In vivo Models for Drug Discovery

This one-stop reference is the first to present the complete picture -- covering all relevant organisms, from single cells to mammals, as well as all major disease areas, including neurological disorders, cancer and infectious diseases.
Addressing the needs of the pharmaceutical industry, this unique handbook adopts a broad perspective on the use of animals in the early part of the drug development process, including regulatory rules and limitations, as well as numerous examples from real-life drug development projects.
After a general introduction to the topic, the expert contributors from research-driven pharmaceutical companies discuss the basic considerations of using animal models, including ethical issues. The main part of the book systematically surveys the most important disease areas for current drug development, from cardiovascular to endocrine disorders, and from infectious to neurological diseases. For each area, the availability of animal models for target validation, hit finding and lead profiling is reviewed, backed by numerous examples of both successes and failures among the use of animal models. The whole is rounded off with a discussion of perspectives and challenges.
Key knowledge for drug researchers in industry as well as academia.

Auteur
Jose Miguel Vela obtained his PhD at the Autonomous University of Barcelona (UAB). He was working as a faculty member engaged in both teaching and research at the Department of Cell Biology, Physiology and Immunology of the UAB. In 2003 he joined ESTEVE R&D as Head of Target Validation, was then Director of Pharmacology, and currently is the Head of Drug Discovery and Preclinical Development. Starting as a neurobiologist he progressed as a neuropharmacologist. His current research is focused on the discovery and development of new analgetics. He has authored more than 100 scientific publications and 80 patent applications.

Rafael Maldonado is Professor of Pharmacology at the University Pompeu Fabra in Barcelona (Spain), where he founded the Laboratory of Neuropharmacology. His research is focused on the study of the neurochemical basis of drug dependence and related disorders, including affective, pain and eating disorders, with a particular focus on the development of novel behavioral models. He has published over 250 scientific articles in international journals and he has been Principal Investigator for 20 years of research grants funded by the main French, Spanish, European, and USA agencies. He is also member of the editorial board of several scientific journals, and has also collaborated with public authorities and private companies in the research policy and pharmaceuticals development on drug abuse and pain.

Michel Hamon is Professor of Neuropharmacology at the University Pierre and Marie Curie in Paris (France). He founded and led a Neuropsychopharmacology Unit of the French Institute for Health and Medical Research (INSERM) at the Faculty of Medicine Pitie-Salpetriere, with the focus on neurobiological mechanisms underlying key brain functions (nociception, sleep, neurovegetative regulations) and behavioral controls by using validated animal models. He has published more than 600 scientific articles. He edited 6 books, and was president of the French Society for Neuroscience and executive officer of the European College of Neuropsychopharmacology (ECNP).

Texte du rabat
This one-stop reference presents the complete picture - covering all relevant organisms and physiological functions, from single cells to mammals, as well as all major disease areas.

This handbook adopts a broad perspective on the use of animals in the early part of the drug development process, including regulatory rules and limitations, as well as numerous examples from real-life drug development projects.

After a general introduction to the topic, the expert contributors discuss the basic considerations of using animal models, including ethical issues. The main part of the book systematically surveys the most important disease areas for current drug development, from cardiovascular to endocrine, gastro-intestinal, urogenital disorders, cancer, migraine and chronic pain, and from infectious to neuropsychiatric diseases. For each area, the availability of animal models for target validation, hit finding and lead profiling is reviewed, backed by numerous examples of both successes and failures among the use of animal models. The whole is rounded off with a discussion of perspectives and challenges.

Key knowledge for drug researchers in industry as well as academia.

Contenu

List of Contributors xix

Preface xxix

A Personal Foreword xxxi

Part I Transversal Issues Concerning Animal Models in Drug Discovery 1

1 The 3Ns of Preclinical Animal Models in Biomedical Research 3
*José Miguel Vela, Rafael Maldonado, and Michel Hamon*

1.1 First N: The Need for Use of Animal Models 3

1.2 Second N: The Need for Better Animal Models 5

1.2.1 Unbiased Design 8

1.2.2 Comprehensive Reporting 8

1.2.3 Selection of the Animal Model Based on Its Validity Attributes 9

1.2.4 Appropriate Time and Dosing 11

1.2.5 Use of Biomarkers 12

1.2.6 Use of Various Animal Models 13

1.2.7 Quantitative, Multiple, and Cross-Predictive Measurements 14

1.2.8 PharmacokineticPharmacodynamic Integration 15

1.2.9 Predefinition and Adherence to the Desired Product Profile 16

1.2.10 Comparison with Gold Standard References 18

1.2.11 Reverse Translation/Backtranslation (Bedside-to-Bench Approach) 18

1.3 Third N: The Need for 3Rs Guiding Principles 19

References 22

2 Alternative Models in Drug Discovery and Development Part I: In Silico and In Vitro Models 27
*Luz Romero and José Miguel Vela*

2.1 Introduction 27

2.2 In Silico Models 34

2.2.1 Quantitative StructureActivity Relationship 34

2.2.2 Biokinetic Modeling 37

2.2.3 Disease- and Patient-Specific In Silico Models 42

2.3 In Vitro Models 43

2.3.1 Primary Cells, Cell Lines, Immortalized Cell Lines, and Stem Cells 44

2.3.2 Advanced In Vitro Models for the Prediction of Drug Toxicity 46

2.3.3 In Vitro Tumor Models 47

References 50

3 Alternative Models in Drug Discovery and Development Part II: In Vivo Nonmammalian and Exploratory/Experimental Human Models 59
*Luz Romero and José Miguel Vela*

3.1 Introduction 59

3.2 In Vivo Nonmammalian Models 59

3.2.1 Zebrafish 61

3.2.2 D. melanogaster 66

3.2.3 C. elegans 71

3.3 In Vivo Exploratory and Experimental Human Models 74

3.3.1 Phase 0 (Exploratory Human Models): Microdosing Studies 76

3.3.2 Phase IB/IIA (Proof-of-Concept) Studies: Experimental Human Models 81

References 84

4 Ethical Issues and Regulations and Guidelines Concerning Animal Research 91
*David Sabaté*

4.1 Introduction 91

4.2 Current Use of Animals in Biomedical and Pharmaceutical Research 92

4.3 Ethical Concerns and Positions on Animal Research 93

4.4 General Principles for the Ethical Use of Animals in Research 95

4.4.1 The 3Rs Principles (Replacement, Reduction, and Refinement) 95

4.4.2 The Principle of Justification 96

4.4.3 The Principle of Responsibility 97

4.5 Regulatory Framework for Use of Animals in Research 98

4.5.1 European Union 98

4.5.2 The United States 100

4.5.3 Canada 100

4.5.4 Japan 100

4.5.5 Australia 101

4.5.6 India 101

4.5.7 China 101

4.5.8 Brazil 102

4.5.9 Countries without a Specific Legal Framework 102

Acknowledgment 102

References 102

5 Regulatory Issues: Safety and Toxicology Assessment 107
*Antonio Guzmán*

5.1 Introduction 107

5.1.1 Animal Testing 107

5.1.2 Regulatory Context 109

5.1.3 Clinical Context 109

5.2 Animal Species in Toxicology Studies 110

5.2.1 Rodents 111

5.2.2 Nonrodents 112

5.2.3 Nonconventional Animal Models 114

5.3 Toxicology Studies 114

5.3.1…