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Contents

Chapter 1

RSC Drug DiscoHuman-based SEdited by Rober© The Royal SocPublished by th

Access to Human Cells and Tissues

1 Gerry Thomas

1.1

very Seystemst Colemiety ofe Roya

Ethics and Law Regarding Collection of HumanSamples

1 1.1.1

ries No. 4for TrananChemistl Society o

The Four Cornerstones of Ethics andBiological Samples

1

1.1.2

Legal Issues 2 1.2 Practical Issues Regarding Human Tissue

Collection and Annotation

8 1.2.1 Obtaining Tissue with Consent for Research 9 1.2.2 Accessing Material from a Diagnostic

Archive

11 1.3 Improving Access and Annotation 12

1.3.1

Access Policies 12 1.3.2 Annotation 13

1.4

Summary 14 References 14

Chapter 2

Functional Studies with Human Isolated Tissues to BetterPredict Clinical Safety and Efficacy 17 David C. Bunton

2.1

Introduction 17 2.2 Sourcing, Storing and Transporting Human Fresh

Tissues: The First Step is the Most Important

21

1slational Research

ry 2015f Chemistry, www.rsc.org

xi

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2.3

Common Experimental Approaches toInvestigations in Isolated Fresh Human Tissues 23 2.3.1 Tissue Baths and Wire Myographs 23 2.3.2 Perfusion Myographs 25 2.3.3 Organoculture Systems and Precision-Cut

Tissue Slices

25 2.3.4 Membrane Transport and Ussing Chambers:

Skin, Lung Mucosa, Gastrointestinal Tractand Glandular Tissues

28

2.4

Applications of Functional Tissues in DrugDevelopment: Safety, Efficacy and PersonalisedMedicines 29 2.4.1 Predicting Efficacy in Clinically Relevant

Human Tissues

30 2.4.2 Predicting Safety and Toxicology Risks Using

Functional Tissues

31 2.4.3 Functional Tissues and the Development of

Personalised Medicines

32 2.5 Summary 35

Acknowledgements 35

References 35

Chapter 3

Translational Research in Pharmacology and ToxicologyUsing Precision-Cut Tissue Slices 38 G. M. M. Groothuis, A. Casini, H. Meurs, and P. Olinga

3.1

Introduction 38 3.1.1 Precision-Cut Tissue Slices 38 3.1.2 Availability of Different Sources of Human

Organs and Tissues

40 3.1.3 Techniques to Prepare and Incubate

Precision-Cut Tissue Slices from VariousOrgans and Tissues

41

3.2

Human Precision-Cut Tissue Slices in ADME andToxicology 43

3.3

Application of Human Precision-Cut Tissue Slices inDisease Models 47 3.3.1 Fibrosis in Liver and Intestine 47 3.3.2 Obstructive Lung Diseases 50 3.3.3 Cancer Research 54 3.3.4 Viral Infection Research 57

3.4

Concluding Remarks 58 References 58

Contents xiii

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Chapter 4

Modelling the Human Respiratory System: Approachesfor in Vitro Safety Testing and Drug Discovery 66 Human-Derived Lung Models; The Future of ToxicologySafety Assessment Zoe Prytherch and Kelly BeruBe

4.1

Introduction 66 4.1.1 Overview of the Respiratory System 66 4.1.2 Inhalation Toxicology 67 4.1.3 Status Quo in Safety Assessment 68 4.1.4 In Vitro Toxicology 68 4.1.5 Trends and Technology Uptake 69

4.2

Current Human-Based Models of the RespiratorySystem: An Overview 70 4.2.1 Cells and Tissues 70 4.2.2 General Culture Conditions 76

4.3

Discussion 80 References 81

Chapter 5

Complex Primary Human Cell Systems for Drug Discovery 88 Ellen L. Berg and Alison O'Mahony

5.1

Introduction 88 5.1.1 Challenges of Target-Based Drug Discovery 88 5.1.2 Kinase Inhibitors – An Example Target Class 89 5.1.3 Complex Primary Human Cell Systems for

Translational Biology

90 5.2 Case Studies – Anti-Inammatory Kinase Inhibitors 95

5.2.1

JAK Kinase Inhibitors 95 5.2.2 SYK Kinase Inhibitors 101

5.3

Conclusions 105 Acknowledgements 106 References 106

Chapter 6

Human in Vitro ADMET and Prediction of HumanPharmacokinetics and Toxicity Liabilities at theDiscovery Stage 110 Katya Tsaioun

6.1

Introduction 110 6.2 The Science of ADMET 112 6.3 The ADMET Optimisation Loop 113 6.4 Impact of Early Human Pharmacokinetics

Prediction

116

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6.5

New Human ADMET Prediction Tools 117 6.5.1 The Blood-Brain Barrier Challenge 117 6.5.2 Mechanisms of Human Toxicity 121 6.5.3 The Power of Multiparametric Screening

in Toxicology

125 6.6 Bridging the Gap between in Vitro and in Vivo 126 6.7 Conclusions and Future Directions 128

References 129

Chapter 7

‘Body-on-a-Chip’ Technology and SupportingMicrouidics 132 A. S. T. Smith, C. J. Long, C. McAleer, X. Guo, M. Esch,J. M. Prot, M. L. Shuler, and J. J. Hickman

7.1

Introduction 132 7.2 Multi-Organ in Vitro Models 133 7.3 Functional Single-Organ in Vitro Models 136

7.3.1

Heart/Cardiac Tissue 137 7.3.2 Lung 137 7.3.3 Gastrointestinal (GI) Tract 139 7.3.4 Liver 141 7.3.5 Kidney 143 7.3.6 Adipose Tissue 143 7.3.7 Central Nervous System (CNS)/Peripheral

Nervous System (PNS)

144 7.3.8 Skeletal Muscle 150 7.3.9 Blood Surrogate 150

7.4

Microuidics 151 7.5 Concluding Remarks 153

Acknowledgements 153

References 153

Chapter 8

Utility of Human Stem Cells for Drug Discovery 162 Satyan Chintawar, Martin Graf, and Zameel Cader

8.1

Introduction 162 8.2 Existing Approaches to Drug Discovery 164 8.3 Advances in Human Stem Cell Technology 165

8.3.1

Embryonic Stem Cells 165 8.3.2 Reprogramming Somatic Cells 166

8.4

iPSC-Based Disease Models 167 8.4.1 iPSC-Based Neurological and Psychiatric

Disease Models

167 8.4.2 iPSC-Based Cardiovascular Disease Models 169 8.4.3 Other Examples of iPSC-Based Disease

Models

172 8.4.4 Genome Editing Tools 173

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8.5

Use of iPSCs in Drug Efficacy Assessment 173 8.5.1 Target-Based Screening versus Phenotypic

Screening

173 8.5.2 Examples of Drug Testing to Validate iPSC-

Based Models

175 8.5.3 Drug Screens on iPSC-Based Models 176

8.6

Toxicity Testing Using iPSC-Based Models 177 8.6.1 Cardiotoxicity 177 8.6.2 Hepatotoxicity 178 8.6.3 Neurotoxicity 178

8.7

Integration of iPSCs in Drug Discovery 179 8.7.1 Challenges 179 8.7.2 Future Directions 180

8.8

Emerging Resources of Diseased iPS Cell Lines 181 8.8.1 StemBANCC (Stem Cells for Biological

Assays of Novel Drugs and PredictiveToxicology)

181

8.8.2

EBiSC (European Bank for InducedPluripotent Stem Cells) 182

8.8.3

HipSci (Human Induced Pluripotent StemCells Initiative) 183

8.9

Summary 183 References 183

Chapter 9

In Silico Solutions for Predicting Efficacy and Toxicity 194 Glenn J. Myatt and Kevin P. Cross

9.1

Introduction 194 9.2 Representing Chemical Structures and

Associated Data

196 9.2.1 Overview 196 9.2.2 Chemical Representation 196 9.2.3 Biological Data Representation 199 9.2.4 Calculated Data 199

9.3

Searching Chemical Databases 199 9.4 Calculating Molecular Fragment Descriptors 201

9.4.1

Overview of Fragment Types 201 9.4.2 Predened Features 202 9.4.3 Structural Alerts 203 9.4.4 Common Chemical Scaffolds 204 9.4.5 Scaffolds Associated with Data 204

9.5

Understanding Structure–Activity or ToxicityRelationships 205 9.5.1 Overview 205 9.5.2 Classication Based on Substructures 205

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9.5.3

Clustering 205 9.5.4 Decision Trees 207

9.6

Quantitative Structure–Activity Relationship (QSAR)Modelling 208 9.6.1 Overview 208 9.6.2 Building Models 208 9.6.3 Applying Models 210 9.6.4 Model Validation 211 9.6.5 Explaining the Results 211

9.7

Regulatory in Silico Case Study 212 9.8 Prediction of Human Adverse Events Case Study 215 9.9 Conclusions 216

References 217

Chapter 10

In Silico Organ Modelling in Predicting Efficacy andSafety of New Medicines 219 Blanca Rodriguez

10.1

Introduction 219 10.2 State-of-the-Art Computational Cardiac

Electrophysiology

220 10.2.1 Single Cardiomyocyte Models 220 10.2.2 Whole Organ Heart Models 223 10.2.3 Simulating Interactions of Medicines with

Ionic Channels

226 10.3

230

Investigating Variability: Population of ModelsApproach

10.4

Validation of in Silico Models and Simulations 234 References 236

Chapter 11

Human Microdosing/Phase 0 Studies to Accelerate DrugDevelopment 241 R. Colin Garner

11.1

Introduction 241 11.2 What is Microdosing (Human Phase 0 Studies) and

Where Does it Add Value?

243 11.3 Scientic, Regulatory and Ethical Aspects of

Microdosing

244 11.3.1 Scientic Considerations 244 11.3.2 Regulatory 245 11.3.3 Ethical Considerations in Conducting

Microdose Studies

247 11.4 Analytical Technologies used for Microdosing

Studies

247 11.5 Applications of Microdosing 249

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11.5.1

Example of a Microdosing Study with SeveralMolecules and Practical Implications 249

11.5.2

Microdosing Use for Clarication ofConicts in Metabolism between in Vitroand Animal Models for Human PKPrediction 251

11.5.3

Microdosing to Assist in Determining theStarting Dose in a Phase 1 Study 251

11.6

Microdosing and Drug Targeting 252 11.7 Special Applications of Microdosing 255

11.7.1

Use in Paediatric Studies 255 11.7.2 Use of AMS in Fluxomics 257 11.7.3 Microdosing of Protein Therapeutics 257 11.7.4 Drug–Drug Interaction Studies 258 11.7.5 Absolute Bioavailability Determination 259

11.8

Conclusions 261 References 262

Subject Inde

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