Drug discovery and development

✍ Scribed by O'Donnell, James J

• Publisher: CRC Press
• Year: 2020
• Tongue: English
• Leaves: 697
• Edition: Third edition
• Category: Library

✦ Synopsis

"The Process of New Drug Discovery and Development, Third Edition presents up-to-date scientific information for maximizing the ability of a multidisciplinary research team to discover and bring new drugs to the marketplace. It explores many scientific advances in new drug discovery and development for areas such as screening technologies, biotechnology approaches, and evaluation of efficacy and safety of drug candidates through pre-clinical testing. This book also greatly expands the focus on the clinical pharmacology, regulatory, and business aspects of bringing new drugs to the market and offers coverage of essential topics for companies involved in drug development. Historical perspectives and predicted trends are also provided"--

✦ Table of Contents

Cover......Page 1
Half Title......Page 2
Title Page......Page 4
Copyright Page......Page 5
Dedication......Page 6
Contents......Page 8
Acknowledgments......Page 12
Introduction to the First Edition (1992)......Page 14
Introduction to the Second Edition (2006)......Page 18
Editors......Page 24
Contributors......Page 26
Chapter 1 Introduction to Drug Discovery and Development......Page 30
Chapter 3. Innovation in Drug Development: Perspectives of a Venture Capitalist......Page 33
Chapter 6. Bio-targeted Nanomaterials for Theranostic Applications......Page 34
Chapter 9. Probiotics in the World: “Bugs as Drugs.”......Page 35
Chapter 12. New Trends in Pharmacological and Pharmaceutical Profiling......Page 36
Chapter 16. Safety Pharmacology: Past, Present, and Future......Page 37
Chapter 19. Academic Research Enterprise......Page 38
Chapter 23. Drug Repurposing: Academic Clinician Research Endeavors......Page 39
Chapter 25. Orphan Drug Development and Regulations......Page 40
Chapter 28. Pharmacy Compounding Regulations......Page 41
SECTION I: Overview......Page 44
2.1 Introduction......Page 46
2.2 Drugs from Plants......Page 47
2.3 Synthetic Biology......Page 48
2.4 Biotechnology, Genomics, and Proteomics......Page 50
2.5 Gene Therapy......Page 52
2.6 The Developers......Page 53
2.8 Academicians and Entrepreneurs......Page 54
2.9 Government, Regulation, and Drug Development......Page 56
2.10 Government Research......Page 57
2.11 The FDA Regulators......Page 58
2.12 The Academic and Clinical Investigator......Page 60
References......Page 61
3.1 Introduction......Page 62
3.2.2 Two-Dimensional Phenotypic Models (hESC and iPSC)......Page 65
3.2.4 Genetically Engineered Phenotypic Models......Page 66
3.3.1 Challenges in Funding Tools, Platforms, and Disease Models......Page 67
3.3.2 Company Incubation Models......Page 68
3.3.4 Insourcing from Pharma/Megarounds......Page 69
References......Page 70
SECTION II: Drug Discovery......Page 74
4.1 Introduction to High-Throughput Screening and Drug Discovery......Page 76
4.2 Target Identification......Page 77
4.4 Automated versus Nonautomated Drug Discovery......Page 78
4.5 Assay Optimization for HTS......Page 80
4.6 HTS Process Overview......Page 81
4.8 Assay Implementation......Page 83
4.10 Hit to Lead......Page 84
4.11 Informatics......Page 85
4.12 Modulating Biological Responses: Agonists, Antagonists, Inverse Agonists, PAMS, and NAMS......Page 86
4.14 How Are Results Determined?......Page 87
4.15 Medicinal Chemistry......Page 91
4.17 Preclinical Development......Page 93
4.19 New Frontiers in HTS......Page 94
References......Page 96
5.1 Introduction......Page 100
5.2.1 Assembly Strategies......Page 101
5.2.2 Encoding Molecules with DNA......Page 102
5.2.3 On-DNA Organic Synthesis......Page 106
5.3.1 Screening Protocols......Page 109
5.3.2 Data Analysis......Page 110
5.4.2 The Effect of Library Size......Page 113
5.5.2 Targeting Challenging Proteins......Page 114
5.5.3 Portable Protein Binders......Page 116
References......Page 117
6.1 Introduction......Page 128
6.2.1 Cancer......Page 129
6.2.2 Inflammatory Bowel Disease (IBD)......Page 132
6.2.3 Diabetes......Page 135
6.2.4 Ocular Diseases......Page 137
6.2.5 Cardiovascular Diseases......Page 139
6.3 Conclusion......Page 141
References......Page 142
Chapter 7 The Development of Adoptive T-Cell Immunotherapies for Cancer: Challenges and Prospects......Page 148
7.1.3 Adoptive T-Cell Therapy......Page 149
7.2.1 T Cell Biology......Page 150
7.2.3 Engineered T Cells and TCRs......Page 151
7.2.4 Chimeric Antigen Receptors (CARs)......Page 152
7.2.6 Targets for T-Cell Immunotherapies......Page 154
7.3 Translational Challenges of T-Cell Therapies: Concept to Clinic......Page 155
7.4.2 Production of Viral Vectors......Page 156
7.4.3 Cell Processing......Page 158
7.4.4 Analytics and Quality Control......Page 159
7.5 Clinical Development and Safety......Page 160
7.5.1 Cytokine Release Syndrome......Page 162
7.5.2 Neurotoxicity......Page 163
7.5.4 Survival of the Fittest......Page 164
7.5.6 Solid Tumors......Page 166
7.6.2 Cell Switch Systems......Page 167
References......Page 168
8.1 Introduction......Page 174
8.2.2 Adapting a Defense System in Bacteria to a Genome-Editing Tool in Eukaryotic Cells......Page 175
8.3.3 Gene Silencing via CRISPRi......Page 177
8.3.4 Gene Activation via CRISPRa......Page 178
8.4 CRISPR/Cas9 Screens for Drug Target Discovery......Page 179
8.4.1 LOF Screens Using CRISPR KO and CRISPRi......Page 180
8.4.3 In Vivo CRISPR Screens......Page 182
8.5 Limitations of CRISPR/Cas9 and Strategies for Improvement......Page 183
Disclaimer......Page 184
References......Page 185
9.1 Introduction......Page 190
9.2 The Human Microbiome......Page 191
9.3 Probiotics Foundations......Page 193
9.4 Microbiome Methods......Page 196
9.5 Lactobacilli......Page 198
9.6 Bifidobacteria......Page 200
9.7 What’s Next?......Page 203
References......Page 204
Chapter 10 Discovery and Early Development of the Next-Generation ALK Inhibitor, Lorlatinib (18): Agent for Non–Small-Cell Lung Cancer......Page 214
10.1 Introduction......Page 215
10.2 Discovery and Development of Crizotinib (1)......Page 216
10.3.1 Efficacy Against ALK-Resistance Mutants......Page 218
10.3.3 Overcoming ROS1-Resistance Mutations......Page 219
10.4 Second-Generation ALK Inhibitors......Page 220
10.5 Laboratory Objectives......Page 221
10.6 Acyclic Inhibitors: Design of PF-06439015 (5)......Page 222
10.7 The Challenge of Balancing Properties: Acyclics......Page 224
10.8.1 Opportunities and Challenges......Page 225
10.8.3 Amide-Linked Macrocycles......Page 227
10.9 Development of a Selectivity Strategy for CNS Penetration......Page 229
10.9.1 Targeting H-5 in the ATP-Binding Pocket......Page 230
10.9.2 The Benzylic Methyl Substituent: Encounters with Atropisomerism......Page 231
10.10 Synthesis of Lorlatinib (18)......Page 235
10.11 Accessing the CNS: PET Studies......Page 237
10.12 Revisiting Laboratory Objectives......Page 239
Acknowledgments......Page 242
References......Page 243
SECTION III: Drug Development......Page 250
Chapter 11 Integrated Drug Product Development: From Lead Candidate Selection to Life-Cycle Management......Page 252
11.1 Introduction......Page 253
11.2 Developability Assessment......Page 254
11.2.2 Screening for Druggability or Developability......Page 255
11.2.2.2 High-Throughput Screening (HTS) Methods......Page 256
11.2.2.3 In-Depth Physicochemical Profiling......Page 257
11.3 Overview of Dosage-Form Development and Process Scale-Up......Page 258
11.4.1.1 Dissociation Constant......Page 259
11.4.1.3 Solution Stability Studies......Page 260
11.4.2.2 Salt-Form Selection......Page 261
11.4.2.3 Co-Crystal Formation......Page 262
11.4.2.4 Polymorphism......Page 263
11.4.2.6 Drug-Excipient Interactions......Page 264
11.4.2.7 Powder Properties of Drug Substance......Page 265
11.5 Biopharmaceutical Considerations in Dosage-Form Design......Page 266
11.5.1.2 Dissolution......Page 267
11.5.2.1 Assessment of In Vivo Performance......Page 268
11.6 Biopharmaceutics Risk Assessment Roadmap (BioRAM): A Patient-Centric Drug Development Approach......Page 269
11.7 Clinical Formulation Development: Clinical Trial Materials......Page 271
11.7.1 Phase I Clinical Trial Material......Page 272
11.7.2 Phase II Clinical Trial Material......Page 273
11.7.3 Phase III Clinical Trial Material......Page 274
11.8.1 Parenteral Systems......Page 276
11.9 Drug-Delivery Systems......Page 277
11.10 Product Life-Cycle Management......Page 280
11.11.1 Quality by Design......Page 281
11.11.3 Continuous Processing......Page 282
11.12 Summary......Page 283
References......Page 284
Chapter 12 New Trends in Pharmacological and Pharmaceutical Profiling......Page 292
12.2.1 Understanding the Causes of Drug Failures......Page 293
12.2.3 The Regulatory Drive for Safe Medicines......Page 294
12.2.4 Benefit to Drug Discovery and Development......Page 295
12.3.1 Strategy......Page 297
12.3.2.1 Radioligand-Binding Assays......Page 298
12.3.2.2 Functional In Vitro Assays......Page 299
12.3.2.3 Comparative Assay Formats......Page 300
12.3.2.4 Complex Assay Systems......Page 301
12.4 Impact of Pharmacological Profiling: Data Interpretation and Risk Assessment......Page 302
12.4.2 Therapeutic Profile and Patient Population......Page 304
12.4.3 Integrated Risk Assessment (In Vitro to In Vivo)......Page 305
12.5 Physicochemical Properties and In Silico Pharmacological Profiling......Page 306
12.5.1 Predicting Bioavailability......Page 307
12.5.2 In Silico Pharmacological Profiling......Page 310
12.5.3 In Silico Prediction of hERG Inhibition and Cardiotoxicity......Page 311
12.7 Concluding Remarks......Page 312
References......Page 313
Chapter 13 Pharmacokinetics–Pharmacodynamics in New Drug Development......Page 320
13.1.1 Background......Page 321
13.1.2 The Exposure–Response Relationship......Page 323
13.1.3 Biomarkers......Page 326
13.2.1 Introduction......Page 328
13.2.1.1 Assumptions in Pharmacokinetic/Pharmacodynamic Modeling......Page 329
13.2.2.1 Compartment Pharmacokinetic Modeling......Page 330
13.2.2.2 Physiologically Based Pharmacokinetic (PBPK) Studies......Page 333
13.2.2.4 Deconvolution Techniques......Page 337
13.2.2.5 Population Pharmacokinetics......Page 339
13.2.2.6 Pharmacokinetics in Disease States......Page 341
13.2.2.7 Computational Support......Page 344
13.2.2.8 Concentration–Response Relationships......Page 345
13.2.3.1 The Hill Model......Page 347
13.2.3.2 The Receptor Theory Model......Page 348
13.2.4 The Hysteresis Loop Phenomenon......Page 349
13.2.5 The Effect-Compartment Model......Page 350
13.2.6 The Indirect Action Models......Page 352
13.3 Examples......Page 353
13.4 Conclusions and Recommendations......Page 354
References......Page 355
14.1 Introduction......Page 362
14.2 Caco-2 Cells as an Intestinal Permeability Model......Page 363
14.2.1 Caco-2 Cell Culture......Page 364
14.2.2 Caco-2 Permeability Assay......Page 365
14.2.4 Inter-Laboratory Variability in Caco-2 Permeability Measurements......Page 366
14.3 Use of Caco-2 Cells in Drug Discovery......Page 367
14.4.1 General......Page 368
14.4.2 Drug Delivery......Page 369
14.4.3 Formulation Development......Page 370
14.5 Mechanistic Studies with Caco-2 Cells......Page 371
14.6.1 Biopharmaceutics Classification System......Page 373
14.6.2 Membrane Transporters and Transporter-Mediated Drug–Drug Interactions (IH)......Page 375
14.6.3 P/D Chamber, IDAS1, and IDAS2 Systems for Simultaneous Assessment of Drug Dissolution and Permeation In Vitro......Page 376
14.7 Role of Caco-2 Cells in In Silico Prediction of Drug Absorption......Page 378
Abbreviations......Page 380
References......Page 381
15.1 Introduction......Page 388
15.2.1 History and Evolution of the US Food and Drug Administration......Page 389
15.2.2 Regulation of Drugs by the FDA in the United States......Page 390
15.2.3 Regulation of Drugs in the European Union......Page 391
15.2.5 International Harmonization Conference......Page 393
15.3 Preclinical Toxicology Testing......Page 394
15.3.2 Dose Selection and Routes of Administration......Page 395
15.4.1 Acute/Dose-Range–Finding Toxicity Studies......Page 397
15.5.1 Subacute Toxicity Studies (2–4 Weeks)......Page 398
15.5.2 Subchronic Toxicity Studies (90 Days/13 Weeks)......Page 399
15.5.3 Chronic Toxicity Studies (6–12 Months)......Page 400
References......Page 402
Chapter 16 Safety Pharmacology: Past, Present, and Future......Page 404
16.1.1 Safety-Related Drug Attrition......Page 405
16.2.1 Regulatory Requirements......Page 409
16.2.2 Drivers Influencing the Approach to Safety Pharmacology......Page 411
16.3 Definition and Objectives of Safety Pharmacology Studies......Page 412
16.4.1.2 General Considerations and Principles......Page 413
16.4.2.1 Cardiovascular System......Page 416
16.4.2.3 Central Nervous System......Page 422
16.4.3.1 Gastrointestinal System......Page 423
16.4.3.2 Renal System......Page 426
16.4.4 Integration of Safety Pharmacology Endpoints in Toxicology Studies......Page 427
16.5.1 Cardiovascular Biomarkers......Page 430
16.5.3 Gastrointestinal Biomarkers......Page 431
16.6 Predictive Value of Non-Clinical Safety Pharmacology Testing to Humans......Page 432
16.7 Integrated Risk Assessment......Page 433
16.8.1 Novel Approaches to Treat Diseases......Page 435
16.8.2.1 In Silico Approach......Page 436
16.8.2.3 In Vivo Approach......Page 437
16.8.3 Regulatory Requirements......Page 438
16.9 Conclusion......Page 439
References......Page 440
Chapter 17 Ethical Concerns in Clinical Research......Page 454
17.2.1 Food and Drug Administration......Page 455
17.2.2 Clinical Trial Sponsor......Page 456
17.2.3 Contract Research Organizations......Page 457
17.3 Clinical Trial Site......Page 458
17.3.1 Site Management Organizations......Page 459
17.3.2 Institutional Review Boards......Page 460
17.4 The Evolution of Ethical Principles in Clinical Research......Page 461
17.4.1 Respect for Persons......Page 462
17.5 Regulations Governing Institutional Review Boards......Page 463
17.5.2 What Institutional Review Board Members Should Know about Their Responsibilities......Page 465
17.6 What the Site Should Know about Institutional Review Boards......Page 466
17.6.2 Requirements of an Investigator for Institutional Review Board Research Approval......Page 467
17.7 Risks vs. Benefits Analysis: The Human Advocate......Page 470
17.7.1 Identifying and Assessing the Risks......Page 471
17.7.4 Determining Whether Risks Are Minimized......Page 472
17.7.7 Continuing Review and Monitoring of Data......Page 473
17.8 Informed Consent: Not Just a Document......Page 474
17.8.2 Additional Required Elements......Page 475
17.9 Research Participants......Page 476
17.11 Summary: Ethical Dilemmas in Clinical Research......Page 477
References......Page 479
Chapter 18 Clinical Trials Methodology......Page 482
18.1 Overview......Page 483
18.2.3 Starting Dose Estimation......Page 485
18.2.4 Study Participants......Page 486
18.2.5 Study Design......Page 487
18.2.7.1 Population Pharmacokinetic Studies......Page 488
18.2.9 Mass Balance Studies......Page 489
18.2.12 Drug–Drug Interaction Trials......Page 490
18.2.13 Food–Drug Interaction Clinical Trials......Page 491
18.3.1 Overview......Page 492
18.3.2.1 Definition......Page 493
18.3.2.2 Correlation with Clinical Endpoints......Page 494
18.3.2.4 Development and Utility of Biomarkers and/or Surrogate Endpoints......Page 495
18.3.3.2 Blinding......Page 496
18.3.3.3 Randomization......Page 497
18.3.4 Placebo versus Active Controls in Clinical Trials......Page 498
18.3.5 Study Designs......Page 499
18.3.5.2 Study Design: Crossover Studies......Page 500
18.3.5.4 Factorial Design......Page 501
18.3.5.6 Miscellaneous Considerations......Page 502
18.3.5.7 Dose–Response Studies......Page 503
18.4.2 The Concept of Clinical Equipoise......Page 504
18.4.3.3 Equivalence Clinical Trials......Page 505
18.4.3.4 Non-Inferiority Clinical Trials......Page 506
18.4.3.5 Patient Allocation Designs......Page 507
18.4.3.7 Adaptive Clinical Trials Designs......Page 508
18.4.4 Intention-to-Treat Analysis......Page 509
18.5.2 Post-Marketing Drug Safety Monitoring......Page 511
18.5.6 Special Populations......Page 512
18.5.7 Pharmacoeconomic Analysis......Page 513
18.5.8 Comparative Effectiveness Research......Page 514
18.6.1 Pharmacogenetics......Page 515
18.6.2 Data Safety Monitoring Board......Page 516
18.6.3 Master Protocols......Page 517
References......Page 518
19.1 Introduction......Page 522
19.2 Academic Research: Budgeting and Financial Oversight......Page 524
19.3 Preclinical Research......Page 525
19.4.1 Contract Review and Negotiation......Page 526
19.4.2 Grants......Page 527
19.4.3 Billing......Page 528
19.5 Intellectual Property: Division of Innovation and Technology Transfer......Page 529
19.6.1 Programmatic Elements......Page 530
19.6.3 Research Quality Improvement Audit/Review......Page 531
19.6.7 Federally Mandated COI Training (FCOI)......Page 532
19.6.10 Research Misconduct......Page 533
19.7 Conclusions......Page 534
References......Page 535
Additional Resources......Page 536
20.1 Introduction......Page 538
20.2 Pathogenesis of HIV Infection and Viral Persistence with Reservoirs......Page 539
20.3 Role of Highly Active Antiretroviral Therapy (HAART) and Its Challenges in Low-to Middle-Income Countries......Page 541
20.4 Prevention......Page 543
20.5 Vaccines and Microbicides Initial Development Concepts......Page 544
20.6 Summary and Conclusions......Page 546
References......Page 548
21.1 Introduction......Page 550
21.2.1 Pharmacy Focus on Patient Care......Page 551
21.2.2 Pharmacists Focus on Research......Page 552
21.3 Pharmacist Roles in the Pharmaceutical Industry Environment......Page 553
21.4 Pharmacist Roles in Academia/Hospital Environments......Page 554
21.5 Pharmacist Roles in Clinical Pharmacy Research Conducted in the Critically Ill......Page 556
21.5.2 Food and Drug Administration (FDA)......Page 557
21.5.3.4 Vasoactive Therapies......Page 558
References......Page 559
22.1 Introduction......Page 560
22.2.1 Best Practices for Patent Prosecution and Portfolio Development......Page 562
22.2.1.1 Portfolio Development......Page 563
22.2.2 Antitrust and Unfair Competition Issues......Page 564
22.2.3 Patent Litigation Essentials......Page 566
22.3 Hatch–Waxman and Balancing Innovation and Price......Page 567
22.4 BPCIA and the Patent Dance......Page 568
22.5.1 Trade Secrets......Page 570
Notes......Page 571
23.1 Introduction......Page 574
23.2 Identifying a Candidate Drug......Page 575
23.4.1 Investigational New Drug Process......Page 576
23.5 FDA Involvement: Positive Interactions that Promote the IND Research Initiative......Page 577
23.6.1 Abstract......Page 578
23.6.2 Background......Page 579
23.6.4 Specific Aims......Page 580
23.6.5 Loperamide......Page 581
23.6.6 Loperamide Pharmacokinetics and Safety......Page 582
23.8 Formulation......Page 583
23.9 Topical Loperamide Effectiveness......Page 584
23.9.1 Key Take Home Points......Page 585
References......Page 586
SECTION IV: Regulations......Page 590
Chapter 24 The Role of the Regulatory Affairs Professional in Guiding New Drug Research, Development, and Approval......Page 592
24.1 A Brief Overview of FDA and Other Major Drug Regulation Contributors......Page 593
24.3 Dual, Global Responsibilities of the Regulatory Affairs Professional......Page 594
24.4.1 Phase 1......Page 595
24.4.2 Phase 2......Page 596
24.4.4 Phase 3......Page 597
24.7 Advisory Committee Meetings......Page 598
24.8 FDA Meetings......Page 599
24.11 Drug Safety Reports......Page 600
24.14 Prescription Drug User Fees......Page 601
24.15 Changes to the Submission Process; The eCTD and ESG......Page 602
24.16 Combination Products......Page 603
24.17.2 The ANDA......Page 604
24.19 Company Responsibility for FDA Compliance and Conduct......Page 605
24.21 Career Progression: The Levels of Practice......Page 606
24.23 FDA Statistics – FDA by the Numbers FY 2017......Page 607
24.24 FDA and Drug Development Stories......Page 608
References......Page 609
25.1 Introduction......Page 612
25.2 Regulatory History of the Orphan Drug Act......Page 613
25.3 Results of the ODA Enactment......Page 614
25.4 Costs......Page 615
25.5 The US Orphan Drug Application Process......Page 616
25.6.2 Japan......Page 617
25.8 Concluding Remarks......Page 618
References......Page 619
26.1 Introduction......Page 622
26.2 Physiological Changes due to Aging......Page 625
26.3 Polypharmacy......Page 626
26.4 Age of Patients in Drug Trials and the Age of Actual Patients Taking the Drugs......Page 627
26.5 Barriers and Solutions to Include Older Adult Patients with Multimorbidity in Drug Trials......Page 628
26.6.1 Regulatory Development......Page 629
26.6.2 FDA Guidances for Drug Development......Page 631
26.8.2 Pharmacometrics and Quantitative Systems Pharmacology Approaches from Bench to Bedside......Page 633
26.9 Summary......Page 634
References......Page 635
27.1.1 Pediatric Drug Development and the Science of Clinical Pharmacology......Page 640
27.1.2 Federal Regulations That Have Changed Pediatric Drug Development......Page 641
27.2.1 Clinical Trial Design and Success......Page 642
27.2.2 Extrapolation......Page 643
27.3.3 Endpoints and Surrogate Endpoints......Page 644
27.4.1 Remaining Questions......Page 645
References......Page 646
Chapter 28 Pharmacy Compounding Regulations......Page 648
28.2 Definitions......Page 649
28.4 Adverse Compounding Events: The NECC Tragedy......Page 650
28.4.2 Regulatory Lapses......Page 651
28.4.4 Personnel Licensure......Page 652
28.4.6 Sterility Testing......Page 653
28.5.1 Drug Quality and Security Act: Title I: Drug Compounding: Compounding Quality Act (Sec. 102)......Page 655
28.5.1.1 503A Pharmacies......Page 656
28.5.1.2 503B Outsourcing Facilities......Page 657
28.5.2.4 Substances That May Not Be Used in Compounding......Page 658
28.5.5.1 Draft Guidances......Page 659
28.5.5.3 Lists......Page 661
28.6.1.1 Chapter <795>: Pharmaceutical Compounding: Nonsterile Preparations......Page 662
28.6.1.2 Chapter <797>: Pharmaceutical Compounding: Sterile Preparations......Page 663
28.6.2 Individual Compounding Monographs......Page 664
28.6.4 Marketed but Not FDA-Approved Drugs......Page 665
28.7.1 DQSA and the Advent of “Outsourcing Facilities”......Page 666
28.7.3 FDA Inspections of Outsourcing Facilities......Page 667
28.7.3.1 Initial Inspections......Page 669
28.7.4 Response Letters by Outsourcing Facilities to FDA......Page 670
28.7.5 FDA’s Approach to Encourage Registration......Page 671
Appendix 28.A: List of Drugs That Were Withdrawn or Removed from the Market for Safety Reasons......Page 673
References......Page 675
Index......Page 678

✦ Subjects

Drug Design;Drug Evaluation;Drug Evaluation, Preclinical;Drugs--Design;Drugs--Design--History;Drugs--Research;Drugs--Research--History;Electronic books;History;Drugs -- Research -- History;Drugs -- Design -- History;Drugs -- Design;Drugs -- Research