ADME-Enabling Technologies in Drug Design and Development
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"This book fills time needs of ADME researchers andprovides a fine reference book for scientists engaged in the areasof medicinal chemistry, pharmaceutics, bioanalytical sciences,pharmacology and toxicology in academia and pharmaceuticalindustry." (British Toxicology Society, 1 July2013)More details
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FOREWORD xxi
Lisa A. Shipley
PREFACE xxv
Donglu Zhang and Sekhar Surapaneni
CONTRIBUTORS xxvii
PART A ADME: OVERVIEW AND CURRENT TOPICS 1
1 Regulatory Drug Disposition and NDA Package Including MIST 3
Sekhar Surapaneni
1.1 Introduction 3
1.2 Nonclinical Overview 5
1.3 PK 5
1.4 Absorption 5
1.5 Distribution 6
1.6 Metabolism 7
1.7 Excretion 11
1.8 Impact of Metabolism Information on Labeling 11
1.9 Conclusions 12
References 12
2 Optimal ADME Properties for Clinical Candidate and Investigational New Drug (IND) Package 15
Rajinder Bhardwaj and Gamini Chandrasena
2.1 Introduction 15
2.2 NCE and Investigational New Drug (IND) Package 16
2.3 ADME Optimization 17
2.4 ADME Optimization for CNS Drugs 23
2.5 Summary 24
References 25
3 Drug Transporters in Drug Interactions and Disposition 29
Imad Hanna and Ryan M. Pelis
3.1 Introduction 29
3.2 ABC Transporters 31
3.3 SLC Transporters 33
3.4 In vitro Assays in Drug Development 39
3.5 Conclusions and Perspectives 45
References 46
4 Pharmacological and Toxicological Activity of Drug Metabolites 55
W. Griffith Humphreys
4.1 Introduction 55
4.2 Assessment of Potential for Active Metabolites 56
4.3 Assessment of the Potential Toxicology of Metabolites 59
4.4 Safety Testing of Drug Metabolites 62
4.5 Summary 63
References 63
5 Improving the Pharmaceutical Properties of Biologics in Drug Discovery: Unique Challenges and Enabling Solutions 67
Jiwen Chen and Ashok Dongre
5.1 Introduction 67
5.2 Pharmacokinetics 68
5.3 Metabolism and Disposition 70
5.4 Immunogenicity 71
5.5 Toxicity and Preclinical Assessment 74
5.6 Comparability 74
5.7 Conclusions 75
References 75
6 Clinical Dose Estimation Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation 79
Lingling Guan
6.1 Introduction 79
6.2 Biomarkers in PK and PD 80
6.3 Model-Based Clinical Drug Development 83
6.4 First-in-Human Dose 86
6.5 Examples 89
6.6 Discussion and Conclusion 90
References 93
7 Pharmacogenomics and Individualized Medicine 95
Anthony Y.H. Lu and Qiang Ma
7.1 Introduction 95
7.2 Individual Variability in Drug Therapy 95
7.3 We Are All Human Variants 96
7.4 Origins of Individual Variability in Drug Therapy 96
7.5 Genetic Polymorphism of Drug Targets 97
7.6 Genetic Polymorphism of Cytochrome P450s 98
7.7 Genetic Polymorphism of Other Drug Metabolizing Enzymes 100
7.8 Genetic Polymorphism of Transporters 100
7.9 Pharmacogenomics and Drug Safety 101
7.10 Warfarin Pharmacogenomics: A Model for Individualized Medicine 102
7.11 Can Individualized Drug Therapy Be Achieved? 104
7.12 Conclusions 104
Disclaimer 105
Contact Information 105
References 105
8 Overview of Drug Metabolism and Pharmacokinetics with Applications in Drug Discovery and Development in China 109
Chang-Xiao Liu
8.1 Introduction 109
8.2 PK-PD Translation Research in New Drug Research and Development 109
8.3 Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADME/T) Studies in Drug Discovery and Early Stage of Development 110
8.4 Drug Transporters in New Drug Research and Development 111
8.5 Drug Metabolism and PK Studies for New Drug Research and Development 113
8.6 Studies on the PK of Biotechnological Products 117
8.7 Studies on the PK of TCMS 118
8.8 PK and Bioavailability of Nanomaterials 123
References 125
PART B ADME SYSTEMS AND METHODS 129
9 Technical Challenges and Recent Advances of Implementing Comprehensive ADMET Tools in Drug Discovery 131
Jianling Wang and Leslie Bell
9.1 Introduction 131
9.2 "A" Is the First Physiological Barrier That a Drug Faces 131
9.3 "M" Is Frequently Considered Prior to Distribution Due to the "First-Pass" Effect 139
9.4 "D" Is Critical for Correctly Interpreting PK Data 142
9.5 "E": The Elimination of Drugs Should Not Be Ignored 145
9.6 Metabolism- or Transporter-Related Safety Concerns 146
9.7 Reversible CYP Inhibition 147
9.8 Mechanism-Based (Time-Dependent) CYP Inhibition 149
9.9 CYP Induction 152
9.10 Reactive Metabolites 153
9.11 Conclusion and Outlook 154
Acknowledgments 155
References 155
10 Permeability and Transporter Models in Drug Discovery and Development 161
Praveen V. Balimane, Yong-Hae Han, and Saeho Chong
10.1 Introduction 161
10.2 Permeability Models 162
10.3 Transporter Models 163
10.4 Integrated Permeability-Transporter Screening Strategy 166
References 167
11 Methods for Assessing Blood-Brain Barrier Penetration in Drug Discovery 169
Li Di and Edward H. Kerns
11.1 Introduction 169
11.2 Common Methods for Assessing BBB Penetration 170
11.3 Methods for Determination of Free Drug Concentration in the Brain 170
11.4 Methods for BBB Permeability 172
11.5 Methods for Pgp Efflux Transport 173
11.6 Conclusions 174
References 174
12 Techniques for Determining Protein Binding in Drug Discovery and Development 177
Tom Lloyd
12.1 Introduction 177
12.2 Overview 178
12.3 Equilibrium Dialysis 179
12.4 Ultracentrifugation 180
12.5 Ultrafiltration 181
12.6 Microdialysis 182
12.7 Spectroscopy 182
12.8 Chromatographic Methods 183
12.9 Summary Discussion 183
Acknowledgment 185
References 185
13 Reaction Phenotyping 189
Chun Li and Nataraj Kalyanaraman
13.1 Introduction 189
13.2 Initial Considerations 190
13.3 CYP Reaction Phenotyping 193
13.4 Non-P450 Reaction Phenotyping 199
13.5 UGT Conjugation Reaction Phenotyping 201
13.6 Reaction Phenotyping for Other Conjugation Reactions 204
13.7 Integration of Reaction Phenotyping and Prediction of DDI 205
13.8 Conclusion 205
References 206
14 Fast and Reliable CYP Inhibition Assays 213
Ming Yao, Hong Cai, and Mingshe Zhu
14.1 Introduction 213
14.2 CYP Inhibition Assays in Drug Discovery and Development 215
14.3 HLM Reversible CYP Inhibition Assay Using Individual Substrates 217
14.4 HLM RI Assay Using Multiple Substrates (Cocktail Assays) 222
14.5 Time-Dependent CYP Inhibition Assay 226
14.6 Summary and Future Directions 228
References 230
15 Tools and Strategies for the Assessment of Enzyme Induction in Drug Discovery and Development 233
Adrian J. Fretland, Anshul Gupta, Peijuan Zhu, and Catherine L. Booth-Genthe
15.1 Introduction 233
15.2 Understanding Induction at the Gene Regulation Level 233
15.3 In silico Approaches 234
15.4 In vitro Approaches 235
15.5 In vitro Hepatocyte and Hepatocyte-Like Models 238
15.6 Experimental Techniques for the Assessment of Induction in Cell-Based Assays 239
15.7 Modeling and Simulation and Assessment of Risk 244
15.8 Analysis of Induction in Preclinical Species 245
15.9 Additional Considerations 245
15.10 Conclusion 246
References 246
16 Animal Models for Studying Drug Metabolizing Enzymes and Transporters 253
Kevin L. Salyers and Yang Xu
16.1 Introduction 253
16.2 Animal Models of DMEs 253
16.3 Animal Models of Drug Transporters 263
16.4 Conclusions and the Path Forward 270
Acknowledgments 271
References 271
17 Milk Excretion and Placental Transfer Studies 277
Matthew Hoffmann and Adam Shilling
17.1 Introduction 277
17.2 Compound Characteristics That Affect Placental Transfer and Lacteal Excretion 277
17.3 Study Design 281
17.4 Conclusions 289
References 289
18 Human Bile Collection for ADME Studies 291
Suresh K. Balani, Lisa J. Christopher, and Donglu Zhang
18.1 Introduction 291
18.2 Physiology 291
18.3 Utility of the Biliary Data 292
18.4 Bile Collection Techniques 293
18.5 Future Scope 297
Acknowledgment 297
References 297
PART C ANALYTICAL TECHNOLOGIES 299
19 Current Technology and Limitation of LC-MS 301
Cornelis E.C.A. Hop
19.1 Introduction 301
19.2 Sample Preparation 302
19.3 Chromatography Separation 302
19.4 Mass Spectrometric Analysis 304
19.5 Ionization 304
19.6 MS Mode versus MS/MS or MSn Mode 305
19.7 Mass Spectrometers: Single and Triple Quadrupole Mass Spectrometers 306
19.8 Mass Spectrometers: Three-Dimensional and Linear Ion Traps 308
19.9 Mass Spectrometers: Time-of-Flight Mass Spectrometers 308
19.10 Mass Spectrometers: Fourier Transform and Orbitrap Mass Spectrometers 309
19.11 Role of LC-MS in Quantitative in vitro ADME Studies 309
19.12 Quantitative in vivo ADME Studies 311
19.13 Metabolite Identification 312
19.14 Tissue Imaging by MS 313
19.15 Conclusions and Future Directions 313
References 314
20 Application of Accurate Mass Spectrometry for Metabolite Identification 317
Zhoupeng Zhang and Kaushik Mitra
20.1 Introduction 317
20.2 High-Resolution/Accurate Mass Spectrometers 317
20.3 Postacquisition Data Processing 318
20.4 Utilities of High-Resolution/Accurate Mass Spectrometry (HRMS) in Metabolite Identification 320
20.5 Conclusion 328
References 329
21 Applications of Accelerator Mass Spectrometry (AMS) 331
Xiaomin Wang, Voon Ong, and Mark Seymour
21.1 Introduction 331
21.2 Bioanalytical Methodology 332
References 337
22 Radioactivity Profiling 339
Wing Wah Lam, Jose Silva, and Heng-Keang Lim
22.1 Introduction 339
22.2 Radioactivity Detection Methods 340
22.3 AMS 346
22.4 Intracavity Optogalvanic Spectroscopy 349
22.5 Summary 349
Acknowledgments 349
References 349
23 A Robust Methodology for Rapid Structure Determination of Microgram-Level Drug Metabolites by NMR Spectroscopy 353
Kim A. Johnson, Stella Huang, and Yue-Zhong Shu
23.1 Introduction 353
23.2 Methods 354
23.3 Trazodone and Its Metabolism 355
23.4 Trazodone Metabolite Generation and NMR Sample Preparation 356
23.5 Metabolite Characterization 356
23.6 Comparison with Flow Probe and LC-NMR Methods 361
23.7 Metabolite Quantification by NMR 361
23.8 Conclusion 361
References 362
24 Supercritical Fluid Chromatography 363
Jun Dai, Yingru Zhang, David B. Wang-Iverson, and Adrienne A. Tymiak
24.1 Introduction 363
24.2 Background 363
24.3 SFC Instrumentation and General Considerations 364
24.4 SFC in Drug Discovery and Development 369
24.5 Future Perspective 375
References 376
25 Chromatographic Separation Methods 381
Wenying Jian, Richard W. Edom, Zhongping (John) Lin, and Naidong Weng
25.1 Introduction 381
25.2 LC Separation Techniques 383
25.3 Sample Preparation Techniques 388
25.4 High-Speed LC-MS Analysis 390
25.5 Orthogonal Separation 394
25.6 Conclusions and Perspectives 395
References 396
26 Mass Spectrometric Imaging for Drug Distribution in Tissues 401
Daniel P. Magparangalan, Timothy J. Garrett, Dieter M. Drexler, and Richard A. Yost
26.1 Introduction 401
26.2 MSI Instrumentation 403
26.3 MSI Workfl ow 406
26.4 Applications of MSI for in situ ADMET Tissue Studies 408
26.5 Conclusions 413
References 414
27 Applications of Quantitative Whole-Body Autoradiography (QWBA) in Drug Discovery and Development 419
Lifei Wang, Haizheng Hong, and Donglu Zhang
27.1 Introduction 419
27.2 Equipment and Materials 419
27.3 Study Designs 420
27.4 QWBA Experimental Procedures 420
27.5 Applications of QWBA 421
27.6 Limitations of QWBA 432
References 433
PART D NEW AND RELATED TECHNOLOGIES 435
28 Genetically Modified Mouse Models in ADME Studies 437
Xi-Ling Jiang and Ai-Ming Yu
28.1 Introduction 437
28.2 Drug Metabolizing Enzyme Genetically Modified Mouse Models 438
28.3 Drug Transporter Genetically Modifi ed Mouse Models 442
28.4 Xenobiotic Receptor Genetically Modified Mouse Models 446
28.5 Conclusions 448
References 448
29 Pluripotent Stem Cell Models in Human Drug Development 455
David C. Hay
29.1 Introduction 455
29.2 Human Drug Metabolism and Compound Attrition 455
29.3 Human Hepatocyte Supply 456
29.4 hESCS 456
29.5 hESC HLC Differentiation 456
29.6 iPSCS 456
29.7 CYP P450 Expression in Stem Cell-Derived HLCs 457
29.8 Tissue Culture Microenvironment 457
29.9 Culture Defi nition for Deriving HLCS from Stem Cells 457
29.10 Conclusion 457
References 458
30 Radiosynthesis for ADME Studies 461
Brad D. Maxwell and Charles S. Elmore
30.1 Background and General Requirements 461
30.2 Radiosynthesis Strategies and Goals 463
30.3 Preparation and Synthesis 467
30.4 Analysis and Product Release 469
30.5 Documentation 471
30.6 Summary 471
References 471
31 Formulation Development for Preclinical in vivo Studies 473
Yuan-Hon Kiang, Darren L. Reid, and Janan Jona
31.1 Introduction 473
31.2 Formulation Consideration for the Intravenous Route 473
31.3 Formulation Consideration for the Oral, Subcutaneous, and Intraperitoneal Routes 474
31.4 Special Consideration for the Intraperitoneal Route 475
31.5 Solubility Enhancement 475
31.6 pH Manipulation 476
31.7 Cosolvents Utilization 477
31.8 Complexation 479
31.9 Amorphous Form Approach 479
31.10 Improving the Dissolution Rate 479
31.11 Formulation for Toxicology Studies 479
31.12 Timing and Assessment of Physicochemical Properties 480
31.13 Critical Issues with Solubility and Stability 481
31.14 General and Quick Approach for Formulation Identification at the Early Discovery Stages 482
References 482
32 In vitro Testing of Proarrhythmic Toxicity 485
Haoyu Zeng and Jiesheng Kang
32.1 Objectives, Rationale, and Regulatory Compliance 485
32.2 Study System and Design 486
32.3 Good Laboratory Practice (GLP)-hERG Study 489
32.4 Medium-Throughput Assays Using PatchXpress as a Case Study 490
32.5 Nonfunctional and Functional Assays for hERG Traffi cking 491
32.6 Conclusions and the Path Forward 491
References 492
33 Target Engagement for PK/PD Modeling and Translational Imaging Biomarkers 493
Vanessa N. Barth, Elizabeth M. Joshi, and Matthew D. Silva
33.1 Introduction 493
33.2 Application of LC-MS/MS to Assess Target Engagement 494
33.3 LC-MS/MS-Based RO Study Designs and Their Calculations 494
33.4 Leveraging Target Engagement Data for Drug Discovery from an Absorption, Distribution, Metabolism, and Excretion (ADME) Perspective 497
33.5 Application of LC-MS/MS to Discovery Novel Tracers 502
33.6 Noninvasive Translational Imaging 503
33.7 Conclusions and the Path Forward 507
References 508
34 Applications of iRNA Technologies in Drug Transporters and Drug Metabolizing Enzymes 513
Mingxiang Liao and Cindy Q. Xia
34.1 Introduction 513
34.2 Experimental Designs 514
34.3 Applications of RNAi in Drug Metabolizing Enzymes and Transporters 527
34.4 Conclusions 538
Acknowledgment 539
References 539
Appendix Drug Metabolizing Enzymes and Biotransformation Reactions 545
Natalia Penner, Caroline Woodward, and Chandra Prakash
A.1 Introduction 545
A.2 Oxidative Enzymes 547
A.3 Reductive Enzymes 550
A.4 Hydrolytic Enzymes 551
A.5 Conjugative (Phase II) DMEs 553
A.6 Factors Affecting DME Activities 555
A.7 Biotransformation Reactions 557
A.8 Summary 561
Acknowledgment 562
References 562
Index 567
