Translational ADMET for Drug Therapy

Souzan B. Yanni, PhD, is Founder and President of DMPK Consultants, Inc., which leads ADME/PK in support of preclinical and clinical investigations for of pharmaceutical and biotech companies.  She has over 20 years of hands-on leadership experience in planning, executing, and overseeing drug discovery and early development for therapeutic programs with national and international pharmaceutical companies, biotech groups, and CROs. Dr. Yanni possesses a PhD in Pharmaceutical Sciences, MS in Biochemistry, and BS in Chemistry. She is the author of several peer-reviewed articles, review articles, and book chapters on ADMET/PK as well as an external reviewer / editor for other journals.

Contributors xv

Preface xvii

Acknowledgement xxi

1 Translational Concept and Determination of Drug Absorption 1

1.1 Drug Absorption, Mechanism, and its Impact on Drug Bioavailability, Drug Disposition, and Drug Safety 1

1.1.1 Drug Absorption and Oral Bioavailability 2

1.1.2 Contribution of Intestinal Drug Transporters and Drug-Metabolizing Enzymes on Extent of Absorption and Mechanism 4

1.1.2.1 Intestinal Transporters 4

1.1.2.2 The Impact of Intestinal Metabolism on Drug Absorption 8

1.2 Effect of Physiochemical Property–Related Factors on Drug Absorption 9

1.2.1 Lipophilicity, Solubility and Dissolution, and Permeability 9

1.2.1.1 Lipophilicity 9

1.2.1.2 Solubility 11

1.2.1.3 Permeability 12

1.3 Effect of GI-Physiological Factors and Patient Condition on Drug Absorption 14

1.3.1 Effect of pH, Intestinal Surface Area, Gastric Emptying, Transient Time, and Bile Acid 14

1.3.1.1 Effect of pH and Surface Area 14

1.3.1.2 Effect of Gastric Emptying and Intestinal Transit Time 17

1.3.1.3 Effect of Bile and Bile Salts 17

1.3.2 Impact of Age and Disease State on Drug Absorption 18

1.3.2.1 Drug Absorption in Pediatric Populations 18

1.3.2.2 Drug Absorption in Disease State 19

1.4 Effect of Food and Formulation on Drug Absorption 20

1.4.1 Effect of Food 20

1.4.2 Formulation Effect 21

1.4.3 The BCS in Relation to Intestinal Absorption 22

1.5 Translational Approaches to Determine Drug Absorption in Clinical Studies 24

1.5.1 Cellular Intestinal Model 24

1.5.2 In Vitro Artificial Membrane 24

1.5.3 Non–In Vitro Models: In Situ and In Vivo 25

References 27

2 Distribution: Principle, Methods, and Applications 37

2.1 Introduction: Drug Distribution in Relation to Drug Disposition in Humans 37

2.2 Influence of Drug-Related Physiochemical Factors on Drug Distribution 39

2.3 Influence of Physiological Factors on Drug Distribution 42

2.3.1 Effect of BodyWater Content, Perfusion, and Diffusion on Drug Distribution 43

2.3.1.1 Effect of Body Water 43

2.3.1.2 Effect of Perfusion and Diffusion on Drug Distribution 44

2.4 Plasma Protein Binding 45

2.4.1 Effect of Biomedical Conditions: Disease State and Pregnancy 45

2.4.2 Protein Binding as a Function of Age 46

2.5 Role of Drug Transporters in Drug Distribution 47

2.5.1 Drug Distribution as a Function of Efflux Drug Transporters 48

2.6 Translational Methods and Approaches in Determining Drug Distribution 49

2.6.1 In Vitro Methods for Determination of Protein Binding 49

2.6.2 In Vivo Protein Binding Studies in Preclinical Animals and Humans 51

2.6.2.1 Using Radiolabeled Drugs 51

2.6.2.2 Applying Advanced Translational Tools for Determining Drug Distribution in Humans 52

2.6.3 Assess Drug Distribution from Transporter Studies 53

2.6.3.1 Use of Membrane Vesicles 53

2.6.3.2 Use Cultured-Cell Based Assay 53

2.7 Impact of Drug Distribution in Drug Disposition DDI in Clinic 55

References 58

3 Metabolism: Principle, Methods, and Applications 63

3.1 Introduction: An Overview on Drug Metabolism in Relation to Clearance—Mediated by Phase I, Phase II, and Phase III Drug-Metabolizing Enzymes 63

3.2 Common Phase I, II, and III Drug Metabolism Reactions 69

3.2.1 Phase I Drug Metabolism 69

3.2.1.1 Oxidation Reaction 70

3.2.2 Phase II Conjugation Biotransformation Reactions 71

3.2.2.1 UDP-Glucuronosyltransferase (UGT) 71

3.2.2.2 Other Conjugation Reactions: Sulfonyltransferase, Glutathione-S-Transferases, Methyl Transferases, and N-Acetyl Transferases 75

3.2.3 Phase III Metabolism 77

3.2.4 Localization of Drug Metabolism in Organ Cells 78

3.3 Metabolic Clearance as a Critical Factor Influencing Drug Action and Safety 78

3.3.1 Effect of Physiological Factors on Drug Metabolism-Mediated Drug Clearance 80

3.3.1.1 Protein Binding 81

3.3.1.2 Hepatic Blood Flow (QH) 82

3.3.1.3 Liver Size Relative to Body Weight 82

3.3.1.4 Milligram Microsomal Protein per Gram of Liver 82

3.3.2 Role of Drug Transporters 82

3.3.3 Effect of Age on Drug Metabolism and Clearance 84

3.3.4 Effect of Hormones on Metabolic Clearance and Gender Difference in Drug Metabolism 86

3.3.5 Effects of Disease on Drug Metabolism 86

3.3.6 Genetic Polymorphism and Ethnic Variability Effect on Metabolic Clearance 87

3.4 Species Differences in Drug Metabolism 89

3.5 Translational Technologies and Methodologies and Regulatory Recommendation for Drug Metabolism 91

3.5.1 In Vitro Models of Drug Metabolism 92

3.5.1.1 Single-cDNA Expressed Enzymes 92

3.5.1.2 Subcellular Fractions 93

3.5.1.3 Cellular Systems 94

3.5.2 In Vivo Models of Drug Metabolism 95

3.5.2.1 Preclinical Animal Studies 95

3.5.2.2 Genetically Modified Animal/Chimeric Mouse Model/Ex Vivo/In Situ Organ Perfusion 96

References 98

4 Excretion: Principle, Methods, and Applications for Better Therapy 111

4.1 Outline of Drug Excretion and Mechanisms 111

4.2 Excretion of Drugs in Humans as Function of Drug Transporters 112

4.2.1 Biliary and Renal Excretion 112

4.2.1.1 Biliary Excretion 113

4.2.1.2 Renal Excretion 115

4.2.2 Drug Transporter Function in Renal Excretion 118

4.3 Translational Tools to Determine the Biliary and Renal Clearance 119

4.3.1 In Vitro Methods in Determination of Biliary Clearance 119

4.3.2 In Vitro Methods in Determination of Renal Clearance 122

4.3.3 In Vivo Methods in Determination of Biliary and Renal Clearances 125

4.3.3.1 MBSs in Humans 125

4.3.4 In Vivo Model to Study Excretion and Toxicity: Chimeric Mice with Humanized Liver 128

4.4 Impairment of Drug Elimination 128

4.4.1 Hepatic Impartment: Cholestasis 128

4.4.2 Renal Impartment: Chronic Kidney Disease (CKD) 130

References 133

5 Drug–Drug Interaction: From Bench to Drug Label 139

5.1 Introduction: The Impact of Drug–Drug Interaction on Drug Disposition and Drug Safety 139

5.2 DDIs Implicated with Drug-Metabolizing Enzymes (DMEs) and Drug Metabolism 141

5.2.1 DDI Mediated by P450 Inhibition 141

5.2.1.1 In Vitro P450 Inhibition Models and Methodologies 142

5.2.1.2 Translating In Vitro P450 Inhibition Data to Clinical DDI 144

5.2.2 Mechanism-Based P450 Inactivation DDI 146

5.2.2.1 Translating the In Vitro Information to Clinical Pharmacology Investigation 147

5.2.3 DDI Mediated by P450 Induction 152

5.2.3.1 In Vitro P450 Induction Models and Methodologies 152

5.2.3.2 Translating In Vitro P450 Induction Data to Clinical DDI 156

5.3 Incidence of DDI Due to Drug Transporters 158

5.3.1 DDI-Mediated Uptake Transporters 159

5.3.2 DDI-Mediated Efflux Transporters 162

5.4 Clinical DDI 163

5.4.1 DDI in Pediatric Patients 164

5.4.2 Clinical DDI Study Designs 166

5.4.3 Statistical Approach in Clinical DDI Studies 168

5.5 Conclusion 169

References 169

6 General Toxicology: Principle, Methods, and Applications 179

6.1 Introduction: The History of Toxicology 179

6.2 The Multifaceted Field of Toxicology 183

6.2.1 Various Disciplines in Toxicology 183

6.2.2 Principles of Toxicology 184

6.3 Characteristics of Toxicants, Toxins, and Exposures 184

6.3.1 Use Classes 185

6.3.2 Characteristics of Exposure 186

6.3.3 Length of Exposure 186

6.3.4 Routes of Exposure 187

6.3.5 Dose Response 187

6.3.6 Tolerance 188

6.4 Adverse Drug Reactions: Idiosyncratic and Drug-Induced Liver Injury (DILI) 188

6.4.1 Idiosyncratic Drug Reactions (IDRs) 188

6.4.2 Drug-Induced Liver Injury 190

6.5 In Vitro Determination of Reactive Metabolite Formation, Oxidative Stress, Mitochondrial Damage, and Nephrotoxicity 193

6.6 Present and Future for Assessing Toxicity in Drug Discovery and Development 197

References 200

7 Toxicokinetics and Toxicity Testing in Drug Development 205

7.1 Introduction: Toxicokinetics and Its Relationship with Pharmacokinetics and ADME in Preclinical Development 205

7.2 Types of Preclinical Dosing that Support Toxicokinetics 206

7.2.1 Single-Dose Toxicity Studies 207

7.2.2 Repeated-Dose Toxicity Studies 207

7.3 Pharmacokinetic Parameters in Support of Toxicokinetic Assessments 209

7.3.1 Area Under the Curve (AUC) 209

7.3.2 Maximum Plasma Concentration (Cmax) and Time of Maximum Concentration (Tmax) 210

7.3.3 Clearance 210

7.3.4 Apparent Volume of Distribution (Vd) 211

7.3.5 Apparent Volume of Distribution at Steady State (Vdss) 211

7.3.6 Half-Life (t1¨M2) 212

7.3.7 Bioavailability (F%) 212

7.4 Genotoxicity, Oncogenicity, Reproductive Toxicity versus Toxicogenomics and Biomarkers in Preclinical Species 213

7.4.1 Genotoxicity Studies 213

7.4.2 Carcinogenicity (Oncogenicity) Studies 214

7.4.3 Reproductive Toxicity Studies 214

7.4.4 Toxicogenomics Studies 215

7.5 Drug Metabolism and Drug Related-Toxicities 215

References 218

8 PBPK Modeling and In Silico Prediction for ADME and Drug–Drug Interaction 221

8.1 Introduction: Computational Assessment of ADME and Drug–Drug Interaction (DDI) within Pharmaceutical R&D Paradigm 221

8.2 PBPK Models for ADMET and DDI 223

8.2.1 General PBPK Model and Physiological Parameters that Affect Drug Disposition 223

8.2.2 Simple Organ-Based PBPK Models 227

8.2.2.1 PBPK for Liver 227

8.2.2.2 Whole-Body PBPK Models 229

8.2.3 PBPK Model for DDI 230

8.2.4 PBPK and Genetic Polymorphism 232

8.3 In Silico Prediction of ADMET 232

8.3.1 Significance of Using In Silico Modeling: In Silico versus PBPK Modeling 233

8.3.2 Methods for In Silico ADMET Prediction 233

8.3.2.1 Data Modeling 233

8.3.2.2 Molecular Modeling 234

8.4 Applications of In Silico Models in ADME, DDI, and Drug Toxicity 234

8.4.1 Prediction of the Rate of Metabolism 235

8.4.2 DDI of Metabolism 235

8.4.3 Identifying Substrates for Transporters 235

References 236

9 Translational Tools toward Better Drug Therapy in Human Populations 241

9.1 Introduction: Translational ADMET and its Therapeutic Value 241

9.2 Translational Bioinformatics and Biomarkers: Utilization for Better Drug Therapy 244

9.2.1 In Cancer 245

9.2.2 In Chronic Kidney Disease (CKD) 245

9.2.3 Role of Biomarkers in CNS 246

9.2.4 Biomarkers in Diabetes and Their Role in AD 247

9.3 Genomics and Pharmacogenomics in Translational ADMET 249

9.3.1 Influence of Pharmacogenomics on Drug Metabolism-Mediated Drug Development 250

9.3.2 Influence of Pharmacogenomics on Drug Transporter-Mediated Drug Development 255

9.4 Translational ADMET, Approaches and Tools 257

9.4.1 From Bedside to Bench to Bedside: POC Investigations 257

9.4.1.1 Individualized Antifungal Drug Therapy in Pediatric Patients 257

9.4.1.2 “From Bedside to Bench” in Rare Pediatric Leukemia 261

9.4.2 From Juvenile Animal Model to Human Adult 262

9.4.3 Use of Chimeric Rodents with Humanized Liver as a Translation Model in Bridging the Gap between Preclinical and Clinical Trials in ADMET 263

9.5 Scaling of PK in Prediction of Human PK and Dosing 264

9.5.1 From Adult PK to Pediatric: Calculation of In Vivo CL in Children 264

9.5.2 From Animal PK to Human Dose 268

9.5.2.1 CL and PK/TK Modeling in Predicting Clinical Dose 270

References 271

10 Phase 1–Phase 3 Clinical Studies, Procedures, Responsibilities, and Documentation 277

10.1 Introduction: What is Clinical Investigation? Goals, Utility, and Processes of Four Phases in Clinical Drug Development 277

10.2 General Clinical Study Design: Enrollment, Responsibilities, and Documentation 282

10.2.1 Clinical Study Protocol 283

10.2.2 Patient Selection and Eligibility Criteria 284

10.2.3 Typical Study Design Features 285

10.2.3.1 Randomized Clinical Trials 285

10.2.3.2 Blinding versus Masking 286

10.2.4 Responsibilities: IRBs, Regulatory Authorities, Sponsor, PI, Patients 287

10.2.4.1 Institutional Review Boards 287

10.2.4.2 Role of Regulatory Agencies 287

10.2.4.3 Responsibility of Sponsor 289

10.3 Integration of Clinical Trials with Preclinical Absorption, Distribution, Metabolism, and Excretion (ADME), Drug–Drug Interaction (DDI), and Pharmacogenomics in Investigating 290

10.3.1 Assessment of DDI and Disposition 290

10.3.2 Mechanism Underlying Drug Therapy (Aromatase Inhibitors) for Breast Cancer 295

10.3.3 Mechanism Underlying Drug Therapy (Metformin) for Type 2 Diabetes 297

10.4 Clinical Pharmacology Studies of Special Populations 298

10.4.1 Pediatrics and Geriatrics 299

10.4.2 Renal Impaired 300

10.4.3 Hepatic Impaired 300

10.4.4 Genetic Polymorphic Populations 301

10.4.5 Different Ethnic Populations 302

References 302

11 Regulatory Submission: MIST and Drug Safety Assessment 307

11.1 Drug Development and Approval Processes According to the Food and Drug Administration (FDA), European Medicines Agency (EMA), and Other Regulatory Authorities 307

11.2 Studies Required for IND and NDA 309

11.2.1 Types of INDs, Types of Information, and Timelines 309

11.2.1.1 Chemistry and Manufacturing Control 309

11.2.1.2 Pharmacology/Toxicology 310

11.2.1.3 Pharmacology and Drug Distribution (21 CFR 312.23(a)(8)(I)) 310

11.2.1.4 Toxicology Data Present Regulations (21 CFR 312.23(a)(8)(ii)(a)) 310

11.2.1.5 Medical Review 310

11.2.1.6 Safety Review 311

11.2.1.7 Statistical Review 311

11.2.1.8 Timelines and Clinical Hold Decision 311

11.2.1.9 Notify Sponsor 311

11.2.2 Metabolites in Safety Testing (MIST) Regulation—Safety Assessments in Humans 311

11.2.3 Highlights of the AAPS 2013 MIST Symposium 314

11.2.3.1 ICH M3(R2) and Metabolite Issues 314

11.2.3.2 Early Assessment of MIST Liability of a Clinical Drug Candidate without the Use of Radiolabel 316

11.2.3.3 MIST: How Do We Deal with Surprises? 316

11.2.3.4 A Simple LC-MS/MS Method for Evaluating MIST Coverage 316

11.3 Drug Labeling and Black Box Warning 317

11.3.1 Sections Included in Drug Label 319

11.3.1.1 Drug Dosing 319

11.3.1.2 Age in Drug Labeling 319

11.3.1.3 Renal and Hepatic Impairment 320

11.3.1.4 Drug Metabolism 320

11.3.1.5 Genetic Polymorphism, Ethnic Differences 322

References 323

Index 327