Putting Pharmacokinetics and Pharmacodynamics to Work in Drug Discovery

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 2 In Search of ""Good"" Pharmacokinetics 15 2.1 Describing the Concentration-time Profile 16 2.2 Half-life (T1/2) 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 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 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 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 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 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 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 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 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 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 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 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 Part III Picking the Right Human Dose 413 14 Human Dose Prediction: An Overview 415 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 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 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 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 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 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 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