A Comprehensive Guide to Toxicology in Preclinical Drug Development
- 1st Edition - November 2, 2012
- Editor: Ali S. Faqi
- Language: English
- Paperback ISBN:9 7 8 - 0 - 1 2 - 8 1 0 0 5 3 - 0
- Hardback ISBN:9 7 8 - 0 - 1 2 - 3 8 7 8 1 5 - 1
- eBook ISBN:9 7 8 - 0 - 1 2 - 3 8 7 8 1 6 - 8
A Comprehensive Guide to Toxicology in Preclinical Drug Development is a resource for toxicologists in industry and regulatory settings, as well as directors working in contract… Read more
A Comprehensive Guide to Toxicology in Preclinical Drug Development is a resource for toxicologists in industry and regulatory settings, as well as directors working in contract resource organizations, who need a thorough understanding of the drug development process. Incorporating real-life case studies and examples, the book is a practical guide that outlines day-to-day activities and experiences in preclinical toxicology. This multi-contributed reference provides a detailed picture of the complex and highly interrelated activities of preclinical toxicology in both small molecules and biologics. The book discusses discovery toxicology and the international guidelines for safety evaluation, and presents traditional and nontraditional toxicology models. Chapters cover development of vaccines, oncology drugs, botanic drugs, monoclonal antibodies, and more, as well as study development and personnel, the role of imaging in preclinical evaluation, and supporting materials for IND applications.
By incorporating the latest research in this area and featuring practical scenarios, this reference is a complete and actionable guide to all aspects of preclinical drug testing.
- Chapters written by world-renowned contributors who are experts in their fields
- Includes the latest research in preclinical drug testing and international guidelines
- Covers preclinical toxicology in small molecules and biologics in one single source
The primary audience includes practicing toxicologists and recent graduates in toxicology who are working in or thinking about working in the pharmaceutical industry. This book will also be valuable for study directors working in contract research organizations (CRO) and toxicologists working for regulatory agencies across the world.
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
- Edition: 1
- Published: November 2, 2012
- Language: English
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.
Affiliations and expertise
ASF Scientific Solutions, Portage, MI, USARead A Comprehensive Guide to Toxicology in Preclinical Drug Development on ScienceDirect