A Comprehensive Guide to Toxicology in Nonclinical Drug Development

3rd Edition - February 11, 2024
Imprint: Academic Press
Editor: Ali S. Faqi
Language: English
Hardback ISBN:
9 7 8 - 0 - 3 2 3 - 8 5 7 0 4 - 8
eBook ISBN:
9 7 8 - 0 - 3 2 3 - 9 8 4 6 2 - 1

**Selected for 2025 Doody’s Core Titles® in Toxicology**A Comprehensive Guide to Toxicology in Nonclinical Drug Development, Third Edition is a valuable reference providing a co… Read more

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**Selected for 2025 Doody’s Core Titles® in Toxicology**

A Comprehensive Guide to Toxicology in Nonclinical Drug Development, Third Edition is a valuable reference providing a complete understanding of all aspects of nonclinical toxicology in pharmaceutical research. This updated edition has been expanded and re-developed covering a wide-range of toxicological issues in small molecules and biologics. Topics include ADME in drug discovery, pharmacokinetics, toxicokinetics, formulations, and genetic toxicology testing. The book has been thoroughly updated throughout to reflect the latest scientific advances and includes new information on antiviral drugs, anti-diabetic drugs, immunotherapy, and a discussion on post-pandemic drug development challenges and opportunities. This is an essential and practical resource for all toxicologists involved in nonclinical testing in industry, academic, and regulatory settings.

Cover image
Title page
Table of Contents
Copyright
Dedication
Contributors
Preface
Section I. Drug Discovery, Metabolism, and Toxicokinetic
Chapter 1. Introduction to Drug Development
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. Overview of ADME Science
Introduction
Drug Absorption
Drug Distribution and Excretion
Drug Metabolism
Summary and Trends
Chapter 4. Pharmacokinetics and Toxicokinetics in Drug Development
Introduction
Design of Nonclinical PK Experiments
Drug Concentration–Time Relationship
PK Analysis of Drug Concentration Time–Curves: Noncompartmental versus Compartmental PK Analysis
Noncompartmental PK Analysis Following a Single Dose
Noncompartmental PK Analysis Following Multiple Dosing and Intravenous Infusion
Compartmental PK Analysis
Predicting Human PK Based on Allometric Scaling
Toxicokinetics in Preclinical Drug Development
Physiologically Based Pharmacokinetic
Conclusions
Section II. Toxicological Studies and IND Application and First-In-Human Clinical Trial and Abuse Liability
Chapter 5. Development of Preclinical Formulations for Toxicology Studies
Introduction
In Silico, Animal Species, Sampling Volumes, and Sampling Sites
Dosing Route
Dosing Volume
Formulation Development
Physicochemical Property Characterization
Solubility Enhancement
Special Dosage Forms
Decision Tree
In Vitro Evaluation of the Performance of a Toxicological Study
Case Study
Concluding Remarks
Chapter 6. Acute, Subacute, Subchronic, and Chronic General Toxicity Testing for Preclinical Drug Development
Introduction
Regulatory Considerations for Conducting Nonclinical 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 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
Chapter 8. The Preparation of a Preclinical Dossier to Support an Investigational New Drug Application and First-In-Human Clinical Trial
Overview of the Nonclinical Toxicology Support for Clinical Trials
The Drug Development Pipeline and the FIH-Enabling Nonclinical Dossier
Presentation of the Nonclinical Package
Establishing the Clinical Safety of a New Drug Candidate
Safety Factor Considerations
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 (ICH S5 R3Annex 1 1.2.1)
Pre- and Postnatal Development Studies ICH Annex 1 1.3.1
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
Evaluation of Humoral Immunity
Evaluation of Innate Immunity
Evaluation of Complement
Evaluation of Phagocyte Function
Evaluation of NK Cell Activity
Evaluation of Immune Cell Phenotypes
Evaluation of Lymphocyte Proliferation and Cytokine Production
Evaluation of Cytokines
Evaluation of Cell-Mediated Immunity
Interpretation of Immunotoxicology Data
Evaluation of TDAR Data
Evaluation of ELISPOT and Fluorospot Data
Evaluation of Immunophenotyping Data
Evaluation of Proliferation, NK Cell, and Cell-Mediated Immunity Data
Evaluation of Complement Data
Evaluation of Cytokine Data
Evaluation of Phagocytosis Data
Immunotoxicity Testing for the Future
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
Section III. Clinical Pathology, Toxicological Pathology, Molecular Biology, and Biomarkers
Chapter 14. Clinical Pathology in Nonclinical Toxicity Studies
Introduction
Core Clinical Pathology Testing
Laboratory/Instrumentation
Overall Results Interpretation and Integration
Effects Unrelated to Test-Article Treatment
Hematology
Bone Marrow Microscopy
Coagulation
Clinical Biochemistry and Noncore Biomarkers
Urinalysis and Urine Chemistry
Additional Noncore Biomarkers
Conclusions
Chapter 15. Best Practice in Toxicologic Pathology
Introduction to Toxicologic Pathology
Preanalytical Phases—Histology Processes and Procedures
Analytical Phases—the Role of the Toxicologic Pathologist
Nonclinical Studies to Support Human Trials—Toxicologic Pathology
Spontaneous and Induced Histopathological Lesions in Animals Used in Nonclinical Studies
Conclusion
Chapter 16. Molecular Pathology: Applications in Nonclinical Drug Development
Introduction
Immunohistochemistry
Biomarkers: Best Practices for Pathology Evaluation
Digital Pathology: Overview, Approaches, and Regulatory Perspectives
Toxicogenomics
RNAscope
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
Study Design
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. Study Directors and Study Monitors in Drug Development Safety Studies
Background
Background
Study Directors
Study Monitors
Study Director Checklist
Study Monitor Checklist
Bringing in Experts
Regulations
Impact of COVID-19 Pandemic
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 Rat
The Guinea Pig
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 First-in-Human Study
Repeat-Dose Toxicology Studies Beyond First-in-Human
Immunogenicity of Monoclonal Antibodies
Immunotoxicity
Reproductive and Developmental Toxicity Evaluation
Carcinogenicity
Drug Interactions
Partnership in mAb Development
Summary
Chapter 24. Preclinical Development of Antibody–Drug Conjugates
Introduction
History of Antibody–Drug Conjugates
ADC Nomenclature
ADC Structure
Mechanism of Action
Preclinical Development of ADCs
Summary
Chapter 25. Nonclinical Safety Assessment of Cell and Gene Therapies
Introduction
CT Sources
CGT Characterization
Regulatory Framework for Nonclinical Assessment
Preclinical Study Objectives
Preclinical Study Design
Considerations for Dose and Route of Administration in CT Testing
Biodistribution
Safety Concerns Associated With CT
Concluding Remarks
Chapter 26. How Gene Editing Is Changing Drug Development
History of Gene Editing
CRISPR/Cas Technology
Gene Therapy
The Development of New Drugs
Conclusions
Section VII. Nonclinical Development of Oncogenic and Nononcogenic Drugs and Oligonucleotidebased Therapies and Vaccines
Chapter 27. Nonclinical Development of Oncology Drugs
Introduction
Types of Cancer Therapeutics
Preclinical Cancer Models and Translational Biomarkers
Pharmacokinetic and Pharmacodynamic Modeling
Toxicology Evaluation
Drug Metabolism and Pharmacokinetics
Other Considerations: Changes in Clinical Schedule, Route, or Formulation
Chapter 28. Preclinical Development of Nononcogenic Drugs (Small and Large Molecules)
Introduction
Preclinical Development of Small Molecules
Pharmacology Studies
Cardiovascular System
Central Nervous System
Respiratory System
Pharmacokinetics and Toxicokinetics
Absorption
Distribution
Metabolism
Elimination
Toxicity Studies
Safety Evaluation of Impurities and Degradants in New Drug Products
Considerations for the Conduct of Juvenile Animal Toxicity Studies
Special Toxicology Studies
Local Tolerance Studies
Preclinical Development of Biotechnology-Derived Pharmaceuticals (Large Molecules)
Preclinical Safety Testing of Biotechnology-Derived Pharmaceuticals
Pharmacodynamics (Biological Activity)
Safety Pharmacology Studies
Pharmacokinetics and Toxicokinetics
Toxicology Assessment
Selection of a Relevant Animal Species
Toxicology Studies
Chapter 29. Overview of the Nonclinical Development Strategies and Class Effects of Oligonucleotide-based Therapeutics
Introduction
Review of Pharmacological Classes of ONTs
Overview of Common Chemical Structure–Activity Relationships
Delivery and Pharmacokinetic Properties
General Strategy for Toxicology Testing of ONTs
Discovery Toxicology of ONTs
Nonspecific Class Effects of ONTs
Translation of Key Preclinical Safety Findings to Humans
Expanding Prospects for ONTs
Chapter 30. Animal Models for Infectious Disease Vaccine Development
Introduction
Adenovirus
Bacillus Anthracis
Bordetella Pertussis
Campylobacter Jejuni
Chikungunya Virus
Clostridium Tetani
Coronavirus; SARS-CoV-2
Corynebacterium Diphtheriae
Dengue Virus
Ebola Virus
Escherichia Coli
Haemophilus Influenzae Serotype B
Herpes Simplex Virus
Hepatitis A, B, and C Virus
Human Immunodeficiency Virus
Human Papilloma Virus
Influenza Virus
Japanese Encephalitis Virus
Measles Virus
Mumps Virus
Mycobacterium Tuberculosis
Neisseria Meningitides
Norovirus
Plasmodium Malaria Parasites
Poliovirus
Rabies Virus
Respiratory Syncytial Virus
Rubella Virus
Salmonella Enterica Serovar Typhi
Streptococcus Agalactiae
Streptococcus Pneumoniae
Vaccinia and Variola Viruses
Varicella Zoster Virus
Vibrio Cholerae
West Nile Virus
Yellow Fever
Yersinia Pestis
Zika Virus
Summary
Chapter 31. 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)
Section VIII. Safety Evaluation of Ocular Drugs, Botanical Products, and Medicinal Devices
Chapter 32. Safety Evaluation of Ocular Drugs
Introduction
Pharmacokinetics and Drug Disposition in the Eye
Pharmacokinetic Considerations for Large Molecules
Gene Therapy in the Eye
Practical Considerations in Assessing Ocular Safety
Ocular Immunology: Special Considerations for Biologic Therapeutics and Understanding Preclinical Findings
Factors Affecting Immunogenicity
Ocular Immunopathology
Techniques for In-Life Ocular Evaluation
Examples of Adverse Effects in the Eye
Structure and Function of the Eye
Integrated Assessment of Ocular Toxicity
Chapter 33. 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
General Regulatory Approaches
Safety Package to Support Phase III Clinical Studies and NDA of Botanical Drugs
Genetic Toxicity
Pharmacokinetics and Toxicokinetics
Safety Pharmacology Studies and Special Toxicity Studies
Developmental and Reproductive Toxicity Studies
Carcinogenicity Studies
Evidence to Ensure Therapeutic Consistency
Concluding Remarks
Chapter 34. Biocompatibility Evaluation of Medical Devices
Introduction
Evaluation of the Biological Effects of Medical Devices
Cytotoxicity
Irritation
Systemic Toxicity
Genotoxicity
Chemical Characterization and Risk Assessment
Risk Assessment of Medical Devices
Consideration of Available Data for Risk Mitigation
Section IX. Predictive Toxicology and Imaging
Chapter 35. Application of Evolving New Approach Methodologies for Chemical Safety Assessment
Introduction
New Needs of the 21st Century Require New Approaches
Scenarios for the Application of NAMs
Conclusions
Chapter 36. Use of Imaging for Preclinical Evaluation
Multimodality Imaging Modalities
Molecular Imaging
Biomarkers and Imaging Probes
Functional Molecular Imaging Techniques
Application of Molecular Imaging in Drug Development
Final 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.

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ASF Scientific Solutions, Portage, MI, USA

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A Comprehensive Guide to Toxicology in Nonclinical Drug Development

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