Early drug development : bringing a preclinical candidate to the clinic / Volume 1-2.

Cover......Page 1
Title Page......Page 5
Copyright......Page 7
Contents......Page 10
Preface......Page 30
A Personal Foreword......Page 34
Chapter 1 Early Drug Development: Progressing a Candidate Compound to the Clinics......Page 36
References......Page 42
Part I Drug Substance......Page 44
2.1 Introduction......Page 46
2.2.2 Early Development Drivers and Constraints......Page 47
2.3 The Transition from Discovery to Development......Page 49
2.4.1 Core Functions......Page 51
2.4.2 Specialized Technology Groups......Page 56
2.4.3 Partner Functions......Page 58
2.5.1 Lab Equipment......Page 60
2.5.2 Scale-up Equipment in the Laboratory......Page 61
2.5.3 cGMP Manufacturing Equipment......Page 62
References......Page 63
3.2 Discovery-to-development Transition Before 1980......Page 66
3.3 Discovery-to-development Transition in the 1980s......Page 68
3.4 Discovery-to-development Transition in the 1990s......Page 69
3.4.1 Development Time......Page 70
3.4.2 The BMS IND Initiative......Page 71
3.4.2.1 Parallel Activities......Page 72
3.4.2.2 Integration......Page 73
3.4.2.3 Optimization......Page 74
3.5 Present Practice at BMS......Page 75
3.5.1 The Role of Chemical Complexity......Page 77
3.5.2 An Example of Early Prospective Chemical Development......Page 78
3.6 Application in Small Biotechnology Companies Today......Page 80
3.7 Application in CROs......Page 81
3.7.1 Colocation of CMC Activities......Page 82
References......Page 83
4.1 Introduction......Page 84
4.2 Stages of Research......Page 85
4.3 Synthetic Route Translatability and Scalability: Strategy......Page 86
4.5 Continual Assessment of Alternative Routes and Technologies, Including Preparative Chromatography......Page 88
4.6 Initial CoG Projections......Page 90
4.7 CoG Versus Campaign Time Cycle......Page 91
4.8 Synthetic Route Translatability and Scalability: Tactics......Page 92
4.9 Preparing a CoG Estimate......Page 94
4.10.2 Polymorph Screening and Salt Screening......Page 100
4.10.4 Critique of the Abilities of Process Groups and Drug Discovery Groups to Advance Development of APIs......Page 101
4.11 Long-Term Considerations......Page 103
4.12 Summary......Page 104
References......Page 105
5.1 Introduction......Page 108
5.2 Synthetic Biochemistry......Page 111
5.2.1 Current State Biocatalysis......Page 113
5.2.2 New Single-step Biotransformations......Page 117
5.2.3 Cascade Biotransformations......Page 121
5.2.4 The Future of Synthetic Biochemistry......Page 124
5.3 Chemical Catalysis......Page 125
5.3.1 Considerations for Application on Process Scale......Page 129
5.3.2 Examples of Recent Catalysis Developments Applied in an Industrial Setting......Page 131
5.3.3 The Future of Chemical Catalysis......Page 136
5.4 Continuous Chemistry......Page 138
5.4.2 Fast Reactions with Unstable Intermediates......Page 139
5.4.3 High Temperature and Pressure......Page 140
5.4.5 Safety......Page 141
5.4.6 Photochemistry......Page 142
5.4.7 Electrochemistry......Page 143
5.4.8 Multistage Continuous Processing......Page 144
5.4.9 The Future of Continuous Chemistry......Page 145
5.5 Conclusion......Page 146
References......Page 148
6.1 Introduction......Page 160
6.2 Synthesis of Vortioxetine......Page 161
6.2.1 Iron-mediated Synthetic Route......Page 163
6.2.2 Mustard Route......Page 164
6.2.3 Palladium-mediated Route......Page 167
6.3 Metabolites of Vortioxetine......Page 170
Abbreviations......Page 176
References......Page 177
7.1 Introduction......Page 180
7.2 New Synthesis of (2'R)-2'-deoxy-2'-C-methyl uridine (10)......Page 184
7.3 Dehydration and Iodoazidation Steps......Page 189
7.4 Functionalization at C-4'......Page 190
7.6 Solid Form Selection......Page 194
7.7 Process Safety......Page 196
7.8 Impurity Strategy......Page 197
References......Page 199
Part II Drug Product......Page 204
8.1 Introduction......Page 206
8.2.1 Solubility and Dissolution Rate......Page 210
8.2.3 pH......Page 212
8.2.5 The Particle Size......Page 213
8.3 Permeability......Page 214
8.3.1 Passive Diffusion......Page 215
8.3.3 Membrane Transporters......Page 217
8.3.4 P-Glycoprotein (P-gp)......Page 218
8.3.6 PEPT1......Page 219
8.4 The Solubility-Permeability Interplay......Page 220
References......Page 223
9.1 Introduction......Page 238
9.2 Amorphous and Crystalline States: Basic Concepts......Page 239
9.2.1 Crystalline States: Polymorphs, Hydrates, Solvates, Salts, and Cocrystals......Page 240
9.2.2.1 Goal of Form Selection......Page 241
9.2.2.2 Characterization of the Starting Material......Page 243
9.2.2.3 Polymorph Screening Methods......Page 244
9.2.2.4 Assessing the Relative Stability of Multiple Physical Forms......Page 246
9.2.3 Amorphous Solid Dispersions......Page 247
9.2.3.1 Spray Drying......Page 248
9.2.3.4 Dissolution and Stability Issue......Page 249
9.3.1 Particle Habit......Page 250
9.3.2 Particle Size......Page 254
9.4 Summary......Page 256
References......Page 257
10.1 Introduction......Page 264
10.2 Screening......Page 265
10.2.1 Counterions and Coformers......Page 266
10.2.2 Manual Versus Automated Screening......Page 271
10.2.3 Computational Approaches......Page 273
10.2.4 Salt and Cocrystal Screening Strategies......Page 274
10.2.5 Polymorph Screen of Salts/Cocrystals......Page 276
10.3 Salt/Cocrystal Selection......Page 277
10.4 Scale-Up......Page 282
10.5 Formulation Considerations......Page 284
10.6 Regulatory Aspects......Page 290
10.7.1 Indinavir: Early Salt Form Change......Page 292
10.8 Summary......Page 293
List of Abbreviations......Page 294
References......Page 295
11.1 Strategic Plans and Risk Management of Particle Size......Page 306
11.2 Particle Size Reduction Techniques......Page 308
11.2.1 Top-Down Approaches......Page 309
11.2.2 Bottom-Up Approaches......Page 310
11.3.1 Regulatory and Quality Considerations......Page 311
11.3.2 Particle Size Techniques......Page 312
11.3.3 Selection of Appropriate Technique or Set of Techniques......Page 313
11.4.1 Particle Size and Bioavailability......Page 325
11.4.2 Initial Desired Particle Size......Page 326
11.5 Enabling Formulation Approach by Particle Size Reduction in Early Drug Development......Page 329
11.6 Benefits of Commercial Products Using Nanosized Crystalline Particles......Page 332
11.7.1 Nanoparticles and Targeting Delivery......Page 334
11.7.2 Emerging Nanoparticle Techniques......Page 335
11.8 Conclusions......Page 336
References......Page 337
12.1.1 Guiding Principles and Technology Selection for Preclinical Formulation......Page 340
12.1.2 Predicting Preclinical Formulation Performance......Page 343
12.2 Formulation Selection for FiH......Page 347
12.2.2 Powder in Capsule (PIC) Formulation......Page 348
12.2.2.1 Clinical Performance of PIC Dosage Forms: A Retrospective Data Analysis of Pfizer NCEs......Page 349
12.2.2.2 Clinical Data Analysis Methodology......Page 350
12.2.2.3 Relationship Between Physicochemical Properties and Clinical Performance for PIC Dosage Forms: Results from Clinical Data Analysis......Page 353
12.3 Conclusion......Page 361
References......Page 362
13.1 Introduction......Page 368
13.2 Selecting the Appropriate Type of Formulation Based on Compound Properties and Type of Study......Page 370
13.2.1.1 pH Adjustment......Page 371
13.2.1.4 Solubilization in Surfactants......Page 372
13.4.1 Amorphous or Crystalline Nanosuspension?......Page 374
13.4.2 Selection of Stabilizers......Page 375
13.4.3.1 Low API Concentrations (Up to Approximately 10 mM)......Page 376
13.4.3.2 High API Concentrations (Above 10 mM)......Page 377
13.5.1 Amorphous Nanoparticles at Low Compound Concentrations: The Precipitation Method......Page 378
13.5.2 Amorphous Nanoparticles at High Compound Concentrations: The Melt Emulsion Method......Page 379
13.5.3 Crystalline Drug Nanoparticles at Low Compound Concentrations: The Ultrasonic Crystallization Method......Page 381
13.5.4 Crystalline Drug Nanoparticles at High Compound Concentrations: The Wet Milling Method......Page 383
13.6.1 Solubility Measurements......Page 385
13.6.2 Measurements of Dissolution Rate......Page 386
13.7.1 Case Study 1: Milled Nanocrystals of a Compound for Toxicological Studies......Page 387
13.7.2 Case Study 2: Amorphous Nanosuspensions Selected for Preclinical and Toxicological Studies Due to Improved Exposure Versus Crystalline Suspensions with Different Particle Sizes......Page 391
13.7.3 Case Study 3: Amorphous Nanoparticles as a Screening Approach During Lead Optimization and in Repeated Toxicological Studies......Page 393
13.8 Conclusions......Page 395
References......Page 396
Part III Pharmacokinetics and Pharmacodynamics......Page 400
14.1 Introduction......Page 402
14.2 Understand Your Target Biology......Page 404
14.2.1 Physiological Context......Page 406
14.2.4 Target vs Off-Target or Confounding Factors......Page 407
14.2.6 Experimental Design Aiming at Target Biology......Page 408
14.3 Understand Your Concentration-Response Relationship and Time Delays......Page 409
14.3.1 Nonmonotonous Concentration-Response Curves......Page 410
14.3.2 Dose Scheduling ("Dose Fractioning")......Page 412
14.3.3 What Matters Is Steady State for Chronic Indications......Page 413
14.4 Understand Temporal Differences Between Concentration and Response......Page 417
14.5.1 Matching Drug Delivery to Target Biology......Page 420
14.5.2 Designing Experiments for Discrimination of Drug Candidates......Page 422
14.6.1 Misconceptions in Cross-Functional Communication......Page 424
14.6.3 Integrated Thinking......Page 427
14.7 Final Remarks......Page 430
References......Page 431
15.1 General Introduction......Page 434
15.1.1 PK, PKPD, and Dose Prediction: Overview......Page 435
15.2.1 Experimental Data......Page 436
15.2.2 Predicting Clearance......Page 437
15.2.2.1 Hepatic Metabolic Clearance......Page 438
15.2.2.2 Hepatic Biliary Clearance......Page 441
15.2.2.3 Renal Clearance......Page 442
15.2.2.4 Scaling of Clearance: Points to Consider......Page 443
15.2.3 Volume of Distribution......Page 445
15.2.4 Oral Bioavailability, Rate, and Extent of Absorption......Page 447
15.2.4.1 Extent of Absorption and Gut First-Pass Metabolism......Page 448
15.2.5 Predicting PK Profiles......Page 449
15.2.5.2 PBPK Models......Page 450
15.3.2 Fundamental Principles for Successful PKPD Prediction and Translation......Page 451
15.3.2.1 Target Modulation/Engagement and the Pharmacologic Effect......Page 453
15.3.2.2 Relationship Between Pharmacokinetics and Target Engagement/Modulation......Page 454
15.3.2.4 Predicting Efficacious Concentration Without a Target Engagement or Mechanistic Biomarker......Page 456
15.4 Dose Predictions......Page 457
15.6 Future Perspectives......Page 460
References......Page 461
16.1 Introduction......Page 468
16.2 Translational Pharmacology in Oncology......Page 469
16.3 Quantitative M&S Approach......Page 471
16.3.1 PK Modeling......Page 472
16.3.2 PKPD Modeling......Page 473
16.3.3 PKDZ Modeling......Page 475
16.4 Case Study: Crizotinib (PF02341066)......Page 476
16.4.1 Nonclinical Study Outlines......Page 477
16.4.2 PK Analysis......Page 478
16.4.3 PKPD Relationships......Page 479
16.4.5 PK-PDDZ Understanding......Page 481
16.4.6 Translational Pharmacology......Page 484
16.5 Case Study: Lorlatinib (PF06463922)......Page 486
16.5.2 PK Analysis......Page 487
16.5.3 PKPD Relationships......Page 488
16.5.4 PKDZ Relationships......Page 489
16.5.5 PK-PDDZ Understanding......Page 491
16.5.6 Translational Pharmacology......Page 492
16.6 Closing Remarks......Page 494
List of Abbreviations......Page 495
References......Page 496
17.1 Introduction......Page 502
17.1.1 Translational Plan......Page 505
17.2 Neuroscience: Prediction of the Clinically Efficacious Exposure and Dose Regimen for a Novel Target......Page 507
17.3.1 Evolution of Pharmacology Experiments......Page 511
17.3.2 Development of a Translational PK/PD Model......Page 514
17.3.4 Application of the GPR40 Agonist Translational PK/PD Model to Predict Clinical Outcomes......Page 515
17.4 Antibacterials: Semi-mechanistic Translational PK/PD Approach to Inform Optimal Dose Selection in Human Clinical Trials for Drug Combinations......Page 518
17.4.1 Development of the Semi-mechanistic Translational PK/PD Model......Page 519
17.4.2 Application of the Translational PK/PD Model to Predict Preclinical Efficacy......Page 521
17.4.3 Application of the Translational PK/PD Model to Predict Clinical Efficacy......Page 522
17.5 Anti-inflammation: Early Go/No-Go Based on Differentiation Potential Compared with Competitors......Page 524
17.6 Summary......Page 526
List of Abbreviations......Page 528
References......Page 529
Part IV Toxicology......Page 532
18.1 Introduction......Page 534
18.1.1 Target Safety Assessment......Page 535
18.1.2 Compound Safety Assessment......Page 539
18.1.2.2 Mitochondrial Toxicity......Page 540
18.1.2.3 Biotransformation and Reactive Metabolites......Page 541
18.1.2.4 Secondary Pharmacology......Page 542
18.1.2.5 Phototoxicity......Page 543
18.1.2.6 Genetic Toxicology......Page 544
18.1.2.7 Genotoxic Impurities......Page 545
18.1.2.8 Incorporation of Safety Endpoints in Preclinical Efficacy and PK Studies......Page 546
18.1.2.10 Maximum Tolerated Dose (MTD) / Dose Range Finding (DRF) Studies......Page 547
18.1.3 GLP Toxicology......Page 548
18.1.3.1 General Toxicology......Page 550
18.1.4 Enabling the First Clinical Trial with Toxicological Data......Page 551
18.2 Conclusions......Page 552
References......Page 554
19.1 Introduction......Page 562
19.2 Historical Background......Page 563
19.3 Regulatory Framework......Page 564
19.4 Role in Discovery and Candidate Selection......Page 565
19.5.1 Introduction......Page 567
19.5.2 Objectives......Page 568
19.5.4 Central Nervous System......Page 569
19.5.5 Cardiovascular System......Page 571
19.5.5.3 Cardiac Action Potential......Page 573
19.5.5.4 In Vivo Assessments......Page 574
19.5.7 Supplemental Safety Pharmacology Studies......Page 575
19.6 Translation from Nonclinical Safety Pharmacology to the Clinic......Page 576
19.7 Future Directions and Current Discussions......Page 578
List of Abbreviations......Page 579
References......Page 580
20.1 Introduction......Page 584
20.2 Predictive Toxicology......Page 585
20.3.1 Machine Learning Algorithms......Page 587
20.3.1.2 Ensembles of Models......Page 588
20.3.1.3 k-Nearest Neighbors......Page 590
20.3.1.5 Artificial Neural Networks......Page 591
20.3.2 Knowledge-based Methods......Page 592
20.4 Industry Perspectives......Page 593
20.5 Regulatory Perspectives......Page 602
20.6 Conclusion......Page 605
References......Page 607
21.1 Introduction......Page 616
21.3 Transcriptional Profiling to Capture Polypharmacology......Page 618
21.4 High Content Imaging as an Independent Confirmation......Page 620
21.5 In Vitro Micronucleus Testing to Validate Transcriptional Signature......Page 624
21.6 Data Integration......Page 626
21.7 Hypothesis for a Potential Structure-Activity Relationship......Page 627
21.8.1 Current Situation......Page 629
21.8.2 Suggested Improvements......Page 630
21.8.3 Expected Outcome......Page 631
List of Abbreviations......Page 633
References......Page 634
22.1.1 Objectives and Challenges......Page 638
22.1.2 Overview of the Strategy and Screening Cascade......Page 639
22.2 Early Attention to Preclinical Safety......Page 640
22.3 Aryl Hydrocarbon Receptor Activation Observed in Rat......Page 642
22.4 CYP1A (Auto) Induction Observed in Non-rodent Species......Page 644
22.5.1 CYP1A Induction via the AhR......Page 646
22.5.2 CYP1A Enzyme Family......Page 647
22.6 Considerations of AhR Binding and CYP1A Induction on Compound Progression......Page 648
22.7.2 Evaluating Induction in Human Hepatocytes......Page 650
22.7.3 Screening for Induction Using Rat Hepatocytes......Page 652
22.7.4 Development of a Rat In Vivo Induction Protocol......Page 653
22.8 Iterative Experimentation Identifies Molecules for Progression......Page 654
22.9 Delivery of Human AhR Agonist Assay......Page 657
22.10 Minimizing Cardiovascular Safety Risk Through S1P Receptor Selectivity......Page 658
22.12 Delivery of Multiple Candidates for Development......Page 660
22.13 Conclusions......Page 661
References......Page 662
23.2.1 Choosing to Activate the TRAIL Pathway as a Cancer Therapeutic Strategy......Page 666
23.2.3.1 Using TRAIL......Page 668
23.2.3.3 Using Small Molecules to Activate the TRAIL Pathway......Page 669
23.3.1 Decision making: Choice of Which Compound to Move Forward with (Comparison of the Different TICs) - Balancing Efficacy with Safety......Page 670
23.3.3 Exploring Therapeutic Potential by Performing Ex Vivo Studies......Page 671
23.4.2.2 Pharmacodynamic Analyses......Page 672
23.4.3 Conducting Toxicology Studies in Accordance with Good Laboratory Practices (GLP)......Page 673
23.6 Summary......Page 674
References......Page 675
Part V Intellectural Property......Page 682
24.2.1 What Are Patents?......Page 684
24.2.3 Types of Patents......Page 685
24.3 Requirements for Patent Protection......Page 686
24.3.2 Utility......Page 687
24.3.4 Nonobviousness......Page 688
24.4 Patent Infringement......Page 689
24.5 Overview of Drug Development......Page 691
24.6.1 Hatch-Waxman Act......Page 693
24.6.2.1 Delays Due to USPTO Approval......Page 694
24.6.3.1 New Chemical Entity......Page 695
24.6.3.2 New Clinical Study Exclusivity......Page 696
24.6.3.3 Generic Drugs......Page 697
24.6.3.4 Orphan Drug Exclusivity......Page 698
24.6.3.5 Pediatric......Page 699
24.7 Summary......Page 700
References......Page 701
25.1 Benefits of Patent Protection......Page 702
25.2.1 Subject Matter Eligible for Patent Protection......Page 703
25.2.2 Further Requirements for Patentability: Defining the Invention......Page 704
25.3.1 Protection of Commercial Products and Exclusive Rights......Page 706
25.3.2 Monetization of Patents......Page 707
25.4.1 First- Versus Second-Generation Drugs......Page 708
25.4.2 Active Pharmaceutical Ingredient......Page 709
25.4.3 Formulations......Page 710
25.4.4 Dosages, Administration Forms, and Treatment Methods......Page 711
25.4.6 Anticipating Further Development and Variation......Page 712
25.5 Timing of Patent Applications......Page 713
25.5.2 Patent Cooperation Treaty Applications and International Filings......Page 714
25.5.4 Accounting for Publication or Presentation of Research......Page 715
25.6.2 The Meaning of Patent Claims: Proactive Claim Construction......Page 716
25.6.3 The Importance of the Patent Specification......Page 717
25.6.5 Anticipating Challenges to Infringement and Validity......Page 718
25.7.2 Continuation-in-Part Applications......Page 719
25.7.3 Divisional Applications......Page 720
25.8.1 Correcting Issued Patents Through Reissue......Page 721
25.8.2 Limitations on Broadening Claims......Page 722
25.9 Conclusion......Page 723
26.2 Market Exclusivities That Protect Branded Drugs......Page 726
26.3 The Patent Cliff......Page 730
26.4 Paragraph IV Issues......Page 732
26.5 Injunctions......Page 734
26.6 The Generic Company's Goals......Page 738
26.7 Strategies Adopted by Innovators......Page 739
26.8 Strategies Adopted by Generic Companies......Page 747
26.9 Conclusion......Page 753
27.1 Introduction......Page 756
27.2.1 Patents......Page 757
27.2.3 Trademark and Copyright......Page 759
27.3 Before the Research Begins......Page 760
27.3.2 Is a Freedom to Operate Search Needed?......Page 762
27.3.3 Scope of the Collaboration......Page 763
27.3.4 Trade Secrets......Page 764
27.3.5 Procedures for Making Public Announcements and Publications......Page 765
27.3.6 Ownership......Page 767
27.3.7 Dealing with Problems......Page 770
27.3.8 Costs......Page 771
27.3.8.1 Prosecution Costs......Page 772
27.3.8.2 Enforcement Costs......Page 773
27.3.10 Sharing Technology......Page 774
27.4.1.1 Required Participation in a Litigation......Page 777
27.4.2 Patent Term Extension......Page 779
27.5 Termination of the Relationship (Death and Divorce)......Page 780
List of Abbreviations......Page 781
References......Page 782
Index......Page 784
EULA......Page 801