ADME-Enabling Technologies in Drug Design and Development

Donglu Zhang, PhD, is a Principal Scientist in Pharmaceutical Candidate Optimization at Bristol-Myers Squibb in Princeton, New Jersey. He has published seventy peer-reviewed articles, codiscovered the Mass Defect Filtering technique, and coedited two books.Sekhar Surapaneni, PhD, is Director, DMPK, at Celgene Corporation in New Jersey. He has published extensively in peer-reviewed journals and is a member of ISSX and ACS.

• FOREWORD xxiLisa A. ShipleyPREFACE xxvDonglu Zhang and Sekhar SurapaneniCONTRIBUTORS xxviiPART A ADME: OVERVIEW AND CURRENT TOPICS 11 Regulatory Drug Disposition and NDA Package Including MIST 3Sekhar Surapaneni1.1 Introduction 31.2 Nonclinical Overview 51.3 PK 51.4 Absorption 51.5 Distribution 61.6 Metabolism 71.7 Excretion 111.8 Impact of Metabolism Information on Labeling 111.9 Conclusions 12References 122 Optimal ADME Properties for Clinical Candidate and Investigational New Drug (IND) Package 15Rajinder Bhardwaj and Gamini Chandrasena2.1 Introduction 152.2 NCE and Investigational New Drug (IND) Package 162.3 ADME Optimization 172.4 ADME Optimization for CNS Drugs 232.5 Summary 24References 253 Drug Transporters in Drug Interactions and Disposition 29Imad Hanna and Ryan M. Pelis3.1 Introduction 293.2 ABC Transporters 313.3 SLC Transporters 333.4 In vitro Assays in Drug Development 393.5 Conclusions and Perspectives 45References 464 Pharmacological and Toxicological Activity of Drug Metabolites 55W. Griffith Humphreys4.1 Introduction 554.2 Assessment of Potential for Active Metabolites 564.3 Assessment of the Potential Toxicology of Metabolites 594.4 Safety Testing of Drug Metabolites 624.5 Summary 63References 635 Improving the Pharmaceutical Properties of Biologics in Drug Discovery: Unique Challenges and Enabling Solutions 67Jiwen Chen and Ashok Dongre5.1 Introduction 675.2 Pharmacokinetics 685.3 Metabolism and Disposition 705.4 Immunogenicity 715.5 Toxicity and Preclinical Assessment 745.6 Comparability 745.7 Conclusions 75References 756 Clinical Dose Estimation Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation 79Lingling Guan6.1 Introduction 796.2 Biomarkers in PK and PD 806.3 Model-Based Clinical Drug Development 836.4 First-in-Human Dose 866.5 Examples 896.6 Discussion and Conclusion 90References 937 Pharmacogenomics and Individualized Medicine 95Anthony Y.H. Lu and Qiang Ma7.1 Introduction 957.2 Individual Variability in Drug Therapy 957.3 We Are All Human Variants 967.4 Origins of Individual Variability in Drug Therapy 967.5 Genetic Polymorphism of Drug Targets 977.6 Genetic Polymorphism of Cytochrome P450s 987.7 Genetic Polymorphism of Other Drug Metabolizing Enzymes 1007.8 Genetic Polymorphism of Transporters 1007.9 Pharmacogenomics and Drug Safety 1017.10 Warfarin Pharmacogenomics: A Model for Individualized Medicine 1027.11 Can Individualized Drug Therapy Be Achieved? 1047.12 Conclusions 104Disclaimer 105Contact Information 105References 1058 Overview of Drug Metabolism and Pharmacokinetics with Applications in Drug Discovery and Development in China 109Chang-Xiao Liu8.1 Introduction 1098.2 PK–PD Translation Research in New Drug Research and Development 1098.3 Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADME/T) Studies in Drug Discovery and Early Stage of Development 1108.4 Drug Transporters in New Drug Research and Development 1118.5 Drug Metabolism and PK Studies for New Drug Research and Development 1138.6 Studies on the PK of Biotechnological Products 1178.7 Studies on the PK of TCMS 1188.8 PK and Bioavailability of Nanomaterials 123References 125PART B ADME SYSTEMS AND METHODS 1299 Technical Challenges and Recent Advances of Implementing Comprehensive ADMET Tools in Drug Discovery 131Jianling Wang and Leslie Bell9.1 Introduction 1319.2 “A” Is the First Physiological Barrier That a Drug Faces 1319.3 “M” Is Frequently Considered Prior to Distribution Due to the “First-Pass” Effect 1399.4 “D” Is Critical for Correctly Interpreting PK Data 1429.5 “E”: The Elimination of Drugs Should Not Be Ignored 1459.6 Metabolism- or Transporter-Related Safety Concerns 1469.7 Reversible CYP Inhibition 1479.8 Mechanism-Based (Time-Dependent) CYP Inhibition 1499.9 CYP Induction 1529.10 Reactive Metabolites 1539.11 Conclusion and Outlook 154Acknowledgments 155References 15510 Permeability and Transporter Models in Drug Discovery and Development 161Praveen V. Balimane, Yong-Hae Han, and Saeho Chong10.1 Introduction 16110.2 Permeability Models 16210.3 Transporter Models 16310.4 Integrated Permeability–Transporter Screening Strategy 166References 16711 Methods for Assessing Blood–Brain Barrier Penetration in Drug Discovery 169Li Di and Edward H. Kerns11.1 Introduction 16911.2 Common Methods for Assessing BBB Penetration 17011.3 Methods for Determination of Free Drug Concentration in the Brain 17011.4 Methods for BBB Permeability 17211.5 Methods for Pgp Efflux Transport 17311.6 Conclusions 174References 17412 Techniques for Determining Protein Binding in Drug Discovery and Development 177Tom Lloyd12.1 Introduction 17712.2 Overview 17812.3 Equilibrium Dialysis 17912.4 Ultracentrifugation 18012.5 Ultrafiltration 18112.6 Microdialysis 18212.7 Spectroscopy 18212.8 Chromatographic Methods 18312.9 Summary Discussion 183Acknowledgment 185References 18513 Reaction Phenotyping 189Chun Li and Nataraj Kalyanaraman13.1 Introduction 18913.2 Initial Considerations 19013.3 CYP Reaction Phenotyping 19313.4 Non-P450 Reaction Phenotyping 19913.5 UGT Conjugation Reaction Phenotyping 20113.6 Reaction Phenotyping for Other Conjugation Reactions 20413.7 Integration of Reaction Phenotyping and Prediction of DDI 20513.8 Conclusion 205References 20614 Fast and Reliable CYP Inhibition Assays 213Ming Yao, Hong Cai, and Mingshe Zhu14.1 Introduction 21314.2 CYP Inhibition Assays in Drug Discovery and Development 21514.3 HLM Reversible CYP Inhibition Assay Using Individual Substrates 21714.4 HLM RI Assay Using Multiple Substrates (Cocktail Assays) 22214.5 Time-Dependent CYP Inhibition Assay 22614.6 Summary and Future Directions 228References 23015 Tools and Strategies for the Assessment of Enzyme Induction in Drug Discovery and Development 233Adrian J. Fretland, Anshul Gupta, Peijuan Zhu, and Catherine L. Booth-Genthe15.1 Introduction 23315.2 Understanding Induction at the Gene Regulation Level 23315.3 In silico Approaches 23415.4 In vitro Approaches 23515.5 In vitro Hepatocyte and Hepatocyte-Like Models 23815.6 Experimental Techniques for the Assessment of Induction in Cell-Based Assays 23915.7 Modeling and Simulation and Assessment of Risk 24415.8 Analysis of Induction in Preclinical Species 24515.9 Additional Considerations 24515.10 Conclusion 246References 24616 Animal Models for Studying Drug Metabolizing Enzymes and Transporters 253Kevin L. Salyers and Yang Xu16.1 Introduction 25316.2 Animal Models of DMEs 25316.3 Animal Models of Drug Transporters 26316.4 Conclusions and the Path Forward 270Acknowledgments 271References 27117 Milk Excretion and Placental Transfer Studies 277Matthew Hoffmann and Adam Shilling17.1 Introduction 27717.2 Compound Characteristics That Affect Placental Transfer and Lacteal Excretion 27717.3 Study Design 28117.4 Conclusions 289References 28918 Human Bile Collection for ADME Studies 291Suresh K. Balani, Lisa J. Christopher, and Donglu Zhang18.1 Introduction 29118.2 Physiology 29118.3 Utility of the Biliary Data 29218.4 Bile Collection Techniques 29318.5 Future Scope 297Acknowledgment 297References 297PART C ANALYTICAL TECHNOLOGIES 29919 Current Technology and Limitation of LC-MS 301Cornelis E.C.A. Hop19.1 Introduction 30119.2 Sample Preparation 30219.3 Chromatography Separation 30219.4 Mass Spectrometric Analysis 30419.5 Ionization 30419.6 MS Mode versus MS/MS or MSn Mode 30519.7 Mass Spectrometers: Single and Triple Quadrupole Mass Spectrometers 30619.8 Mass Spectrometers: Three-Dimensional and Linear Ion Traps 30819.9 Mass Spectrometers: Time-of-Flight Mass Spectrometers 30819.10 Mass Spectrometers: Fourier Transform and Orbitrap Mass Spectrometers 30919.11 Role of LC-MS in Quantitative in vitro ADME Studies 30919.12 Quantitative in vivo ADME Studies 31119.13 Metabolite Identification 31219.14 Tissue Imaging by MS 31319.15 Conclusions and Future Directions 313References 31420 Application of Accurate Mass Spectrometry for Metabolite Identification 317Zhoupeng Zhang and Kaushik Mitra20.1 Introduction 31720.2 High-Resolution/Accurate Mass Spectrometers 31720.3 Postacquisition Data Processing 31820.4 Utilities of High-Resolution/Accurate Mass Spectrometry (HRMS) in Metabolite Identification 32020.5 Conclusion 328References 32921 Applications of Accelerator Mass Spectrometry (AMS) 331Xiaomin Wang, Voon Ong, and Mark Seymour21.1 Introduction 33121.2 Bioanalytical Methodology 332References 33722 Radioactivity Profiling 339Wing Wah Lam, Jose Silva, and Heng-Keang Lim22.1 Introduction 33922.2 Radioactivity Detection Methods 34022.3 AMS 34622.4 Intracavity Optogalvanic Spectroscopy 34922.5 Summary 349Acknowledgments 349References 34923 A Robust Methodology for Rapid Structure Determination of Microgram-Level Drug Metabolites by NMR Spectroscopy 353Kim A. Johnson, Stella Huang, and Yue-Zhong Shu23.1 Introduction 35323.2 Methods 35423.3 Trazodone and Its Metabolism 35523.4 Trazodone Metabolite Generation and NMR Sample Preparation 35623.5 Metabolite Characterization 35623.6 Comparison with Flow Probe and LC-NMR Methods 36123.7 Metabolite Quantification by NMR 36123.8 Conclusion 361References 36224 Supercritical Fluid Chromatography 363Jun Dai, Yingru Zhang, David B. Wang-Iverson, and Adrienne A. Tymiak24.1 Introduction 36324.2 Background 36324.3 SFC Instrumentation and General Considerations 36424.4 SFC in Drug Discovery and Development 36924.5 Future Perspective 375References 37625 Chromatographic Separation Methods 381Wenying Jian, Richard W. Edom, Zhongping (John) Lin, and Naidong Weng25.1 Introduction 38125.2 LC Separation Techniques 38325.3 Sample Preparation Techniques 38825.4 High-Speed LC-MS Analysis 39025.5 Orthogonal Separation 39425.6 Conclusions and Perspectives 395References 39626 Mass Spectrometric Imaging for Drug Distribution in Tissues 401Daniel P. Magparangalan, Timothy J. Garrett, Dieter M. Drexler, and Richard A. Yost26.1 Introduction 40126.2 MSI Instrumentation 40326.3 MSI Workfl ow 40626.4 Applications of MSI for in situ ADMET Tissue Studies 40826.5 Conclusions 413References 41427 Applications of Quantitative Whole-Body Autoradiography (QWBA) in Drug Discovery and Development 419Lifei Wang, Haizheng Hong, and Donglu Zhang27.1 Introduction 41927.2 Equipment and Materials 41927.3 Study Designs 42027.4 QWBA Experimental Procedures 42027.5 Applications of QWBA 42127.6 Limitations of QWBA 432References 433PART D NEW AND RELATED TECHNOLOGIES 43528 Genetically Modified Mouse Models in ADME Studies 437Xi-Ling Jiang and Ai-Ming Yu28.1 Introduction 43728.2 Drug Metabolizing Enzyme Genetically Modified Mouse Models 43828.3 Drug Transporter Genetically Modifi ed Mouse Models 44228.4 Xenobiotic Receptor Genetically Modified Mouse Models 44628.5 Conclusions 448References 44829 Pluripotent Stem Cell Models in Human Drug Development 455David C. Hay29.1 Introduction 45529.2 Human Drug Metabolism and Compound Attrition 45529.3 Human Hepatocyte Supply 45629.4 hESCS 45629.5 hESC HLC Differentiation 45629.6 iPSCS 45629.7 CYP P450 Expression in Stem Cell-Derived HLCs 45729.8 Tissue Culture Microenvironment 45729.9 Culture Defi nition for Deriving HLCS from Stem Cells 45729.10 Conclusion 457References 45830 Radiosynthesis for ADME Studies 461Brad D. Maxwell and Charles S. Elmore30.1 Background and General Requirements 46130.2 Radiosynthesis Strategies and Goals 46330.3 Preparation and Synthesis 46730.4 Analysis and Product Release 46930.5 Documentation 47130.6 Summary 471References 47131 Formulation Development for Preclinical in vivo Studies 473Yuan-Hon Kiang, Darren L. Reid, and Janan Jona31.1 Introduction 47331.2 Formulation Consideration for the Intravenous Route 47331.3 Formulation Consideration for the Oral, Subcutaneous, and Intraperitoneal Routes 47431.4 Special Consideration for the Intraperitoneal Route 47531.5 Solubility Enhancement 47531.6 pH Manipulation 47631.7 Cosolvents Utilization 47731.8 Complexation 47931.9 Amorphous Form Approach 47931.10 Improving the Dissolution Rate 47931.11 Formulation for Toxicology Studies 47931.12 Timing and Assessment of Physicochemical Properties 48031.13 Critical Issues with Solubility and Stability 48131.14 General and Quick Approach for Formulation Identification at the Early Discovery Stages 482References 48232 In vitro Testing of Proarrhythmic Toxicity 485Haoyu Zeng and Jiesheng Kang32.1 Objectives, Rationale, and Regulatory Compliance 48532.2 Study System and Design 48632.3 Good Laboratory Practice (GLP)-hERG Study 48932.4 Medium-Throughput Assays Using PatchXpress as a Case Study 49032.5 Nonfunctional and Functional Assays for hERG Traffi cking 49132.6 Conclusions and the Path Forward 491References 49233 Target Engagement for PK/PD Modeling and Translational Imaging Biomarkers 493Vanessa N. Barth, Elizabeth M. Joshi, and Matthew D. Silva33.1 Introduction 49333.2 Application of LC-MS/MS to Assess Target Engagement 49433.3 LC-MS/MS-Based RO Study Designs and Their Calculations 49433.4 Leveraging Target Engagement Data for Drug Discovery from an Absorption, Distribution, Metabolism, and Excretion (ADME) Perspective 49733.5 Application of LC-MS/MS to Discovery Novel Tracers 50233.6 Noninvasive Translational Imaging 50333.7 Conclusions and the Path Forward 507References 50834 Applications of iRNA Technologies in Drug Transporters and Drug Metabolizing Enzymes 513Mingxiang Liao and Cindy Q. Xia34.1 Introduction 51334.2 Experimental Designs 51434.3 Applications of RNAi in Drug Metabolizing Enzymes and Transporters 52734.4 Conclusions 538Acknowledgment 539References 539Appendix Drug Metabolizing Enzymes and Biotransformation Reactions 545Natalia Penner, Caroline Woodward, and Chandra PrakashA.1 Introduction 545A.2 Oxidative Enzymes 547A.3 Reductive Enzymes 550A.4 Hydrolytic Enzymes 551A.5 Conjugative (Phase II) DMEs 553A.6 Factors Affecting DME Activities 555A.7 Biotransformation Reactions 557A.8 Summary 561Acknowledgment 562References 562Index 567

“This book fills time needs of ADME researchers and provides a fine reference book for scientists engaged in the areas of medicinal chemistry, pharmaceutics, bioanalytical sciences, pharmacology and toxicology in academia and pharmaceutical industry.”  (British Toxicology Society, 1 July 2013)