Outlook for Predictive Safety Technologies

Table of Contents

CHAPTER 1. INTRODUCTION

• 1.1. ADME/Tox: The Cornerstone of Safety Assessments
• 1.2. Areas of Potential for Improvement of Safety Pharmacology

CHAPTER 2. PRECLINICAL SAFETY TESTING AND DRUG DEVELOPMENT COSTS

• 2.1. Unexpected Toxicity: A Constant Source of Attrition to Pharmaceutical Productivity
• 2.2. Complex Drug Actions Cause Complex Failures
• 2.3. A Savings Scenario for a Mid-Sized Drug Developer
• 2.4. Cutting Back on Research Animal Use

CHAPTER 3. ASPECTS OF DRUG SAFETY CONCERNS

• 3.1. Relative Drug Safety, Not Absolute Toxicity, is the Issue
• 3.2. Toxicity vs. Side Effects
• 3.3. The Objective for Predictive Safety Testing
• 3.4. Mutagenicity and Reproductive Toxicity
• 3.5. Drug-Drug Interactions and "Metabolic Poisoning"
• 3.6. High-Throughput Testing: A Challenge for Predictive Safety Assessments
• 3.7. Knockout Safety Tests with Essentially Unknown Positive Predictive Value

CHAPTER 4. PREDICTIVE SAFETY TOOLS AND TECHNOLOGIES

• 4.1. Toxicogenomics
  • A New Dynamic
• 4.2. High-Content Cell-Based Screening for Safety Parameters
  • HCS for General Aspects of Drug Safety
  • Rat and Human Hepatocytes
  • Cell Models for Modulation of Cardiac Function
  • In Vitro Nephrotoxicity Evaluation Using Primary Human Kidney Cells
  • HCS for Assessing Hematology Toxicity
  • HCS for Genotoxicity Profiling
  • Biochips as Solid-State Biosensors for Toxicity and Mutagenicity
• 4.3. Tissue Histology and Tissue Proteomics: Creating Powerful New Tools from Old Ones
  • Pioneering Efforts in Histopathology
  • NeuroScience Associates
  • HistoRX
  • Phase I Molecular Toxicology
• 4.4. Metabolite Profiling and Metabonomics As a Tool for Toxicity Prediction
  • Metabolite Profiling
  • Predicting Drug Interactions from In Vitro Metabolic Data
  • Predicting Cytochrome P450 Interactions and Inhibition
  • Pharmaco-Metabolomics
• 4.5. Animal Models
  • The Zebrafish: An Intriguing Vertebrate Model for Toxicity Testing
  • Rodents Tailored for Predictive Toxicology
  • Isogenic Rat Panels
  • Mice Under Realistic Stress Conditions
  • Transgenic Animals for Carcinogenicity Testing
  • Unconventional Animal Models
• 4.6. In Silico Approaches to Toxicity and Carcinogenicity
  • The ToxML Format: A Platform for Toxicity Data Exchange
  • Structure-Based Prediction of Hepatotoxicity
  • In Silico Identification of Compounds at Risk for Inducing Cardiac Arrythmia
  • Other In Silico Toxicity Prediction Models
  • Commercial Software Packages and Services

CHAPTER 5. SAFETY SIGNALS FOR BIOTECH DRUG CANDIDATES: AN EMERGING FIELD

• 5.1. Cases in Point
• 5.2. Predictive Safety Testing and Regulatory Authorities
  • The Predictive Safety Testing Consortium: A Spin-Off from the Critical Path Initiative
  • Voluntary Genomics Data Submissions: An Exercise for the Future
  • The FDA' s Intramural Biomarker Program
• 5.3. The European Innovative Medicines Initiative
• 5.4. A Synopsis of Facts and Perspectives for Predictive Safety Testing Approaches

CHAPTER 6. INTERIVEWS WITH EXPERTS IN THE PREDICTIVE SAFETY TESTING FIELD

• Felix W. Frueh, PhD, US Food and Drug Administration
• Joseph F. Contrera, PhD, US Food and Drug Administration
• Donald Halbert, PhD, Iconix Biosciences
• D. Lansing Taylor, PhD, Cellumen
• Michael Milburn, PhD, Metabolon
• Patricia McGrath, MBA, Phylonix
• Paul Stroobant, PhD, HistoRx
• Peter-Jan van Doorn, MD, MBA, MDS Pharma Services
• Manfred Windisch, PhD, JSW Research

Glossary

Company Index with Web Addresses