[RSC Drug Discovery] Human-based Systems for Translational Research || Contents

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<ul><li><p>Dow</p><p>nloa</p><p>ded </p><p>on 0</p><p>8/12</p><p>/201</p><p>4 17</p><p>:09:</p><p>19. </p><p>Publ</p><p>ishe</p><p>d on</p><p> 08 </p><p>Dec</p><p>embe</p><p>r 20</p><p>14 o</p><p>n ht</p><p>tp://</p><p>pubs</p><p>.rsc</p><p>.org</p><p> | do</p><p>i:10.</p><p>1039</p><p>/978</p><p>1782</p><p>6201</p><p>36-F</p><p>P011ContentsChapter 1RSC Drug DiscoHuman-based SEdited by Rober The Royal SocPublished by thAccess to Human Cells and Tissues 1</p><p>Gerry Thomas1.1very Seystemst Colemiety ofe RoyaEthics and Law Regarding Collection of HumanSamples 1</p><p>1.1.1ries No. 4for TrananChemistl Society oThe Four Cornerstones of Ethics andBiological Samples 11.1.2 Legal Issues 2</p><p>1.2 Practical Issues Regarding Human Tissue</p><p>Collection and Annotation 8</p><p>1.2.1 Obtaining Tissue with Consent for Research 9</p><p>1.2.2 Accessing Material from a Diagnostic</p><p>Archive 11</p><p>1.3 Improving Access and Annotation 121.3.1 Access Policies 12</p><p>1.3.2 Annotation 131.4 Summary 14</p><p>References 14Chapter 2 Functional Studies with Human Isolated Tissues to BetterPredict Clinical Safety and Efficacy 17</p><p>David C. Bunton2.1 Introduction 17</p><p>2.2 Sourcing, Storing and Transporting Human Fresh</p><p>Tissues: The First Step is the Most Important 211slational Research</p><p>ry 2015f Chemistry, www.rsc.org</p><p>xi</p></li><li><p>xii Contents</p><p>Dow</p><p>nloa</p><p>ded </p><p>on 0</p><p>8/12</p><p>/201</p><p>4 17</p><p>:09:</p><p>19. </p><p>Publ</p><p>ishe</p><p>d on</p><p> 08 </p><p>Dec</p><p>embe</p><p>r 20</p><p>14 o</p><p>n ht</p><p>tp://</p><p>pubs</p><p>.rsc</p><p>.org</p><p> | do</p><p>i:10.</p><p>1039</p><p>/978</p><p>1782</p><p>6201</p><p>36-F</p><p>P011</p><p>View Online2.3 Common Experimental Approaches toInvestigations in Isolated Fresh Human Tissues 23</p><p>2.3.1 Tissue Baths and Wire Myographs 23</p><p>2.3.2 Perfusion Myographs 25</p><p>2.3.3 Organoculture Systems and Precision-Cut</p><p>Tissue Slices 25</p><p>2.3.4 Membrane Transport and Ussing Chambers:</p><p>Skin, Lung Mucosa, Gastrointestinal Tractand Glandular Tissues 282.4 Applications of Functional Tissues in DrugDevelopment: Safety, Efficacy and PersonalisedMedicines 29</p><p>2.4.1 Predicting Efficacy in Clinically Relevant</p><p>Human Tissues 30</p><p>2.4.2 Predicting Safety and Toxicology Risks Using</p><p>Functional Tissues 31</p><p>2.4.3 Functional Tissues and the Development of</p><p>Personalised Medicines 32</p><p>2.5 Summary 35Acknowledgements 35</p><p>References 35Chapter 3 Translational Research in Pharmacology and ToxicologyUsing Precision-Cut Tissue Slices 38</p><p>G. M. M. Groothuis, A. Casini, H. Meurs, and P. Olinga3.1 Introduction 38</p><p>3.1.1 Precision-Cut Tissue Slices 38</p><p>3.1.2 Availability of Different Sources of Human</p><p>Organs and Tissues 40</p><p>3.1.3 Techniques to Prepare and Incubate</p><p>Precision-Cut Tissue Slices from VariousOrgans and Tissues 413.2 Human Precision-Cut Tissue Slices in ADME andToxicology 433.3 Application of Human Precision-Cut Tissue Slices inDisease Models 47</p><p>3.3.1 Fibrosis in Liver and Intestine 47</p><p>3.3.2 Obstructive Lung Diseases 50</p><p>3.3.3 Cancer Research 54</p><p>3.3.4 Viral Infection Research 573.4 Concluding Remarks 58</p><p>References 58</p><p>http://dx.doi.org/10.1039/9781782620136-fp011</p></li><li><p>Contents xiii</p><p>Dow</p><p>nloa</p><p>ded </p><p>on 0</p><p>8/12</p><p>/201</p><p>4 17</p><p>:09:</p><p>19. </p><p>Publ</p><p>ishe</p><p>d on</p><p> 08 </p><p>Dec</p><p>embe</p><p>r 20</p><p>14 o</p><p>n ht</p><p>tp://</p><p>pubs</p><p>.rsc</p><p>.org</p><p> | do</p><p>i:10.</p><p>1039</p><p>/978</p><p>1782</p><p>6201</p><p>36-F</p><p>P011</p><p>View OnlineChapter 4 Modelling the Human Respiratory System: Approachesfor in Vitro Safety Testing and Drug Discovery 66</p><p>Human-Derived Lung Models; The Future of ToxicologySafety Assessment</p><p>Zoe Prytherch and Kelly BeruBe4.1 Introduction 66</p><p>4.1.1 Overview of the Respiratory System 66</p><p>4.1.2 Inhalation Toxicology 67</p><p>4.1.3 Status Quo in Safety Assessment 68</p><p>4.1.4 In Vitro Toxicology 68</p><p>4.1.5 Trends and Technology Uptake 694.2 Current Human-Based Models of the RespiratorySystem: An Overview 70</p><p>4.2.1 Cells and Tissues 70</p><p>4.2.2 General Culture Conditions 764.3 Discussion 80</p><p>References 81Chapter 5 Complex Primary Human Cell Systems for Drug Discovery 88</p><p>Ellen L. Berg and Alison O'Mahony5.1 Introduction 88</p><p>5.1.1 Challenges of Target-Based Drug Discovery 88</p><p>5.1.2 Kinase Inhibitors An Example Target Class 89</p><p>5.1.3 Complex Primary Human Cell Systems for</p><p>Translational Biology 90</p><p>5.2 Case Studies Anti-Inammatory Kinase Inhibitors 955.2.1 JAK Kinase Inhibitors 95</p><p>5.2.2 SYK Kinase Inhibitors 1015.3 Conclusions 105</p><p>Acknowledgements 106</p><p>References 106Chapter 6 Human in Vitro ADMET and Prediction of HumanPharmacokinetics and Toxicity Liabilities at theDiscovery Stage 110</p><p>Katya Tsaioun6.1 Introduction 110</p><p>6.2 The Science of ADMET 112</p><p>6.3 The ADMET Optimisation Loop 113</p><p>6.4 Impact of Early Human Pharmacokinetics</p><p>Prediction 116</p><p>http://dx.doi.org/10.1039/9781782620136-fp011</p></li><li><p>xiv Contents</p><p>Dow</p><p>nloa</p><p>ded </p><p>on 0</p><p>8/12</p><p>/201</p><p>4 17</p><p>:09:</p><p>19. </p><p>Publ</p><p>ishe</p><p>d on</p><p> 08 </p><p>Dec</p><p>embe</p><p>r 20</p><p>14 o</p><p>n ht</p><p>tp://</p><p>pubs</p><p>.rsc</p><p>.org</p><p> | do</p><p>i:10.</p><p>1039</p><p>/978</p><p>1782</p><p>6201</p><p>36-F</p><p>P011</p><p>View Online6.5 New Human ADMET Prediction Tools 117</p><p>6.5.1 The Blood-Brain Barrier Challenge 117</p><p>6.5.2 Mechanisms of Human Toxicity 121</p><p>6.5.3 The Power of Multiparametric Screening</p><p>in Toxicology 125</p><p>6.6 Bridging the Gap between in Vitro and in Vivo 126</p><p>6.7 Conclusions and Future Directions 128References 129Chapter 7 Body-on-a-Chip Technology and SupportingMicrouidics 132</p><p>A. S. T. Smith, C. J. Long, C. McAleer, X. Guo, M. Esch,J. M. Prot, M. L. Shuler, and J. J. Hickman7.1 Introduction 132</p><p>7.2 Multi-Organ in Vitro Models 133</p><p>7.3 Functional Single-Organ in Vitro Models 1367.3.1 Heart/Cardiac Tissue 137</p><p>7.3.2 Lung 137</p><p>7.3.3 Gastrointestinal (GI) Tract 139</p><p>7.3.4 Liver 141</p><p>7.3.5 Kidney 143</p><p>7.3.6 Adipose Tissue 143</p><p>7.3.7 Central Nervous System (CNS)/Peripheral</p><p>Nervous System (PNS) 144</p><p>7.3.8 Skeletal Muscle 150</p><p>7.3.9 Blood Surrogate 1507.4 Microuidics 151</p><p>7.5 Concluding Remarks 153Acknowledgements 153</p><p>References 153Chapter 8 Utility of Human Stem Cells for Drug Discovery 162</p><p>Satyan Chintawar, Martin Graf, and Zameel Cader8.1 Introduction 162</p><p>8.2 Existing Approaches to Drug Discovery 164</p><p>8.3 Advances in Human Stem Cell Technology 1658.3.1 Embryonic Stem Cells 165</p><p>8.3.2 Reprogramming Somatic Cells 1668.4 iPSC-Based Disease Models 167</p><p>8.4.1 iPSC-Based Neurological and Psychiatric</p><p>Disease Models 167</p><p>8.4.2 iPSC-Based Cardiovascular Disease Models 169</p><p>8.4.3 Other Examples of iPSC-Based Disease</p><p>Models 172</p><p>8.4.4 Genome Editing Tools 173</p><p>http://dx.doi.org/10.1039/9781782620136-fp011</p></li><li><p>Contents xv</p><p>Dow</p><p>nloa</p><p>ded </p><p>on 0</p><p>8/12</p><p>/201</p><p>4 17</p><p>:09:</p><p>19. </p><p>Publ</p><p>ishe</p><p>d on</p><p> 08 </p><p>Dec</p><p>embe</p><p>r 20</p><p>14 o</p><p>n ht</p><p>tp://</p><p>pubs</p><p>.rsc</p><p>.org</p><p> | do</p><p>i:10.</p><p>1039</p><p>/978</p><p>1782</p><p>6201</p><p>36-F</p><p>P011</p><p>View Online8.5 Use of iPSCs in Drug Efficacy Assessment 173</p><p>8.5.1 Target-Based Screening versus Phenotypic</p><p>Screening 173</p><p>8.5.2 Examples of Drug Testing to Validate iPSC-</p><p>Based Models 175</p><p>8.5.3 Drug Screens on iPSC-Based Models 1768.6 Toxicity Testing Using iPSC-Based Models 177</p><p>8.6.1 Cardiotoxicity 177</p><p>8.6.2 Hepatotoxicity 178</p><p>8.6.3 Neurotoxicity 1788.7 Integration of iPSCs in Drug Discovery 179</p><p>8.7.1 Challenges 179</p><p>8.7.2 Future Directions 1808.8 Emerging Resources of Diseased iPS Cell Lines 181</p><p>8.8.1 StemBANCC (Stem Cells for Biological</p><p>Assays of Novel Drugs and PredictiveToxicology) 1818.8.2 EBiSC (European Bank for InducedPluripotent Stem Cells) 1828.8.3 HipSci (Human Induced Pluripotent StemCells Initiative) 1838.9 Summary 183</p><p>References 183Chapter 9 In Silico Solutions for Predicting Efficacy and Toxicity 194</p><p>Glenn J. Myatt and Kevin P. Cross9.1 Introduction 194</p><p>9.2 Representing Chemical Structures and</p><p>Associated Data 196</p><p>9.2.1 Overview 196</p><p>9.2.2 Chemical Representation 196</p><p>9.2.3 Biological Data Representation 199</p><p>9.2.4 Calculated Data 1999.3 Searching Chemical Databases 199</p><p>9.4 Calculating Molecular Fragment Descriptors 2019.4.1 Overview of Fragment Types 201</p><p>9.4.2 Predened Features 202</p><p>9.4.3 Structural Alerts 203</p><p>9.4.4 Common Chemical Scaffolds 204</p><p>9.4.5 Scaffolds Associated with Data 2049.5 Understanding StructureActivity or ToxicityRelationships 205</p><p>9.5.1 Overview 205</p><p>9.5.2 Classication Based on Substructures 205</p><p>http://dx.doi.org/10.1039/9781782620136-fp011</p></li><li><p>xvi Contents</p><p>Dow</p><p>nloa</p><p>ded </p><p>on 0</p><p>8/12</p><p>/201</p><p>4 17</p><p>:09:</p><p>19. </p><p>Publ</p><p>ishe</p><p>d on</p><p> 08 </p><p>Dec</p><p>embe</p><p>r 20</p><p>14 o</p><p>n ht</p><p>tp://</p><p>pubs</p><p>.rsc</p><p>.org</p><p> | do</p><p>i:10.</p><p>1039</p><p>/978</p><p>1782</p><p>6201</p><p>36-F</p><p>P011</p><p>View Online9.5.3 Clustering 205</p><p>9.5.4 Decision Trees 2079.6 Quantitative StructureActivity Relationship (QSAR)Modelling 208</p><p>9.6.1 Overview 208</p><p>9.6.2 Building Models 208</p><p>9.6.3 Applying Models 210</p><p>9.6.4 Model Validation 211</p><p>9.6.5 Explaining the Results 2119.7 Regulatory in Silico Case Study 212</p><p>9.8 Prediction of Human Adverse Events Case Study 215</p><p>9.9 Conclusions 216References 217Chapter 10 In Silico Organ Modelling in Predicting Efficacy andSafety of New Medicines 219</p><p>Blanca Rodriguez10.1 Introduction 219</p><p>10.2 State-of-the-Art Computational Cardiac</p><p>Electrophysiology 220</p><p>10.2.1 Single Cardiomyocyte Models 220</p><p>10.2.2 Whole Organ Heart Models 223</p><p>10.2.3 Simulating Interactions of Medicines with</p><p>Ionic Channels 226</p><p>10.3230</p><p>Investigating Variability: Population of ModelsApproach10.4 Validation of in Silico Models and Simulations 234</p><p>References 236Chapter 11 Human Microdosing/Phase 0 Studies to Accelerate DrugDevelopment 241</p><p>R. Colin Garner11.1 Introduction 241</p><p>11.2 What is Microdosing (Human Phase 0 Studies) and</p><p>Where Does it Add Value? 243</p><p>11.3 Scientic, Regulatory and Ethical Aspects of</p><p>Microdosing 244</p><p>11.3.1 Scientic Considerations 244</p><p>11.3.2 Regulatory 245</p><p>11.3.3 Ethical Considerations in Conducting</p><p>Microdose Studies 247</p><p>11.4 Analytical Technologies used for Microdosing</p><p>Studies 247</p><p>11.5 Applications of Microdosing 249</p><p>http://dx.doi.org/10.1039/9781782620136-fp011</p></li><li><p>Contents xvii</p><p>Dow</p><p>nloa</p><p>ded </p><p>on 0</p><p>8/12</p><p>/201</p><p>4 17</p><p>:09:</p><p>19. </p><p>Publ</p><p>ishe</p><p>d on</p><p> 08 </p><p>Dec</p><p>embe</p><p>r 20</p><p>14 o</p><p>n ht</p><p>tp://</p><p>pubs</p><p>.rsc</p><p>.org</p><p> | do</p><p>i:10.</p><p>1039</p><p>/978</p><p>1782</p><p>6201</p><p>36-F</p><p>P011</p><p>View Online11.5.1 Example of a Microdosing Study with SeveralMolecules and Practical Implications 24911.5.2 Microdosing Use for Clarication ofConicts in Metabolism between in Vitroand Animal Models for Human PKPrediction 25111.5.3 Microdosing to Assist in Determining theStarting Dose in a Phase 1 Study 25111.6 Microdosing and Drug Targeting 252</p><p>11.7 Special Applications of Microdosing 25511.7.1 Use in Paediatric Studies 255</p><p>11.7.2 Use of AMS in Fluxomics 257</p><p>11.7.3 Microdosing of Protein Therapeutics 257</p><p>11.7.4 DrugDrug Interaction Studies 258</p><p>11.7.5 Absolute Bioavailability Determination 25911.8 Conclusions 261</p><p>References 262Subject Index 267</p><p>http://dx.doi.org/10.1039/9781782620136-fp011</p></li><li><p>Dow</p><p>nloa</p><p>ded </p><p>on 0</p><p>8/12</p><p>/201</p><p>4 17</p><p>:09:</p><p>19. </p><p>Publ</p><p>ishe</p><p>d on</p><p> 08 </p><p>Dec</p><p>embe</p><p>r 20</p><p>14 o</p><p>n ht</p><p>tp://</p><p>pubs</p><p>.rsc</p><p>.org</p><p> | do</p><p>i:10.</p><p>1039</p><p>/978</p><p>1782</p><p>6201</p><p>36-F</p><p>P011</p><p>View Online</p><p>http://dx.doi.org/10.1039/9781782620136-fp011</p><p>Contents</p></li></ul>

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