Drug Discovery and Development

Title page......Page 2
Table of Contents......Page 3
Copyright......Page 12
Foreword......Page 14
Preface to 2nd Edition......Page 16
Preface to 1st edition......Page 18
Contributors......Page 21
Chapter 1: The development of the pharmaceutical industry......Page 23
Antecedents and origins......Page 24
Therapeutics in the 19th century......Page 26
An industry begins to emerge......Page 27
Concluding remarks......Page 52
Chapter 2: The nature of disease and the purpose of therapy......Page 62
Introduction......Page 63
Concepts of disease......Page 64
The aims of therapeutics......Page 72
Function and dysfunction: the biological perspective......Page 77
Therapeutic interventions......Page 85
Measuring therapeutic outcome......Page 86
Pharmacoepidemiology and pharmacoeconomics......Page 89
Summary......Page 96
Chapter 3: Therapeutic modalities......Page 100
Introduction......Page 101
Conventional therapeutic drugs......Page 105
Biopharmaceuticals......Page 107
Gene therapy......Page 110
Cell-based therapies......Page 115
Tissue and organ transplantation......Page 117
Summary......Page 119
Chapter 4: The drug discovery process: General principles and some case histories......Page 122
Introduction......Page 123
The stages of drug discovery......Page 142
Trends in drug discovery......Page 146
Research in the pharmaceutical industry......Page 152
Chapter 5: Choosing the project......Page 156
Introduction......Page 157
Making the decision......Page 158
A final word......Page 170
Chapter 6: Choosing the target......Page 171
Introduction: the scope for new drug targets......Page 172
Conventional strategies for finding new drug targets......Page 179
Target validation......Page 194
Summary and conclusions......Page 199
Chapter 7: The role of information, bioinformatics and genomics......Page 205
The pharmaceutical industry as an information industry......Page 206
Innovation depends on information from multiple sources......Page 208
Bioinformatics......Page 210
Genomics......Page 220
Conclusion......Page 247
Chapter 8: High-throughput screening......Page 252
Introduction: a historical and future perspective......Page 253
Lead discovery and high-throughput screening......Page 259
Screening libraries and compound logistics......Page 296
Profiling......Page 300
Chapter 9: The role of medicinal chemistry in the drug discovery process......Page 308
Introduction......Page 309
Target selection and validation......Page 312
Lead identification/generation......Page 318
Lead optimization......Page 325
Addressing attrition......Page 334
Summary......Page 340
Chapter 10: Metabolism and pharmacokinetic optimization strategies in drug discovery......Page 349
Introduction......Page 350
Optimization of DMPK properties......Page 353
Human PK and dose prediction......Page 388
Summary......Page 397
Acknowledgments......Page 398
Chapter 11: Pharmacology: Its role in drug discovery......Page 404
Introduction......Page 405
Screening for selectivity......Page 409
Pharmacological profiling......Page 413
Animal models of disease......Page 425
Chapter 12: Biopharmaceuticals......Page 441
Introduction......Page 442
Recombinant DNA technology: the engine driving biotechnology......Page 444
The early days of protein therapeutics......Page 445
Currently available classes of biopharmaceuticals......Page 447
Gene therapy......Page 460
Comparing the discovery processes for biopharmaceuticals and small molecule therapeutics......Page 468
Pharmacokinetic, toxicological and drug-delivery issues with proteins and peptides......Page 478
Summary......Page 483
Chapter 13: Scaffolds: Small globular proteins as antibody substitutes......Page 488
Introduction......Page 489
Scaffolds......Page 490
Concluding remarks......Page 514
Chapter 14: Drug development: Introduction......Page 522
Introduction......Page 523
The nature of drug development......Page 524
Components of drug development......Page 527
The interface between discovery and development......Page 532
Decision points......Page 533
The need for improvement......Page 536
Chapter 15: Assessing drug safety......Page 539
Introduction......Page 540
Types of adverse drug effect......Page 544
Safety pharmacology......Page 546
Exploratory (dose range-finding) toxicology studies......Page 551
Genotoxicity......Page 554
Chronic toxicology studies......Page 558
Special tests......Page 565
Toxicokinetics......Page 572
Toxicity measures......Page 573
Variability in responses......Page 574
Conclusions and future trends......Page 575
Chapter 16: Pharmaceutical development......Page 579
Introduction......Page 580
Preformulation studies......Page 581
Routes of administration and dosage forms......Page 587
Formulation......Page 591
Principles of drug delivery systems......Page 594
Summary......Page 607
Chapter 17: Clinical development: present and future......Page 611
Introduction......Page 612
Clinical development phases......Page 615
Clinical trials in children......Page 645
Regulatory and ethical environment......Page 646
Seamless drug development with adaptive clinical trial design: the future of clinical development?......Page 653
Conclusions......Page 659
Chapter 18: Clinical imaging in drug development......Page 661
Introduction......Page 662
Imaging methods......Page 664
Human target validation......Page 669
Biodistribution......Page 672
Target interaction......Page 677
Pharmacodynamics......Page 682
Patient stratification and personalized medicine......Page 691
Imaging as a surrogate marker......Page 695
Imaging in the real world – challenges to implementation......Page 697
Summary......Page 702
Acknowledgments......Page 703
Chapter 19: Intellectual property in drug discovery and development......Page 707
What is a patent?......Page 708
The patent specification......Page 710
What can be patented?......Page 714
Requirements for patentability......Page 716
Patent issues in drug discovery......Page 721
The state of the art......Page 722
Patent documents as state of the art......Page 723
Evaluation by the scientist......Page 724
Evaluation by the patent professional......Page 725
Sources of information......Page 726
Results of the evaluation – NCEs......Page 727
Patenting of research tools......Page 728
Obtaining patent protection for a development compound......Page 730
Chapter 20: Regulatory affairs......Page 746
Introduction......Page 747
Brief history of pharmaceutical regulation......Page 748
International harmonization......Page 751
Roles and responsibilities of regulatory authority and company......Page 753
The drug development process......Page 756
Regulatory procedures......Page 779
Administrative rules......Page 791
List of abbreviations......Page 794
Chapter 21: The role of pharmaceutical marketing......Page 797
Introduction......Page 798
History of pharmaceutical marketing......Page 800
Product life cycle......Page 804
Pharmaceutical product life cycle (Figure 21.3)......Page 810
Traditional Pharmaceutical marketing......Page 812
Pricing......Page 824
Health technology assessment (HTA)......Page 828
New product launch......Page 830
Changing environment – changing marketing......Page 841
The future of marketing......Page 849
Chapter 22: Drug discovery and development: facts and figures......Page 852
Spending......Page 855
Sales revenues......Page 861
Timelines......Page 868
Pipelines and attrition rates......Page 872
Biotechnology-derived medicines......Page 876
Recent introductions......Page 877
Predicting the future?......Page 879
Index......Page 885