Second-Generation Drug Discovery
   • Induction of Drug Metabolizing Enzymes
   • Transient Transfection Assays to Study Ethanol Metabolism
   • Computational Models of Drug Metabolism
   • Use of Metabolic Information in Drug Design
   • Computer Models to Predict Physicochemical Compound Characteristics
   • Computer Models to Predict Substrate Specificity
   • The Future of Drug Discovery
   • Questions & Answers
4. Cytochrome P Assays for Miniaturized Formats and Library Screening
   • Introduction
   • Developing Fluorescent Substrates for Cytochrome P Isozymes
   • Fluorescent Substrates for CYPA
   • Assay Validation by HPLC
   • Calculating Apparent Ki and IC Values
   • Fluorescent Substrates for CYPD
   • Fluorescent Substrates for CYPC
   • Conclusions
   • Questions & Answers
5. Drug-Drug Interactions: High Throughput Assays to Screen for Inhibition of Human Cytochromes P
   • Post-Approval Issues with Drug Interactions
   • Determining the Need and Extent to Test for Metabolic Interactions
   • Requirements for Developing High Throughput Metabolic Assay Systems
   • Gentest's High Throughput Inhibition Assays
   • Cytochrome P Inhibition Screens Using Fluorogenic Substrates
   • Identification of Mechanism-Based Inhibitors
   • Case Study: Prediction of Drug Interactions of Posicor
   • Conclusions
   • Questions & Answers
6. Drug Disposition: Rapid Throughput Methods to Quantify Compound Solubility
   • Combining Bases of Knowledge to Optimize Drug Discovery
   • Oral Absorption Problems
   • Structural Properties of Drug-Like Compounds
   • Other Properties of Drug-Like Compounds
   • Developing Good Drug Candidates
   • Rationale for Turbidimetric Assays in Drug Discovery
   • Pfizer's Flow Cell Assay and Equipment
   • Pfizer's Plate Reader Assay and Equipment
   • System Integration of Tubidimetric Assays
   • Reproducibility and Correlation of Turbidimetric Assays with Other Data
   • Predicting Poor Solubility
7. Screening Compounds for Oral Absorption Using High Throughput Cellular Assays
   • Introduction
   • The Use of Caco Cell Culture Assays in Drug Screening
   • The Cell Automation System
   • Correlation between In Vitro Permeation Values and Absorption in Humans
   • Applications of High Throughput Caco Cell Assays
   • Case Study: The Selection of a Lead Compound from a Series of HNE Inhibitors
   • Conclusion
8. Screening Compounds for CNS Permeability using Blood Brain Barrier Models
   • Introduction
   • Anatomy of the Blood Brain Barrier
   • Anatomy of the Blood CSF Barrier
   • The Metabolic Barrier
   • The CNS Penetration Team at Glaxo Wellcome
   • In Vivo and In Vitro Approaches to Study CNS Permeation
   • Determining the Mechanism of Brain Penetration for an Anti-HIV Drug
   • An Alternative In Vitro Model for Brain Permeation
   • Validation of the MDCK Cell Culture Model
   • Relevance of Early Stage In Vitro Models to In Vivo Brain Permeation
   • Application of the In Vitro Model in a Drug Discovery Project
   • Computational Models
   • Integrating Permeation Screens for CNS Compounds
   • Summary
   • Questions & Answers
9. Pharmacogenomics Impact on Early Lead Selection
   • Introduction
   • Transcriptional and Proteomic Profiling
   • Creating a Proteomic Database
   • Use of Proteomics to Accelerate Targeted Drug Discovery
   • The Role of Transcriptional Analysis in Oncogenesis EGF-Induced Differential Gene Expression in Tumor Cells
   • The Role of Gene Expression Studies in Studying Drug-Target Interactions
   • Anti-Fungal Drugs and Sterol Biosynthesis Construction of Proteome Databases
   • Steroids and the Anti-Inflammatory Response Molecular Dissection of the Human Inflammatory Response
   • Transcription Profiling for Toxicology Testing
   • Looking Forward
   • Questions & Answers

In Silico Biology (Volume 2)

1. Executive Summary
2. Introduction
3. In Silico Biology - Virtual Systems and Organs for the Assessment of Drug Candidates
   • The Biology Data Chain
   • The Rationale for Biological Modeling
   • Single Cell Models
   • Identification of a Knowledge Gap
   • -Dimensional Organ Models
   • Human Surface ECG
   • Clinical Issues to Detect QT Prolongation
   • Preclinical Issues to Detect QT Prolongation
   • The Challenge - Cardiac Toxicity
   • Computational Approach to Predict Cardiac Toxicity
   • Case Study - Ventricular Response to an Anti-Arrhythmic Compound
   • Single Cell Analysis
   • More Issues Related To Drug-Induced Cardiac Toxicity
   • Conclusion
   • Questions & Answers
4. High-Performance Computing in Pharmaceutical R&D
   • Integration of High-Performance Computing into R&D
   • Using High-Performance Computing to Reduce Development Times and Risk
   • Case Studies of Two Anticancer Compounds I BNP II BNP
   • Mechanism-Based Drug Discovery: Role of Physics-Based Supercomputer Simulations
   • BioNumerik's Supercomputing Center
   • Questions & Answers
5. Computational Pharmacokinetics for Drug Discovery
   • Interfacing High Throughput Pharmacokinetics (HTPkS) and PK-Informatics
   • Discovery and Selection of Small Molecule Drug Therapies
   • Revolutionizing Drug Discovery Through Early Pharmacokinetic Studies
   • Gains from Early Pharmacokinetic Studies
   • In Vitro Pharmacokinetic Screening
   • Virtual or In Silico Pharmacokinetic Screening
   • In Vitro ADME Screening
   • In Silico Prediction of Pharmacokinetics - The IDEA Model
   • A Consortium Approach - The IDEA Consortium
   • The IDEA Model - Benefits of Simulation
   • Questions & Answers
6. A Consortium Approach to Building a Toxicology Database from Proprietary Compounds
   • Approaches to Predictive Toxicology
   • Predictive Toxicology Databases
   • Plans for a Shared Industry Database for Toxicology
   • The Ideal Database for Predictive Toxicology
   • Globalization and International Harmonization
   • Approaches to Assembling and Sharing the Toxicology Database
   • The High Production Volume Chemical Program
   • The IUCLID Candidate Database at the ECB
   • An Accelerated Approach to Predictive Toxicology
   • Questions & Answers
7. Use of FDA Databases and Computational Toxicology to Predict Toxicity
   • FDA-CDER is a Unique Source of Scientific Information
   • Mission of the Regulatory Research & Analysis Staff (RRAS)
   • The Agency Information Cycle
   • The Carcinogenicity Database - The First Database for Computational Toxicology
   • Collaborative R&D Agreement with Multicase
   • Factors Used to Predict Carcinogenicity
   • Validation of the Predictive Carcinogenicity Model
   • Computational Toxicology Applications
   • FDA-RRAS Long-Term Objectives
   • Questions & Answers
8. Using State-of-the Art IT Systems to Integrate Preclinical Evaluations into Discovery
   Part I - Dealing with the Data Deluge
   • Dealing with the Quantum Jump in Amounts of Data
   • Challenges in Discovery and Informatics
   • The Scale of the Data Deluge
   • Responses to Challenges in Discovery and Informatics
   • Data Visualization
   • Enabling Technologies
   
   Part II - Materials Management - Pitfalls and Bottlenecks
   • Compound Management Challenge
   • Solutions to Materials and Substance Handling
   • New Technologies Create Compound Overload
   • Bottlenecks and the "Hurry-Up-and-Wait" Syndrome
   • Compound Management: The Hub of Drug Research
   • A Typical Screening Procedure
   • Inventory Management Software: The Missing Link
   • OPTIMA - A Compound Management Solution
   • Compound Management Solutions Drive Process Improvement
   • Open And Integrated Operations
   • Conclusion
   • Summary
9. Better Decision-Making Through Data-Mining and Visualization
   • Managing the Increasing Volume and Complexity of Data
   • Moving from "Analog" to "Digital" Exchange of Knowledge
   • Scalable Systems for Data Storage and Analysis
   • Capturing Lessons and Knowledge
   • Evolution from Static Data Repositories to Interactive Data-mining and Visualization
   • MineSet as a Tool for Data-mining and Visualization
   • Building Predictive Models Using Visualization of Data
   • Building Predictive Models
   • Applications of Data-mining and Visualization to Discovery Research
   • Visualization of Genomics Data
   • Visualization of Chemical Data
   • Visualization of Clinical Trial Data
   • Estimating Errors and Testing Assumptions in Model Design
   • From Information Overload to Insight

Early Compound Attrition (Volume 3)

1. Executive Summary
2. Introduction
3. Using State-of-the Art IT Systems to Integrate Preclinical Evaluations into Discovery
   Part I - Dealing with the Data Deluge
   • Dealing with the Quantum Jump in Amounts of Data
   • Challenges in Discovery and Informatics
   • The Scale of the Data Deluge
   • Responses to Challenges in Discovery and Informatics
   • Data Visualization
   • Enabling Technologies
   
   Part II - Materials Management - Pitfalls and Bottlenecks
   • Compound Management Challenge
   • Solutions to Materials and Substance Handling
   • New Technologies Create Compound Overload
   • Bottlenecks and the "Hurry-Up-and-Wait" Syndrome
   • Compound Management: The Hub of Drug Research
   • A Typical Screening Procedure
   • Inventory Management Software: The Missing Link
   • OPTIMA - A Compound Management Solution
   • Compound Management Solutions Drive Process Improvement
   • Open And Integrated Operations
   • Conclusion
   • Summary
4. Better Decision-Making Through Data-Mining and Visualization
   • Managing the Increasing Volume and Complexity of Data
   • Moving from "Analog" to "Digital" Exchange of Knowledge
   • Scalable Systems for Data Storage and Analysis
   • Capturing Lessons and Knowledge
   • Evolution from Static Data Repositories to Interactive Data-Mining and Visualization
   • MineSet as a Tool for Data-Mining and Visualization
   • Building Predictive Models Using Visualization of Data
   • Building Predictive Models
   • Applications of Data-Mining and Visualization to Discovery Research
   • Visualization of Genomics Data
   • Visualization of Chemical Data
   • Visualization of Clinical Trial Data
   • Estimating Errors and Testing Assumptions in Model Design
   • From Information Overload to Insight
5. Discovery - Solving Developmental Challenges Before They Arise
   • Technological versus Organizational Development Issues
   • Analysis of the Decision-Making Process During R&D
   • Designing an Improved Discovery Template
   • Building Fully Integrated Teams
   • Strengthen Overall Management of the Process
   • Benefits Resulting from a Restructured R&D Process
   • Key Success Factors for Performance Improvement
   • Questions & Answers
6. Informed Early Attrition
   Part I - Pulling Clinical Risk Forward in Drug Development
   • The Clinical Discovery Stage
   • A Process Performance Model for Clinical Discovery
   • New Configurations During Early Clinical Development
   • A Productivity Measure for Clinical Discovery
   
   Part II - Modeling Resource Consumption and Probability of Technical Success
   • Introduction
   • The Rationale for Process Modeling in R&D
   • Evolution of the R&D Process
   • Approaches to Modeling the R&D Process
   • Models to Estimate Resource Requirements
   • Useful Models for Decision-Making
   • Two Case Studies
   • Chemistry Resource Allocation Model
   • Models to Evaluate the Economic Impact of Pulling Risk Forward
   • Conclusion
   • Questions & Answers
7. Cost-Effective Development of Protein Therapeutics
   • Introduction
   • Challenges in the Development of Biotech Products
   • Large Molecule-Specific Challenges Result in Altered Patterns of Clinical Success
   • Potential Cost Savings from Terminating Projects Earlier
   • Improving Survivability of Drug Candidates
   • Preclinical Development of Recombinant Molecules
   • Case Study: NGF for the Treatment of Diabetic Peripheral Neuropathy
   • Risk Management Strategy - Lessons Learned
   • Determination of the Dose Range Based on PK/PD
   • Determination of the Therapeutic Window Based on Toxicity
   • Analyzing and Minimizing Immunogenicity
   • Implications for Clinical Development
   • Defining Early Go/No-Go Criteria
   • Conclusions
   • Questions & Answers
8. Creating Value via Better Resource Allocation
   • The Creative and the Analytical in Decision-Making
   • Balanced Resource Allocation to Improve the Decision-Making Process
   • Resource Constraints Require Difficult Decisions
   • SmithKline Beecham's Approaches to Resource Allocation
   • SmithKline Beecham's Approaches to Asset Evaluation
   • Portfolio Management in a Smart Organization
   • Case Study: The Oncology Project
   • Increasing Shareholder Value from Portfolio Investment
   • Organizational Buy-In
   • Effective Portfolio Management