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A Comprehensive Guide to Toxicology in Preclinical Drug Development - 1st Edition - ISBN: 9780123878151, 9780123878168

A Comprehensive Guide to Toxicology in Preclinical Drug Development

1st Edition

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Editors: Ali S. Faqi
Hardcover ISBN: 9780123878151
eBook ISBN: 9780123878168
Imprint: Academic Press
Published Date: 2nd November 2012
Page Count: 1024
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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.

Key Features

  • 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.

Table of Contents




Chapter 1. Introduction

Chapter 2. ADME in Drug Discovery



Use of Preclinical ADME Data

Two Evolving Technologies Impacting ADME in Drug Discovery


Chapter 3. Pharmacokinetics and Toxicokinetics


Drug Administration and Delivery

Intravenous Administration

Absorption after Extravascular Dosing

Calculation of Exposure-Based Safety Margins

Practical Considerations



Chapter 4. Development of Preclinical Formulations for Toxicology Studies


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


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


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


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


Chapter 7. Genetic Toxicology Testing


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. Clinical Pathology


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 9. Best Practice in Toxicological Pathology


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


Suggested Further Reading for Comprehensive Toxicological Pathology

Chapter 10. Molecular Pathology: Applications in Nonclinical Drug Development



Biomarkers: Best Practices for Pathology Evaluation

Digital Pathology Imaging





Chapter 11. Infusion Toxicology and Techniques


Preclinical Infusion Models

Regulatory Guidelines

Choosing the Appropriate Infusion Model

Infusion Best Practices

Infusion Techniques


Background Data – Resultant Pathologies

Concluding Remarks


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


The Drug Development Pipeline

Presentation of the Nonclinical Package

Establishing the Clinical Safety of a New Drug Candidate

Summary and Conclusions


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


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



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


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


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



Chapter 16. Photosafety: Current Methods and Future Direction

Regulatory Status


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


The Guinea Pig

The Rat

The Rabbit

The Pig


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


The Chronic Carcinogenicity Bioassay in Standard-Bred Rodents


Chapter 18. Carcinogenicity Evaluations using Genetically Engineered Animals


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

Design of Carcinogenicity Studies in Genetically Engineered Mice



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


Experimental Protocols

Regulatory Guidelines


Drug Discrimination

Drug Dependence Liability

Identification of Discontinuation Syndrome


Chapter 20. Impact of Product Attributes on Preclinical Safety Evaluation


Safety Evaluation

Safety Pharmacology

Developmental and Reproductive Toxicology


Carcinogenicity and Tumorigenicity


Drug Interaction Assessment

First-in-Human Dose Selection



Chapter 21. Preclinical Development of Monoclonal Antibodies


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


Reproductive and Developmental Toxicity Evaluation


Drug Interactions

Partnership in mAb Development



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


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 23. Preclinical Development of Oncology Drugs


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


Chapter 24. Safety Evaluation of Ocular Drugs


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


Examples of Adverse Effects in the Eye

Integrated Assessment of Ocular Safety


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)


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


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


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



Chapter 28. Regulatory Toxicology


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?



Chapter 29. New Drug Regulation and Approval in China


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


Chapter 30. Biostatistics for Toxicologists


Basic Statistical Concepts

Case Studies



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


Study Directors

Study Monitors

Study Director Check List

Study Monitor Check List

Bringing in Experts




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


Applications of Preclinical Imaging

Remarks and Future Directions



Chapter 33. Predictive Toxicology: Biological Assay Platforms


New Needs of the 21st Century Require New Approaches

A New Approach: Predictive Toxicology

Biological Profiling Platforms

Scenarios for the Application of Predictive Toxicology




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


Chapter 35. Toxicogenomics in Preclinical Development



Toxicogenomic Approaches

Toxicogenomics Technologies

Data Analysis – Biostatistical Analysis of Genomic Data

Toxicogenomics in Drug Development

Examples of the Use of Toxicogenomics in Preclinical Toxicology


Specific Applications of Toxicogenomics

Study Design of Toxicogenomic Approaches in Preclinical Toxicology

Future Perspectives



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


Disease Background/Therapeutic Hypothesis

Development History

Virtual Team

Recruitment of Key Consultants

CMC Aspects

Preclinical Development





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© Academic Press 2013
2nd November 2012
Academic Press
Hardcover ISBN:
eBook ISBN:

About the Editor

Ali S. Faqi

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


"…a wide-ranging overview of various areas of toxicology, covering a relatively novel selection of subject areas that are not normally seen together...This book is reasonably priced…it would be a good addition to a toxicologist’s bookshelf or an Institution’s library."--BTS Newsletter, Summer 2013
"This book will be an important addition to the libraries of researchers in toxicology and related disciplines, and with its comprehensive approach to preclinical toxicology, it will be a key reference for any medical professional interested in drug development."--Journal of the American Veterinary Medicine Association, December 15, 2013
"The first new toxicology text to address both small and large molecules within the drug development process with contributions from leading scientists from around the globe is now available. Published by Elsevier, A Comprehensive Guide to Toxicology in Preclinical Drug Development covers the entire process of preclinical drug testing, beginning with investigative toxicology and includes the evaluation of the toxicologic and pharmacologic effects of new chemical entities, as well as in vitro and in vivo laboratory animal testing."--Drug Discovery Online, March 29, 2013
"Incorporating real-life case studies and examples, the book is a practical guide that outlines day-to-day activities and experiences in preclinical toxicology…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.", April 17, 2013

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