Preface xiii
Part I Optimizing Pharmacokinetics in Discovery 1
1 The Importance of Pharmacokinetics in Early Drug Discovery 3
1.1 PK as a Surrogate for Efficacy 3
1.2 The Many Faces of Pharmacokineticists 6
1.3 The Criteria for Good PK of a Therapeutically Useful Drug 9
1.4 The Goals of Early Discovery 10
References 13
2 In Search of “Good” Pharmacokinetics 15
2.1 Describing the Concentration-time Profile 16
2.2 Half-life (T 1/2) 20
2.3 Area Under the Curve (AUC) 24
2.4 Biphasic PK Parameters 28
2.5 Constant Intravenous Infusion PK 32
2.6 Extravascular PK 33
2.7 Repeat-dose PK 37
2.8 Using Secondary PK Parameters to Guide Compound Selection 44
2.9 Practical Considerations of Conducting In Vivo PK Studies 49
References 52
3 Linking Descriptive Pharmacokinetics to Underlying ADME Processes 55
3.1 The Body as Compartments: Exponential Time Courses Explained 57
3.2 Relating Descriptive PK Parameters to the Underlying ADME Process 66
3.3 Using Primary PK Parameters to Identify ADME Liabilities 74
3.4 Volume of Distribution and Clearance for Compounds with Biphasic PK 77
3.5 Conversion Between Blood, Plasma, and Unbound PK Parameters 82
3.6 Ranges of PK Parameters 85
3.7 Using Primary PK Parameters to Guide Compound Selection 87
3.8 Linking Primary PK Parameters to Intrinsic Compound Properties 97
References 98
4 Mechanistic Basis of Distribution 101
4.1 Overview of Distribution Process 101
4.2 Factors Affecting Extent of Distribution 101
4.3 Using Volume of Distribution to Guide Drug Design and Selection 109
4.4 Mechanistic Basis of Biphasic PK 112
4.5 Using Rate of Distribution to Guide Lead Optimization 121
4.6 Mechanistic Basis of Plasma Protein Binding 122
References 124
5 Mechanistic Basis of Clearance 127
5.1 Liver Metabolism as the Primary Clearance Pathway 128
5.2 Mechanistic Basis of Hepatic Metabolic Clearance 129
5.3 Applications of Clearance Concept in Drug Discovery 136
5.4 Other Routes of Elimination 144
5.5 Identifying the Rate-limiting Clearance Mechanisms 151
5.6 Drug–Drug Interaction and Metabolism Considerations 152
References 153
6 Mechanistic Basis of Absorption 159
6.1 Overview of the Absorption Process 160
6.2 Factors Affecting Fraction Absorbed 161
6.3 First Pass Extraction 169
6.4 Interplay Between Absorption, First-pass Elimination, and Transporters 173
6.5 Applications of Absorption Concepts in Drug Discovery 174
6.6 Effect of Food on Oral Bioavailability 181
6.7 Lymphatic Absorption of Lipophilic Compounds 182
References 184
7 Integrated Pharmacokinetic Analysis in Discovery 189
7.1 Integration of PK Concepts: A Road Map 189
7.2 Is Plasma Protein Binding Important? 194
7.3 How Potent Is Enough to Elicit Efficacy In Vivo? 197
7.4 Compounds/Series Selection 199
7.5 Drug Design 207
7.6 Identify ADME Liabilities 208
7.7 Study Design 213
7.8 Physiologically Based Pharmacokinetic (PBPK) Modeling 220
References 229
8 Pharmacokinetics of Therapeutic Antibodies and Derivatives 235
8.1 General PK Characteristics of mAbs 237
8.2 Absorption of Monoclonal Antibodies 239
8.3 Distribution of Monoclonal Antibodies 241
8.4 Clearance of Monoclonal Antibodies 244
8.5 PBPK Modeling for Monoclonal Antibodies 246
8.6 PK Screening and Optimization of Monoclonal Antibodies 250
References 253
Part 2 From Pharmacokinetics to Efficacy 259
9 The Importance of Pharmacodynamics in Early Drug Discovery 261
9.1 The PK-PD Disconnect 262
9.2 The Three Pillars of PD 264
9.3 Experimental Approaches for Studying Pharmacological Effects 267
References 269
10 Reaching the Site of Action 271
10.1 Free Drug Hypothesis 272
10.2 Asymmetry in Unbound Tissue and Systemic Concentration 273
10.3 Time-course of Unbound Concentration in Target Tissue 278
10.4 Tissue Disposition Considerations in Drug Discovery 286
10.5 Target Organs with Complex Structures 295
10.6 When Systemic PK Is Not the Main Driver for Tissue Exposure 299
10.7 Tissue Disposition for Therapeutic Antibodies 303
References 304
11 Hitting a Moving Target 311
11.1 Concentration-response Relationships 311
11.2 Receptor Kinetics Theory 315
11.3 Agonism 317
11.4 Antagonism 319
11.5 Slow Association and Disassociation 320
11.6 Target Turnover 322
11.7 Irreversible Inactivation 325
11.8 Proteolysis Targeting Chimeras (PROTACs) 329
11.9 Bisubstrate Kinetics 330
11.10 Implications to Toxicological Effects 332
11.11 Monoclonal Antibodies Target Engagement 333
References 337
12 The Tangled Web of Pharmacology 343
12.1 Fast Responding Processes 346
12.2 Slow Turnover Processes 346
12.3 Multistage Processes 354
12.4 Activation of Precursor 358
12.5 Tolerance and Resistance 363
12.6 Cell Growth and Death 367
12.7 Importance of Response Duration in Determining PK Endpoints 369
12.8 Monoclonal Antibodies 369
12.9 Complex and Novel Systems 371
12.10 Toxicodynamics 371
References 372
13 Pharmacodynamics-informed Drug Discovery 375
13.1 Selection of Target, Modality, and Mode of Action 376
13.2 Compound Screening 378
13.3 Compound Optimization 384
13.4 Virtual Screening and Drug Design 385
13.5 Design and Interpretation of Pharmacology Studies 387
13.6 Model-informed Drug Discovery 395
References 410
Part III Picking the Right Human Dose 413
14 Human Dose Prediction: An Overview 415
References 420
15 Predicting Human Systemic Pharmacokinetics 421
15.1 Predicting Human Volumes of Distribution and Clearance 421
15.2 Predicting Human Oral Bioavailability 432
15.3 Predicting the Concentration-time Profile 437
15.4 When Prediction of Human Systemic PK Is Unimportant 439
15.5 Predicting Human PK for Monoclonal Antibodies 441
References 442
16 Predicting Human Pharmacodynamics 447
16.1 Species Difference in Tissue Disposition 448
16.2 Species Differences in Target Engagement 449
16.3 Species Differences in the Behaviors of Pharmacology 456
References 468
17 Integrated PK/PD Approaches to Human Dose Prediction 473
17.1 A Simple Example of Starting First-in-human Dose Calculation 475
17.2 PK/PD Model-based MABEL Determination 478
17.3 Evaluating Data Quality 493
17.4 Quantifying the Impact of Uncertainty on Decisions 499
References 504
Appendix A: In Vitro ADME Assays 507
A.1 Permeability 507
A.2 Solubility and Dissolution 508
A.3 Plasma Protein Binding 509
A.4 Blood-to-plasma Ratio, B : P 510
A.5 Tissue Partitioning 510
A.6 Transporters 510
A.7 Intrinsic Metabolic Clearance (Stability) 511
A.8 CYP450 Phenotyping 511
A.9 CYP450 Inhibition 512
A.10 CYP450 Time-dependent Inhibition 513
References 513
Appendix B: QSAR and QSPR Models 515
B. 1 What Are QSAR and QSPR Models? 515
B. 2 Model-building Process 515
B. 3 Molecular Descriptors 516
B. 4 Global Versus Local Models 516
B. 5 Types of Models 516
B. 6 Validation and Prediction 517
References 517
Appendix C: Methods for Monitoring Tissue Concentrations 519
Appendix D: Anatomical and Physiological Parameters 521
D.1 Blood Flows 521
D.2 Volumes of Organs and Body Fluids 522
D.3 Intestinal Physiology 523
D.4 Miscellaneous Properties 523
References 524
Appendix E: Useful Equations 525
E. 1 Calculating Secondary PK Parameters from Concentration-time Data 525
E. 2 Calculating Primary PK Parameters from Secondary PK Parameters 526
E. 3 Conversions Between Plasma, Blood, and Unbound PK Parameters 527
E. 4 Calculating Primary PK Parameters from In Vitro or In Silico Data 527
E. 5 Calculating the Concentration-time Profile from Primary PK Parameters 528
Symbols and Abbreviations 531
Index 537
