A Comprehensive Guide to Toxicology in Nonclinical Drug Development

2nd Edition - November 3, 2016

Editor: Ali S. Faqi

Hardback ISBN:

9 7 8 - 0 - 1 2 - 8 0 3 6 2 0 - 4

eBook ISBN:

9 7 8 - 0 - 1 2 - 8 0 3 6 2 1 - 1

A Comprehensive Guide to Toxicology in Nonclinical Drug Development, Second Edition, is a valuable reference designed to provide a complete understanding of all aspects of… Read more

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A Comprehensive Guide to Toxicology in Nonclinical Drug Development, Second Edition, is a valuable reference designed to provide a complete understanding of all aspects of nonclinical toxicology in the development of small molecules and biologics. This updated edition has been reorganized and expanded to include important topics such as stem cells in nonclinical toxicology, inhalation and dermal toxicology, pitfalls in drug development, biomarkers in toxicology, and more.

Thoroughly updated to reflect the latest scientific advances and with increased coverage of international regulatory guidelines, this second edition is an essential and practical resource for all toxicologists involved in nonclinical testing in industry, academic, and regulatory settings.

Dedication
List of Contributors
Foreword
Chapter 1. Introduction
Section I. Drug Discovery, Metabolism, and Pharmacokinetics
- Chapter 2. Critical Aspects of Integrated Nonclinical Drug Development: Concepts, Strategies, and Potential Pitfalls
  - Introduction
  - Target Identification and Validation
  - Principal Aspects of Preclinical Toxicology Testing
  - Phase I
  - Phase II
  - Phase III
  - Predictivity of Toxicological Findings for Human Safety
  - Postmarketing
  - Concluding Remarks
- Chapter 3. ADME in Drug Discovery
  - Introduction
  - Drug Absorption
  - Drug Distribution and Excretion
  - Drug Metabolism
  - Summary and Trends
- Chapter 4. Pharmacokinetics and Toxicokinetics
  - Introduction
  - Drug Administration and Delivery
  - Intravenous Administration
  - Absorption After Extravascular Dosing
  - Calculation of Exposure-Based Safety Margins
  - Practical Considerations
  - Conclusions
Section II. Toxicological Studies and Ind Application, and First In-Human Clinical Trial
- Chapter 5. Acute, Subacute, Subchronic, 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
  - Repeated-Dose Toxicity Studies
  - Special Considerations for Biopharmaceutical Safety Evaluations
  - Common Protocol Components of General Toxicity Assessments in GLP Studies
  - Final Thoughts
- Chapter 6. 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
- Chapter 7. 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
- Chapter 8. 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
- Chapter 9. Developmental and Reproductive Toxicology
  - Overview and History of Reproductive Testing Guidelines
  - Study Designs
  - Evaluating Fertility and Reproduction
  - Evaluation of Estrous Cycling
  - Hormonal Regulation
  - Embryo-Fetal Development
  - Pre- and Postnatal Development Studies
  - Toxicokinetics
  - Developmental Toxicity Testing of Biopharmaceuticals in Rodents and Rabbits
  - Reproductive and Developmental Assessments in Nonhuman Primates
  - Alternative Methods Used in Reproductive and Developmental Toxicity Testing
  - Concluding Remarks and Future Directions
- Chapter 10. 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
- Chapter 11. Juvenile Testing to Support Clinical Trials in Pediatric Population
  - Introduction
  - EU and FDA Pediatric Regulatory Initiatives
  - The Nonclinical Safety Guidelines
  - Study Design Consideration, Species, Age, and Endpoints
  - Testing Facility
  - Application of Juvenile Data in Risk Assessment
- Chapter 12. Preclinical Evaluation of Carcinogenicity Using Standard-Bred and Genetically Engineered Rodent Models
  - Introduction
  - Chronic Carcinogenicity Bioassays in Standard-Bred Rodents
  - Six-Month Carcinogenicity Bioassays in Genetically Engineered Mice
  - General Experimental Procedures for the Conduct of Carcinogenicity Bioassays
- Chapter 13. Current Strategies for Abuse Liability Assessment of New Chemical Entities
  - Introduction
  - Sample Size Determinations (Power)
  - Dependence Liability Methodologies
  - Sample Size Determinations for Dependence Liability Studies (Power)
  - Ancillary Parallel Behavioral Assays Sensitive to Withdrawal
Section III. Clinical Pathology, Histopathology, and Biomarkers
- Chapter 14. Clinical Pathology
  - Introduction
  - Core Clinical Pathology Testing
  - 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
- Chapter 15. Best Practice in Toxicological Pathology
  - Introduction
  - Histopathology Processes and Procedures
  - Histopathological Examination
  - Interpretation of Pathology Data and Pathology Report
  - Adverse and Nonadverse Findings
  - Spontaneous and Induced Histopathological Lesions in Preclinical Studies
  - Risk Assessment
- Chapter 16. Molecular Pathology: Applications in Nonclinical Drug Development
  - Introduction
  - Immunohistochemistry
  - Biomarkers: Best Practices for Pathology Evaluation
  - Toxicogenomics
  - MicroRNAs
  - Conclusion
- Chapter 17. Biomarkers in Nonclinical Drug Development
  - Biomarkers in Nonclinical Safety Assessment
  - Biomarker Validation, Qualification, and Application in Nonclinical Studies
  - Biomarkers of Liver Injury
  - Biomarkers of Hepatobiliary Injury
  - Renal Injury Biomarkers
  - Cardiac and Skeletal Muscle Injury Biomarkers
  - Vascular Injury Biomarkers
  - Biomarkers of the Immune System
  - Conclusion
Section IV. Biostatistics, Regulatory Toxicology, and Role of Study Directors
- Chapter 18. Biostatistics for Toxicologists
  - Introduction
  - Basic Statistical Concepts
  - Case Studies
  - Discussion
- Chapter 19. 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
  - Developing the Nonclinical Toxicology Program
  - Translating Nonclinical Data Into Clinically Useful Information—Drug Labels
  - The Opposite End of the Spectrum—Homeopathy
  - Advances in Science: Impact on Regulatory Toxicology
  - How Much Progress Have We Made?
  - Conclusions
- Chapter 20. Role of Study Director and Study Monitor in Drug Development Safety Studies
  - Introduction
  - Background
  - Study Directors
  - Study Monitors
  - Study Director Checklist
  - Study Monitor Checklist
  - Bringing in Experts
  - Regulations
  - Conclusions
Section V. Specialty Route of Administration
- Chapter 21. 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
- Chapter 22. Photosafety Assessment
  - Introduction
  - Regulatory Status
  - Photosafety Evaluation Strategy
  - Light Dosimetry
  - Light Sources
  - Spectral Absorption
  - Reactive Oxygen Species Assay
  - In Vitro 3T3 Neutral Red Uptake Phototoxicity Test
  - Reconstructed Skin Epidermis Systems
  - In Vitro Photogenotoxicity
  - General In Vivo Techniques
  - Evaluation of In Vivo Phototoxic Responses
  - The Mouse
  - The Guinea Pig
  - The Rat
  - The Rabbit
  - The Pig
Section VI. Nonclinical Development of Monoclonal Antibodies, Stem Cells, Oncogenic and Non-Oncogenic Drugs, Oligonucleotides, and Vaccines
- Chapter 23. 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 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
- Chapter 24. Nonclinical Safety Assessment of Cell-Based Therapies
  - Introduction
  - CT Sources
  - CT Characterization
  - Regulatory Framework for Nonclinical Assessment of CT
  - Preclinical Study Objectives
  - Preclinical Study Design
  - Considerations for Dose and Route of Administration in CT Testing
  - Fate of CT Postadministration (Biodistribution)
  - Safety Concerns Associated With CT
- Chapter 25. Preclinical Development of Nononcogenic 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
- Chapter 26. Preclinical Development of Oncology Drugs
  - Introduction
  - Cytotoxic Versus Targeted Drugs
  - Cancer Immunotherapy
  - Immune Checkpoint Inhibitors
  - Therapeutic Antibodies
  - Immune-Cell Therapy
  - Other Immunotherapies
  - Pharmacology Evaluation
  - Translational Medicine
  - Pharmacokinetic and Pharmacodynamic Modeling
  - Toxicology Evaluation
  - Drug Metabolism and Pharmacokinetics
  - Other Considerations: Changes in Route or Formulation
- Chapter 27. 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)
- Chapter 28. 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
  - Nonspecific Class Effects of ONTs
  - Expanding Prospects for ONTs
Section VII. Safety Evaluation of Ocular Drugs, Botanical Products, and Medicinal Devices
- Chapter 29. Safety Evaluation of Ocular Drugs
  - Introduction
  - Pharmacokinetics and Drug Disposition in the Eye
  - Pharmacokinetic Considerations for Large Molecules
  - Practical Considerations in Assessing Ocular Safety
  - Techniques for In-Life Ocular Evaluation
  - Examples of Adverse Effects in the Eye
  - Ocular Immunology: Special Considerations for Biologic Therapeutics and Understanding Preclinical Findings
  - Ocular Immunopathology
  - Structure and Function of the Eye
  - Integrated Assessment of Ocular Toxicity
- Chapter 30. Nonclinical Safety Assessment of Botanical Products
  - Introduction of Botanical Products
  - Dietary Supplements
  - Botanical Drug Products
  - Chemistry, Manufacturing, and Controls Information for Botanical Drugs
  - Quality Control for Botanical Products
  - Safety Package for Investigational New Drug (IND) and New Drug Application (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 Studies
  - Carcinogenicity Studies
  - Concluding Remarks
- Chapter 31. Biocompatibility Evaluation of Medical Devices
  - Introduction
  - Evaluation of the Biological Effects of Medical Devices
  - Cytotoxicity
  - Irritation
  - Systemic Toxicity
  - Genotoxicity
  - Chemical Characterization and Risk Assessment
Section VIII. Predictive Toxicology, Toxicometabolomics, Toxicogenomics, and Imaging
- Chapter 32. Application of Evolving Computational and Biological Platforms for Chemical Safety Assessment
  - Introduction
  - New Needs of the 21st Century Require New Approaches
  - A New Approach: Predictive Toxicology
  - Cheminformatics and Biological Profiling Platforms
  - Scenarios for the Application of Predictive Toxicology
  - Conclusions
- Chapter 33. 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
- Chapter 34. Toxicogenomics in Preclinical Development
  - Introduction
  - Toxicogenomics
  - Toxicogenomics Approaches
  - Toxicogenomics Technologies
  - Data Analysis—Biostatistical Analysis of Genomic Data
  - Toxicogenomics in Drug Development
  - Examples for the Use of Toxicogenomics in Preclinical Toxicology
  - Specific Applications of Toxicogenomics
  - Study Design of Toxicogenomics Approaches in Preclinical Toxicology
  - Future Perspectives
  - Conclusion
- Chapter 35. 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
  - Positron-Emission Tomography
  - Micro X-ray Computed Tomography
  - Magnetic Resonance Imaging/Magnetic Resonance Microscopy
  - Optical Imaging
  - Ultrasonography
  - Applications of Preclinical Imaging
  - Remarks and Future Directions
Index

Ali S. Faqi

Ali Said Faqi, DVM, PhD, DABT, ATS, is a Senior Director of Developmental and Reproductive Toxicology, a Senior Principal Scientist at MPI Research and an Adjunct Associate Professor at Wayne State University, School of Medicine, Department of OBGYN in Detroit, MI. He received his Ph.D. from the University of Leipzig in Germany in 1995 and D.V.M. from Somali National University. Dr. Faqi earned a diploma of specialization in Experimental Pharmacology from the University of Milan in Italy.

He was a postdoctoral fellow at the Institute of Clinical Pharmacology and Toxicology at the Free University of Berlin-Germany from 1996 till 1998. He worked as a Research Associate at Morehouse School of Medicine in Atlanta, Georgia and at Thomas Jefferson University in Philadelphia, Pennsylvania. Before joining MPI Research, Dr. Faqi was a Senior Scientist at Allergan Pharmaceuticals in Irvine, California and a Research Toxicologist at IIT Research Institute in Chicago, Illinois. He is a Diplomate of American Board of Toxicology (D.A.B.T.) and a Fellow of Academy of Toxicological Sciences (A.T.S.). Dr. Faqi is a member of the Editorial Board of Reproductive Toxicology Journal and ISRN Toxicology. He served as a Board of Scientific Counselors (BOSC) Computational Toxicology at the United States Environmental Protection Agency (US EPA) from September, 2009-September, 2010. He is also a member of Scientific Advisory Board of the Alzheimer's Art Quilt Initiative (AAQI).

Dr. Ali Faqi is ad-hoc scientific reviewer for the scientific journals (Regulatory Pharmacology and Toxicology, Toxicology Journal, System Biology in Reproductive Medicine, Pesticide Biochemistry and Physiology, PLoS ONE and Birth Defects Research Part B: Developmental & Reproductive Toxicology). He is a Visiting Professor at the University of Palermo, Italy. In 2009, Dr. Faqi was a guest speaker at King Fahd Medical Research Center in King Abdiaziz University, Jeddah (Saudi Arabia) where he lectured on Preclinical Toxicology.

He is a past chairman of the membership committee of the Teratology Society and a past President of Michigan Society of Toxicology. Currently, he is the chairman of the Education Committee of the Teratology Society (2012-2013) and the Vice President of Toxicologists of African Origin (2012-2013). He has published over 100 technical and scientific papers and authored and co-authored 7 book chapters.

Affiliations and expertise

ASF Scientific Solutions, Portage, MI, USA