The Nonhuman Primate in Nonclinical Drug Development and Safety Assessment

The Nonhuman Primate in Nonclinical Drug Development and Safety Assessment PDF

By Joerg Bluemel, Sven Korte, Emanuel Schenck and Gerhard Weinbauer

The Nonhuman Primate in Drug Development and Safety Assessment PDF is a valuable reference dedicated to compiling the latest research on nonhuman primate models in nonclinical safety assessment, regulatory toxicity testing and translational science. By covering important topics such as study planning and conduct, inter-species genetic drift, pathophysiology, animal welfare legislation, safety assessment of biologics and small molecules, immunotoxicology and much more, this book provides scientific and technical insights to help you safely and successfully use nonhuman primates in pharmaceutical toxicity testing. A comprehensive yet practical guide, this book is intended for new researchers or practicing toxicologists, toxicologic pathologists and pharmaceutical scientists working with nonhuman primates, as well as graduate students preparing for careers in this area.

  • Covers important topics such as species selection, study design, experimental methodologies, animal welfare and the 3Rs (Replace, Refine and Reduce), social housing, regulatory guidelines, comparative physiology, reproductive biology, genetic polymorphisms and more
  • Includes practical examples on techniques and methods to guide your daily practice
  • Offers a companion website with high-quality color illustrations, reference values for safety assessment and additional practical information such as study design considerations, techniques and procedures and dosing and sampling volumes

Read more: Animal Behavior and Wildlife Conservation

Table of Contents
  • I: Genetics of Nonhuman Primate Species Commonly Used in Drug Development
    • Chapter 1: Diversity and Evolutionary History of Macaques with Special Focus on Macaca mulatta and Macaca fascicularis
      • Abstract
      • Acknowledgements
      • Macaques
      • The Phylogenetic Position of Macaques Among Primates
      • Evolutionary History of Macaques
      • Taxonomic and Genetic Diversity of Rhesus and Long-Tailed Macaques
      • Conclusion
    • Chapter 2: Evolutionary History and Genetic Variation of Macaca mulatta and Macaca fascicularis
      • Abstract
      • Origin and Dispersal of Cynomolgus Macaques
      • Origin and Dispersal of Rhesus Macaques
      • Genetic Diversity in Rhesus and Cynomolgus Macaques
      • Implications of Ancestral Divergence and Disease Susceptibility
      • NHP Genomic Studies
      • Genomic Sequence Analysis and Evolutionary Implications
      • Comparing Linkage Disequilibrium between Taxa
      • Introgression During Admixture Between Two Taxa
      • Genomic Discovery of Candidate Risk Alleles
      • Functional Allele Comparison in Rhesus and Cynomolgus Macaques
      • G Protein-Coupled Receptor Gene Variation in Rhesus and Cynomolgus Macaques
      • Genetic Variation and Drug Safety Testing
      • Gene Expression Variation
      • Solute Carriers of Organic Anions Sequence Variation in Cynomolgus Macaques
      • The Macaque Cytochrome P450 Gene Family
      • Immune Response Variation as a Variable in Drug Safety Testing
      • Conclusion
    • Chapter 3: Genetic Variation of the Major Histocompatibility Complex in Macaca mulatta and Macaca fascicularis
      • Abstract
      • Acknowledgments
      • General Aspects of the Major Histocompatibility Complex
      • The MHC of M. mulatta and M. fascicularis
      • MHC Disease Associations
      • Conclusion
    • Chapter 4: Genetic Variations in the Macaca fascicularis Genome Related to Biomedical Research
      • Abstract
      • Introduction: Animal Models and Drug Testing
      • Copy Number Variations in the Genome of M. fascicularis
      • Conclusion
  • II: Comparative Physiology of Nonhuman Primate Species Used in Nonclinical Safety Assessment and Drug Development
    • Chapter 5: Basic Physiology of Macaca fascicularis
      • Abstract
      • History and Introduction
      • Appearance and Morphology
      • Hematology
      • Serum Chemistry
      • Reproduction and Development
      • Cardiovascular
      • Hepatic and Urinary
      • Other Organ Systems
      • Endemic Diseases and Susceptibility
      • Behavior
    • Chapter 6: Basic Physiology of Macaca mulatta
      • Abstract
      • General Biology
      • Gastrointestinal Tract and Nutrition
      • Cardiovascular System
      • Respiratory System
      • Neurologic System and Special Senses
      • Development and Reproduction
      • Urinary System
      • Lymphatic System
      • Endocrine System
    • Chapter 7: Basic Physiology of Callithrix jacchus
      • Abstract
      • General Biology
      • Gastrointestinal Tract and Nutrition
      • Complete Blood Count
      • Cardiovascular System
      • Respiratory System
      • Development and Reproduction
      • Conclusion
    • Chapter 8: Comparative Physiology, Growth, and Development
      • Abstract
      • Introduction
      • Comparative Genetics
      • Comparative Growth and Development
      • Comparative Cardiovascular Physiology
      • Comparative Renal Physiology
      • Comparative Respiratory Physiology
      • Neurobiology
      • Visual System
    • Chapter 9: Implications and Limitations of Reference Values and Historical Data for the Interpretation of Nonhuman Primate Toxicology Studies
      • Abstract
      • Introduction
      • Utility of Reference Intervals for Nonhuman Primate Safety Studies
      • Limitations of Reference Intervals for Safety Assessment
  • III: Pathophysiology of Nonhuman Primate Species Used in Nonclinical Safety Assessment and Drug Development
    • Chapter 10: Nonhuman Primate Diseases of Relevance in Drug Development and their Impact on the Interpretation of Study Findings
      • Abstract
      • Introduction
      • Viral Infections
      • Bacterial Infections
      • Parasitic Infections
      • Fungal Infections
      • Conclusion
    • Chapter 11: Consequences and Indicators of Test Article-Related Immune Suppression in Nonhuman Primates
      • Abstract
      • Introduction
      • Selection of the NHP as the Nonclinical Safety Species for Immunomodulatory Drugs
      • Immunologically Relevant End Points in Standard Toxicology Studies of NHPs
      • Specialized Immunologic End Points in NHPs
      • Differential Diagnosis of On-Target, Off-Target, and Stress-Related Effects on the Immune System
      • Clinically Apparent Manifestations of Immune Suppression in NHPs Observed in Nonclinical Safety Studies: Case Examples
      • Identification of a Risk for Clinically Adverse Immune Suppression: Impact on Further Development
      • Conclusion
    • Chapter 12: Toxicologic Pathology and Background Lesions of Nonhuman Primates
      • Abstract
      • Introduction
      • The Art and Practice of Toxicologic Pathology
      • Common Background Microscopic Changes in NHPs
      • Conclusion
    • Chapter 13: Nonhuman Primate Models of Human Disease
      • Abstract
      • Introduction
      • Type 2 Diabetes Mellitus, Cardiovascular Disease, and Metabolic Syndrome
      • Diseases of Aging
      • Female Reproductive Conditions
      • Immunosuppressive Conditions
      • Malaria
  • IV: The 3 Rs and Animal Welfare
    • Chapter 14: Opportunities for Implementing the 3 Rs in Drug Development and Safety Assessment Studies Using Nonhuman Primates
      • Abstract
      • Introduction
      • Study Design Considerations to Minimize Nonhuman Primate Use
      • Refinement of Husbandry and Procedures to Improve Animal Welfare and Quality of Science
    • Chapter 15: Training and Selection of (Mature) Nonhuman Primates for European Housing
      • Abstract
      • Introduction
      • Training of (Mature) Monkeys for European Housing
      • Selection of (Mature) Monkeys for European Housing
  • V: The Role of Nonhuman Primates in Safety Assessment/regulatory Toxicology
    • Chapter 16: Nonclinical Toxicology Testing Strategies and Applicable International Regulatory Guidelines for Using Nonhuman Primates in the Development of Biotherapeutics
      • Abstract
      • Introduction
      • Species of NHPs Used in Nonclinical Toxicity Studies
      • Overview of Nonclinical Toxicity Testing Strategy Using NHPs and Applicable International Regulatory Guidelines
      • Species Selection
      • In Vivo Pharmacology/Toxicology Studies
      • Considerations for Safety Pharmacology Assessment
      • Considerations for Developmental and Reproductive Toxicity Testing
      • Other Considerations for Using NHPs in Nonclinical Testing Programs
      • Conclusion
    • Chapter 17: Alternatives to the Use of Nonhuman Primates in Regulatory Toxicology
      • Abstract
      • Introduction
      • Conventional Nonrodent Species as Alternatives to NHPs
      • Conventional Rodent Species as Alternatives to NHPs
      • Genetically Modified Rodent or Nonrodent Species as Alternatives to NHPs
      • Specific Animal Models for Targets Only Present in Humans/Human Disease
      • Alternative Lower-Order Species
      • Omission of Regulatory Toxicity Animal Studies If No Suitable Models Exist (Alternatives to In Vivo Testing)
  • VI: Translational Aspects for the Use of Nonhuman Primates in Drug Development
    • Chapter 18: Pharmacokinetics of Human Therapeutics Characterized in Nonhuman Primates
      • Abstract
      • Nonhuman Primate Pharmacokinetic Study Designs
      • NHP PK Study Results
      • Determinants for PK in NHPs
      • Other Special PK Studies Using NHPs
      • PK Analysis of Data Obtained from NHPs
      • Species Difference and Prediction for Human PK
  • VII: Nonhuman Primate-specific Aspects of Standard Toxicology Studies
    • Chapter 19: Advantages and Limitations of Commonly Used Nonhuman Primate Species in Research and Development of Biopharmaceuticals
      • Abstract
      • Introduction
      • Use of NHPs in Research and Development
      • Evaluation of Reproductive and Developmental Toxicity
      • Evaluation of Immune Functions
      • Conclusion
    • Chapter 20: Nonhuman Primate Health Screening During Acclimation/Prestudy Conditioning
      • Abstract
      • Abbreviations
      • Introduction
      • Animal Sourcing
      • Qualification of Animals at the Source
      • Quarantine of Animals in the Source Country
      • Transportation to the Test Facility
      • Quarantine in the Receiving Country
      • Acclimation
      • Study Selection
      • Socialization
      • Summary of Animal Sourcing and Acclimation
    • Chapter 21: Study Design Considerations, Technical Procedural Aspects, Scheduling, and Dosing Sampling Volumes
      • Abstract
      • Introduction
      • Animal Welfare, Care, and Use
      • Applicable Guidelines and Regulations
      • Justification of the Test System
    • Chapter 22: Functional Assessments in Nonhuman Primate Toxicology Studies to Support Drug Development
      • Abstract
      • Acknowledgements
      • Introduction
      • Application to Specific Organ Functions
      • Conclusion
    • Chapter 23: Considering the Use of Callithrix jacchus
      • Abstract
      • Introduction
      • Evolutionary Origin of the Common Marmoset
      • Consequences of Phylogenetic Distance
      • Use of Marmosets in Reproductive and Regenerative Research
      • Practical Considerations
      • Use of Marmosets in Toxicological and Pharmacological Studies
    • Chapter 24: Considerations on Immunogenicity
      • Abstract
      • Introduction
      • Effect on PK and PD
      • Impact on Safety
      • Strategies to Minimize Effect
      • Methods to Measure Antibodies Against Protein Therapeutics
      • Conclusion
  • VIII: Special Toxicity Testing with Nonhuman Primates
    • Chapter 25: Developmental and Reproductive Toxicity Testing
      • Abstract
      • Introduction
      • Which NHP Model?
      • Fertility and Early Embryonic Development Study
      • Embryo-Fetal Development
      • Prenatal and Postnatal Development
      • Group Size and “3 R” Considerations
      • Relevance of ADAs
      • Placenta: Target Organ and Transport
      • Data Interpretation Challenges Associated with Background Changes in Pregnant NHPs
      • Conclusion
    • Chapter 26: Juvenile Animal Studies and Experience
      • Abstract
      • Introduction and Regulatory Considerations
      • The Use of Nonhuman Primates for Juvenile Toxicity Testing
      • Organ Systems that Are Well Developed in Macaques at Birth or by 6 Months of Age
      • Organ Systems that Show Significant Development Beyond 6 Months of Age
      • Rationale for Not Conducting a Nonclinical Study Using NHPs
      • Rationale for Conducting a Nonclinical Study in NHPs
      • Conclusion
    • Chapter 27: Immunotoxicology Testing of Monoclonal Antibodies in Macaca fascicularis: From Manufacturing to Preclinical Studies
      • Abstract
      • Immunotoxicology Regulatory Considerations
      • Product- and Process-Related Factors and Immunogenicity
      • State-of-the-Art Immunotoxicology Testing Preclinical Study Designs
      • Developmental Immunotoxicology Testing
    • Chapter 28: Ophthalmological Investigations in Toxicity Studies
      • Abstract
      • Introduction
      • General Considerations
    • Chapter 29: The Use of Nonhuman Primates in Cardiovascular Safety Assessment
      • Abstract
      • Acknowledgements
      • Introduction
      • Basic Cardiovascular Physiology
      • Cardiovascular Evaluation Approaches and Methods
      • Conclusion
    • Chapter 30: Respiratory Function Measurements in Nonhuman Primates
      • Abstract
      • Introduction
      • Strategy for Respiratory Function Assessment
      • Methodologies for Assessing Respiratory Functions
    • Chapter 31: Central Nervous System Assessment in Nonhuman Primates: Behavioral Assessment, Neurological (Electroencephalography, Nerve Conduction), Abuse Liability, and Cognitive Assessment
      • Abstract
      • Observation/General Behavior
      • Electrophysiological Assessment
      • Cognitive Assessment
      • Abuse Liability Potential
      • Conclusion
    • Chapter 32: Skeletal Assessments in the Nonhuman Primate
      • Abstract
      • Introduction to Skeletal Assessments in the Nonhuman Primate NHPs
      • NHP Bone Morphology and Physiology
      • Bone Densitometry
      • Bone Biomechanics
      • The Role of Biomarkers in Skeletal Assessment
      • Bone Histology and Histomorphometry
      • Implementing Skeletal Assessments in Drug Development Programs
    • Chapter 33: Considerations for Special Administration Techniques
      • Abstract
      • Introduction
      • Major Considerations
      • Considerations in Practice
      • Conclusion
  • IX: Future Trends in Primate Toxicology
    • Chapter 34: Considerations Regarding the Future Use of Nonhuman Primates to Support the Clinical Development of Biopharmaceuticals
      • Abstract
      • Introduction
      • Background
      • Regulatory Guidance
      • Improving Predictive Value
      • Species Selection
      • Study Design: General Toxicity
      • Reproductive/Developmental Toxicity
      • Immunogenicity
      • Product Class-Specific Considerations
      • Disease-Specific Considerations
      • Potential Impact of Scientific Innovation on the Use of NHPs
      • Conclusion
    • Chapter 35: Gaps and Future Challenges
  • Index

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