Sheila Annie Peters, PhD, is Head of Translational Quantitative Pharmacology at Merck Healthcare, Darmstadt, Germany. Previously, she was an Associate Principal Scientist for Discovery DMPK and Bioanalytical Chemistry at AstraZeneca and Principal Scientist at Cyprotex Discovery. She has lectured at the Regional Engineering College (Trichy, India) and University of Madras and Pondicherry University.

Preface xix

Acknowledgements xxi

About the companion xxiii

Section I. Principles, Methods, andBackground Information 1

1 A Review of Pharmacokinetic and Pharmacodynamic Principles 3

1.1 Introduction 4

1.2 Pharmacokinetic Principles 4

1.2.1 Routes of Drug Administration 4

1.2.2 Intravenous Bolus 4

1.2.3 Plasma Protein Binding and Blood-Plasma Ratio 9

1.2.4 Hepatic, Renal, and Biliary Clearances 12

1.2.5 Extravascular (Subcutaneous, Intramuscular, and Per Oral) Absorption 16

1.2.6 Absorption from Solid Dosage Forms 20

1.2.7 Role of Transporters in ADME 22

1.2.8 Linear and Non-Linear Pharmacokinetics 24

1.2.9 Intravenous Infusion, Repeated Dosing, Steady State Kinetics, and Accumulation 25

1.2.10 Active Metabolite and Prodrug Kinetics 28

1.3 Pharmacokinetic Variability 32

1.4 Pharmacokinetics Optimization in Drug Discovery 34

1.5 Pharmacodynamic Principles 34

1.5.1 Pharmacological Targets and Drug Action 35

1.5.2 Functional Adaptation Processes 39

1.5.3 Biomarkers, Surrogate Endpoints, and Clinical Endpoints 41

Keywords 47

References 48

2 A Review of Drug-Drug Interactions 51

2.1 Introduction 51

2.2 Drug Interactions Mediated by Enzymes and Transporters at Various Sites 54

2.3 Factors Affecting DDI 54

2.4 In Vitro Methods to Evaluate Drug-Drug Interactions 56

2.4.1 Candidate Drug as a Potential Perpetrator 57

2.4.2 Candidate Drug as a Potential Victim of Inhibition 58

2.5 Sources of Uncertainty 59

2.6 Therapeutic Protein-Drug Interaction 59

References 61

3 Modeling Pharmacokinetics, Pharmacodynamics, And Drug Interactions 65

3.1 Introduction 66

3.2 Modeling Pharmacokinetics 66

3.2.1 Compartmental Modeling of Linear and Nonlinear Pharmacokinetics (Enzyme and/or Transporter Capacity Limitation as Well as Target-Mediated Drug Disposition) 67

3.2.2 Population Pharmacokinetics 76

3.3 Pharmacokinetics/Pharmacodynamics and PK/Efficacy (Exposure/ Response) Modeling 80

3.3.1 PK/PD Models for Direct Effect: Sigmoid Emax Model 84

3.3.2 PK/PD Models for Direct Effect: Classical Receptor Theory 86

3.3.3 PK/PD Models Accommodating Delayed Pharmacological Response 89

3.3.4 PK/PD Models Accommodating Functional Adaptation Leading to Nonlinearity in Pharmacological Response with Respect to Time 96

3.3.5 PK/Efficacy Modeling 97

3.3.6 Translation of PK/PD and PK/Efficacy Modeling to Human 100

3.3.7 Average, Minimum, and Maximum Steady-State Concentrations 104

3.3.8 Estimation of Biologically Effective Dose in Human 107

3.3.9 Therapeutic Window 109

3.3.10 Static Models for Drug Interactions 109

3.4 Physiologically Based Pharmacokinetic (PBPK) Modeling and Its Integration with Pharmacodynamics and Efficacy Models 112

3.4.1 PK Modeling Compartmental vs PBPK 112

3.4.2 PK Variability: Population PK (popPK) Modeling vs PBPK 114

3.4.3 Integration of PBPK with PD, Quantitative Systems Pharmacology (QSP) Models or Quantitative Systems Toxicologyand Safety (QSTS) 114

3.4.4 PBPK Models to Evaluate Drug-Drug Interactions 115

3.4.5 DDI Risk Assessment with PBPK vs Static Models 118

Keywords 123

References 125

4 Physiological Model For Absorption 129

4.1 Introduction 130

4.2 Drug Absorption and Gut Bioavailability 130

4.2.1 Solubility and Dissolution Rate 130

4.2.2 Permeability: Transcellular, Paracellular, and Carrier-Mediated Pathways 136

4.2.3 Barriers to Membrane Transport - Luminal Degradation, Efflux, and Gut Metabolism 138

4.3 Factors Affecting Drug Absorption and Gut Bioavailability 140

4.3.1 Physiological Factors Affecting Oral Drug Absorption and Species Differences in Physiology 140

4.3.2 Compound-Dependent Factors 144

4.3.3 Formulation-Dependent Factors 144

4.4 In Silico Predictions of Passive Permeability and Solubility 147

4.4.1 In Silico Models for Permeability 147

4.4.2 In Silico Models for Solubility 147

4.5 Measurement of Permeability, Solubility, Luminal Stability, Efflux, Intestinal Metabolism 148

4.5.1 In Vitro, In Situ, and In Vivo Models for Effective Permeability 148

4.5.2 Measurement of Thermodynamic or Equilibrium Solubility 153

4.5.3 Luminal Stability 154

4.5.4 Efflux 154

4.5.5 In Vitro Models for Gut Metabolism and Estimation of Fraction Escaping Gut Metabolism 155

4.6 Absorption Modeling 156

Keywords 162

References 163

5 Physiological Model For Distribution 169

5.1 Introduction 170

5.2 Factors Affecting Tissue Distribution of Xenobiotics 170

5.2.1 Physiological Factors and Species Differences in Physiology 171

5.2.2 Compound-Dependent Factors 176

5.3 In Silico Models of Tissue Partition Coefficients 176

5.4 Measurement of Parameters Representing the Rate and Extent of Tissue Distribution 181

5.4.1 Assessment of Rate and Extent of Brain Penetration 181

5.5 Physiological Model for Drug Distribution 186

5.6 Drug Concentrations at the Site of Action 187

Keywords 189

References 189

6 Physiological Models For Drug Metabolism And Excretion 193

6.1 Introduction 193

6.2 Factors Affecting Drug Metabolism and Excretion of Xenobiotics 194

6.3 Models for Hepatobiliary and Renal Excretion 197

6.3.1 In Silico Models 197

6.3.2 In Vitro Models for Hepatic Metabolism 197

6.3.3 In Vitro Models for Transporters 200

6.4 Physiological Models 203

6.4.1 Hepato-Biliary Elimination of Parent Drug and Metabolites 205

6.4.2 Renal Excretion 208

References 211

7 Generic Whole-Body Physiologically Based Pharmacokinetic Modeling 217

7.1 Introduction 217

7.2 Structure of a Generic Physiologically-Based Pharmacokinetic (PBPK) Model 218

7.3 Somatic Compartments 220

7.3.1 Lungs (LU) 220

7.3.2 Arterial Blood (ART) 220

7.3.3 Venous Blood (VEN) 220

7.3.4 Stomach (ST) 220

7.3.5 Gut (GU) 220

7.4 Model Assumptions 221

7.5 PBPK Software 221

References 223

8 Pbpk Modeling Of Biotherapeutics 225

8.1 Introduction 226

8.2 Therapeutic Proteins 226

8.2.1 Peptides and Proteins 226

8.2.2 Antibodies and Antibody-Based Therapies 227

8.3 Pharmacokinetics of Therapeutic Proteins 234

8.3.1 Absorption 234

8.3.2 Renal Elimination 235

8.3.3 Immunogenicity 235

8.3.4 PEGylation 239

8.3.5 Transport by Convective and Transcytotic Extravasation 239

8.3.6 Catabolic Elimination (Proteolysis) 239

8.3.7 FcRn-Mediated Protection of IgGs Against Catabolism in FcRn-Rich Cells 241

8.3.8 Distribution and lymphatic elimination 242

8.3.9 Target-Mediated Drug Disposition and Receptor-Mediated Endocytosis 243

8.4 PBPK Modeling of Monoclonal Antibodies 244

8.4.1 Full PBPK Model for Monoclonal Antibodies 244

8.4.2 Minimal PBPK Model for Monoclonal Antibodies 253

8.5 Applications of PBPK Modeling of Monoclonal Antibodies 253

8.5.1 Pharmacokinetic Scaling 253

8.5.2 PBPK Integration with Pharmacodynamics of Monoclonal Antibodies 255

Keywords 156

References 258

9 Uncertainty And Population Variability 263

9.1 Introduction 264

9.2 Distinguishing Uncertainty and Variability 264

9.3 Sources of Uncertainty in Drug-related Parameters 264

9.4 Sources of Variability in System Parameters 266

9.5 Handling Population Variability 269

9.5.1 A POSTERIORI and A PRIORI Approaches to Handling Population Variability 269

9.5.2 Correlations Between Parameters 271

9.6 Uncertainty and Sensitivity Analysis 272

9.6.1 Local Sensitivity Analysis (One-at-a-time (OAT) and Derivative-based Methods) 272

9.6.2 Parameter Interactions and Global Sensitivity Analysis (GSA) 275

9.6.3 Global Sensitivity Analysis for Correlated Parameters (cGSA) 278

9.6.4 Applications of Sensitivity Analysis for PBPK Models 280

9.6.5 Limitations of Global Sensitivity Analysis 281

9.7 Uncertainty and Population Variability in Clinical Efficacy and Safety 282

Keywords 285

References 285

10 Nonclinical, Clinical, and Model-Informed Drug Development 293

10.1 Introduction: An Overview of Different Phases of Drug Development 294

10.2 Nonclinical Development 295

10.2.1 Preclinical Pharmacology, PK/PD Modeling, and Human Dose Prediction 297

10.2.2 Safety and Toxicology Studies 297

10.2.3 Studies with Radiolabeled Compound 298

10.3 Clinical Pharmacology Studies 302

10.3.1 First-in-Human, Single, and Multiple Ascending Dose Studies 302

10.3.2 Biopharmaceutics - Absolute Oral Bioavailability and Bioequivalence Study 304

10.3.3 Food Effect Study 304

10.3.4 Organ (Hepatic and Renal) Impairment Study 305

10.3.5 Pediatric Assessment 306

10.3.6 Mass Balance Study 307

10.3.7 Drug Interaction Study 307

10.3.8 Pharmacogenomics Study 308

10.3.9 Thorough QT (TQT) and Concentration QT (C-QT) Study 308

10.3.10 Immunogenicity Assays and Comparability Study for Biologics 309

10.3.11 Drug Labelling 309

10.4 Clinical Development in Oncology 310

10.5 Fast Track Routes to Address Unmet Medical Need in the Treatment of...