A Comprehensive Guide to Toxicology in Nonclinical Drug Development
- 3rd Edition - February 11, 2024
- 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
A Comprehensive Guide to Toxicology in Nonclinical Drug Development, Third Edition is a valuable reference providing a complete understanding of all aspects of nonclinical toxico… Read more
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Request a sales quote- Provides updated, unique content not covered in one comprehensive resource, including chapters on stem cells, antiviral drugs, anti-diabetic drugs, and immunotherapy
- Includes the latest international guidelines for nonclinical toxicology in both small and large molecules
- Incorporates practical examples in order to illustrate day-to-day activities and expectations associated with working in nonclinical toxicology
- 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
- No. of pages: 1072
- Language: English
- Edition: 3
- Published: February 11, 2024
- Imprint: Academic Press
- Hardback ISBN: 9780323857048
- eBook ISBN: 9780323984621
AF
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.