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

Description

This one-stop reference systematically covers key aspects in early drug development that are directly relevant to the discovery phase and are required for first-in-human studies. Its broad scope brings together critical knowledge from many disciplines, ranging from process technology to pharmacology to intellectual property issues. After introducing the overall early development workflow, the critical steps of early drug development are described in a sequential and enabling order: the availability of the drug substance and that of the drug product, the prediction of pharmacokinetics and -dynamics, as well as that of drug safety. The final section focuses on intellectual property aspects during early clinical development. The emphasis throughout is on recent case studies to exemplify salient points, resulting in an abundance of practice-oriented information that is usually not available from other sources. Aimed at medicinal chemists in industry as well as academia, this invaluable reference enables readers to understand and navigate the challenges in developing clinical candidate molecules that can be successfully used in phase one clinical trials.  Read more... 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