A Comprehensive Guide to Toxicology in Preclinical Drug Development

Dedication

Foreword

Contributors

Chapter 1. Introduction

Chapter 2. ADME in Drug Discovery

Introduction

ADME

Use of Preclinical ADME Data

Two Evolving Technologies Impacting ADME in Drug Discovery

References

Chapter 3. Pharmacokinetics and Toxicokinetics

Introduction

Drug Administration and Delivery

Intravenous Administration

Absorption after Extravascular Dosing

Calculation of Exposure-Based Safety Margins

Practical Considerations

Conclusions

References

Chapter 4. Development of Preclinical Formulations for Toxicology Studies

Introduction

Animal Species, Sampling Volumes and Sampling Sites

Dosing Route

Dosing Volume

Formulation Development

Physico-Chemical Property Characterization

Solubility Enhancement

Special Dosage Forms

Decision Tree

In Vitro Evaluation of the Performance of a Toxicological Study

Case Study

Concluding Remarks

References

Chapter 5. Acute, Sub-Acute, Sub-Chronic and Chronic General Toxicity Testing for Preclinical Drug Development

Introduction

Regulatory Considerations for Conducting Preclinical Toxicology Studies

General Considerations for the Conduct of Preclinical Toxicology Studies

Study Types Used in the Assessment of General Toxicology

Special Considerations for Biopharmaceutical Safety Evaluations

Common Protocol Components of General Toxicity Assessments in GLP Studies

Final Thoughts

References

Chapter 6. Contemporary Practices in Core Safety Pharmacology Assessments

Background and Overview

Safety Pharmacology as a Regulatory Science

Temporal Application of Current Experimental Paradigms

Cardiovascular System and Models of Safety Assessment

Cardiac Ion Channels and the hERG Assay

In vivo Cardiovascular Safety Study

Respiratory System and Models of Safety Assessment

Central Nervous System and Models of Safety Assessment

Approaches to Tier I CNS Safety Evaluation

Evaluating CNS Safety

References

Chapter 7. Genetic Toxicology Testing

Introduction

The Concept of Thresholds

Genetic Toxicity Testing to Support Clinical Trials

The Sensitivity and Specificity of In vitro Assays

In vivo Core Tests

Other In vivo Tests for Genotoxicity

Additional Tests Indicating Genotoxicity

Genetox Testing Strategy: Discovery Through Development

Concluding Remarks and Future Directions

Acknowledgments

References

Chapter 8. Clinical Pathology

Introduction

Core Clinical Pathology Testing

Hematology

Cytological Evaluation of Bone Marrow

Emerging Biomarkers and Application within the Clinical Pathology Laboratory

Clinical Pathology Indicators of Target Organ Toxicity

Interpretation of Clinical Pathology Data in Preclinical Safety Studies

References

Chapter 9. Best Practice in Toxicological Pathology

Introduction

Histopathology Processes and Procedures

Histopathological Examination

Interpretation of Pathology Data and Pathology Report

Adverse and Non-Adverse Findings

Spontaneous and Induced Histopathological Lesions in Preclinical Studies

Risk Assessment

References

Suggested Further Reading for Comprehensive Toxicological Pathology

Chapter 10. Molecular Pathology: Applications in Nonclinical Drug Development

Introduction

Immunohistochemistry

Biomarkers: Best Practices for Pathology Evaluation

Digital Pathology Imaging

Toxicogenomics

MicroRNAs

Conclusion

References

Chapter 11. Infusion Toxicology and Techniques

Introduction

Preclinical Infusion Models

Regulatory Guidelines

Choosing the Appropriate Infusion Model

Infusion Best Practices

Infusion Techniques

Equipment

Background Data – Resultant Pathologies

Concluding Remarks

References

Chapter 12. The Preparation of a Preclinical Dossier to Support an Investigational New Drug (IND) Application and First-in-Human Clinical Trial

Introduction

The Drug Development Pipeline

Presentation of the Nonclinical Package

Establishing the Clinical Safety of a New Drug Candidate

Summary and Conclusions

References

Chapter 13. Developmental and Reproductive Toxicology

Overview and History of Reproductive Testing Guidelines

Study Designs

Evaluating Fertility and Reproduction

Embryo-Fetal Development

Pre- and Post-Natal Development Studies

Toxicokinetics

Developmental Toxicity Testing of Biopharmaceuticals in Rodents and Rabbits

Reproductive and Developmental Assessments in Non-human Primates

Alternative Methods Used in Reproductive and Developmental Toxicity Testing

Concluding Remarks and Future Directions

Acknowledgments

References

Chapter 14. Immunotoxicology Assessment in Drug Development

History and Current Regulatory Framework for Immunotoxicology Testing

Developmental Immunotoxicology

Evaluation of Humoral Immunity

Evaluation of Innate Immunity

Evaluation of Cell-Mediated Immunity

Interpretation of Immunotoxicology Data

Concluding Remarks and Future Directions

References

Chapter 15. Juvenile Toxicity Testing to Support Clinical Trials in the Pediatric Population

Introduction

Approaches to Study Designs

General Design Considerations

Data Interpretation

Value of Juvenile Toxicity Studies

Case Study #1 – Neonatal Swine Model for Infant Formula Testing

Case Study #2 Influence of Perinatal Metabolism and Stage of Organ Development in Rats

Acknowledgments

References

Chapter 16. Photosafety: Current Methods and Future Direction

Regulatory Status

Dosimetry

Light Sources

Spectral Absorption

Reactive Oxygen Species

The In Vitro 3T3 Neutral Red Uptake Phototoxicity Test

In Vitro Photogenotoxicity

Reconstructed Skin Epidermis Systems

General In Vivo Techniques

Evaluation of In Vivo Phototoxic Responses

The Mouse

Photocarcinogenesis

The Guinea Pig

The Rat

The Rabbit

The Pig

References

Chapter 17. Preclinical Evaluation of Carcinogenicity using the Rodent Two-Year Bioassay

Introduction

The Chronic Carcinogenicity Bioassay in Standard-Bred Rodents

References

Chapter 18. Carcinogenicity Evaluations using Genetically Engineered Animals

Introduction

Development and Validation of Genetically Engineered Mouse Models for Use in Carcinogenicity Testing

Design of Carcinogenicity Studies in Genetically Engineered Mice

Conclusions

References

Chapter 19. Current Strategies for Abuse Liability Assessment of New Chemical Entities

Introduction

Experimental Protocols

Regulatory Guidelines

Self-Administration

Drug Discrimination

Drug Dependence Liability

Identification of Discontinuation Syndrome

References

Chapter 20. Impact of Product Attributes on Preclinical Safety Evaluation

Introduction

Safety Evaluation

Safety Pharmacology

Developmental and Reproductive Toxicology

Genotoxicity

Carcinogenicity and Tumorigenicity

Immunotoxicity

Drug Interaction Assessment

First-in-Human Dose Selection

Conclusion

References

Chapter 21. Preclinical Development of Monoclonal Antibodies

Introduction

History of Antibody Therapeutics: The Discovery of Serum Therapy

Antibody Structure and Function

Nomenclature of Monoclonal Antibodies

Preclinical Development of Monoclonal Antibodies

Nonclinical Safety Evaluation/Toxicology Plans to Support the First-in-Human (FIH) Study

Dose Selection for the FIH Study

Repeat-Dose Toxicology Studies beyond FIH

Immunogenicity of Monoclonal Antibodies

Immunotoxicity

Reproductive and Developmental Toxicity Evaluation

Carcinogenicity

Drug Interactions

Partnership in mAb Development

Summary

References

Chapter 22. Preclinical Development of Non-Oncogenic Drugs (Small and Large Molecules)

Introduction

Preclinical Development of Small Molecules

Pharmacokinetics and Toxicokinetics

Toxicity Studies

Safety Evaluation of Impurities and Degradants in New Drug Products

Considerations for the Conduct of Juvenile Animal Toxicity Studies

Special Toxicology Studies

Preclinical Development of Biotechnology-Derived Pharmaceuticals (Large Molecules)

Preclinical Safety Testing of Biotechnology-Derived Pharmaceuticals

References

Chapter 23. Preclinical Development of Oncology Drugs

Introduction

Cytotoxic vs. Targeted Drugs

Pharmacology Evaluation

Translational Medicine

Pharmacokinetic and Pharmacodynamic Modeling

Toxicology Evaluation

Drug Metabolism and Pharmacokinetics (DMPK)

Other Considerations: Changes in Route or Formulation

References

Chapter 24. Safety Evaluation of Ocular Drugs

Introduction

Structure and Function of the Eye

Pharmacokinetics and Drug Disposition in the Eye

Regulatory Considerations in Ocular Safety Assessment

Practical Considerations in Assessing Ocular Safety

Techniques for In-Life Ocular Evaluation

Histopathology

Examples of Adverse Effects in the Eye

Integrated Assessment of Ocular Safety

References

Chapter 25. Preclinical Toxicology of Vaccines

Introduction to Vaccines/Adjuvants for the Prevention of Infectious Diseases

Special Topics

Toxicities Associated with Vaccines

Toxicology Studies for Vaccines (Adjuvants)

Animal Models for Vaccine Research

Routes of Vaccine Administration

Product Characterization

Pediatric Drug Development (Preclinical Safety Evaluations)

References

Chapter 26. Overview of the Nonclinical Development Strategies and Class-Effects of Oligonucleotide-Based Therapeutics

Introduction

Review of Pharmacological Classes of ONTs

General Strategy for Toxicology Testing of ONTs

Discovery Toxicology of ONTs

Non-Specific Class Effects of ONTs

Expanding Prospects for ONTs

References

Chapter 27. Nonclinical Safety Assessment of Botanical Products

Introduction to Botanical Products

Dietary Supplements

Botanical Drug Products

Chemistry, Manufacturing, and Controls Information for Botanical Drugs

Quality Control of Botanical Products

Safety Package for IND and NDA of Botanical Drugs

Botanical Products without Safety Concerns

Botanical Drugs with Safety Concerns

Safety Package to Support Phase III Clinical Studies and NDA of Botanical Drugs

General Toxicity Studies

Genetic Toxicity

Pharmacokinetics and Toxicokinetics

Safety Pharmacology Studies and Special Toxicity Studies

Developmental and Reproductive Toxicity (DART) Studies

Carcinogenicity Studies

Concluding Remarks

Acknowledgments

References

Chapter 28. Regulatory Toxicology

Introduction

History of Regulations: Why Do We Need Them?

Preventing Drug Disasters from Recurring Today: Laws and Regulations

Translating Regulations into Appropriate Scientific Data – Guidelines

ICH Harmonized (and Other) Preclinical Toxicology Guidelines

Advances in Science: Impact on Regulatory Toxicology

How Much Progress Have We Made?

Conclusions

References

Chapter 29. New Drug Regulation and Approval in China

Introduction

A Brief History of New Drug Regulation in China

New Drug Registration Laws and Regulations in China

The New Drug Registration and Approval Process in China

IND and NDA Safety Packages for Drug Registration in China

References

Chapter 30. Biostatistics for Toxicologists

Introduction

Basic Statistical Concepts

Case Studies

Discussion

References

Chapter 31. Role of Study Director and Study Monitor in Drug Development

Background

Study Directors

Study Monitors

Study Director Check List

Study Monitor Check List

Bringing in Experts

Regulations

Conclusions

References

Chapter 32. Use of Imaging for Preclinical Evaluation

Molecular Imaging Technology and Drug Development

Multimodality Imaging Techniques

Imaging Probes and Biomarkers

Functional Molecular Imaging Techniques

Single-Photon Emission Computed Tomography (SPECT)

Positron-Emission Tomography (PET)

Micro X-Ray Computed Tomography (CT)

Magnetic Resonance Imaging (MRI)/Magnetic Resonance Microscopy (MRM)

Optical Imaging

Ultrasonography

Applications of Preclinical Imaging

Remarks and Future Directions

Acknowledgments

References

Chapter 33. Predictive Toxicology: Biological Assay Platforms

Introduction

New Needs of the 21st Century Require New Approaches

A New Approach: Predictive Toxicology

Biological Profiling Platforms

Scenarios for the Application of Predictive Toxicology

Conclusions

Acknowledgments

References

Chapter 34. Toxicometabolomics: Technology and Applications

Introduction to Biomarker Discovery and Validation in Toxicology

Advantages of Metabolomics in Biomarker Discovery

Toxicometabolomic Platform Technologies

Toxicometabolomic Applications

Concluding Remarks and Future Directions

References

Chapter 35. Toxicogenomics in Preclinical Development

Introduction

Toxicogenomics

Toxicogenomic Approaches

Toxicogenomics Technologies

Data Analysis – Biostatistical Analysis of Genomic Data

Toxicogenomics in Drug Development

Examples of the Use of Toxicogenomics in Preclinical Toxicology

Idiosyncrasy

Specific Applications of Toxicogenomics

Study Design of Toxicogenomic Approaches in Preclinical Toxicology

Future Perspectives

Conclusions

References

Chapter 36. Practical Aspects of Developing In-Licensed Pharmaceutical Products: The Virtual Development Paradigm

Introduction

Disease Background/Therapeutic Hypothesis

Development History

Virtual Team

Recruitment of Key Consultants

CMC Aspects

Preclinical Development

Conclusions

References

Index