Biopharmaceutics

Hannah Batchelor, Strathclyde Institute of Pharmacy and Biomedical Sciences.

List of Contributors xv

Foreword xvii

1 An Introduction to Biopharmaceutics 1
Hannah Batchelor

1.1 Introduction 1

1.2 History of Biopharmaceutics 1

1.3 Key Concepts and Definitions Used Within Biopharmaceutics 3

1.4 The Role of Biopharmaceutics in Drug Development 6

1.5 Conclusions 8

2 Basic Pharmacokinetics 9
Hamid A. Merchant

2.1 Introduction 9

2.2 What is 'Pharmacokinetics'? 9

2.3 Pharmacokinetic Profile 10

2.4 Bioavailability 12

2.5 Drug Distribution 13

2.6 Volume of Distribution 15

2.7 Elimination 16

2.7.1 Metabolism 16

2.7.2 Excretion 17

2.8 Elimination Half-Life (t1/2) 19

2.9 Elimination Rate Constant 20

2.9.1 Clearance 20

2.10 Area Under the Curve (AUC) 21

2.11 Bioequivalence 22

2.12 Steady State 23

2.13 Compartmental Concepts in Pharmacokinetics 24

2.14 Concept of Linearity in Pharmacokinetics 25

2.15 Conclusions 28

3 Introduction to Biopharmaceutics Measures 31
Hannah Batchelor and Pavel Gershkovich

3.1 Introduction 31

3.2 Solubility 31

3.3 Dissolution 33

3.4 Permeability 34

3.5 Absorptive Flux 35

3.6 Lipinsky's Rule of 5 35

3.6.1 Molecular Weight 36

3.6.2 Lipophilicity 36

3.6.3 Hydrogen Bond Donors/Acceptors 37

4 Solubility 39
Hannah Batchelor

4.1 Definition of Solubility 39

4.2 The Importance of Solubility in Biopharmaceutics 39

4.3 What Level of Solubility Is Required? 40

4.4 Solubility-Limited Absorption 41

4.5 Methods to Assess Solubility 41

4.6 Brief Overview of Forces Involved in Solubility 42

4.6.1 van der Waals Interactions 42

4.6.2 Hydrogen Bonding 42

4.6.3 Ionic Interactions 43

4.7 Solid-State Properties and Solubility 43

4.8 pH and Drug Solubility 43

4.9 Solvents 44

4.9.1 Biorelevant Solubility 45

4.9.2 Buffer System - Phosphate vs Bicarbonate 45

4.9.3 Solubilisation by Surfactants 45

4.9.4 Solubilisation During Digestion 47

4.9.5 Excipients and Solubility 47

4.10 Risk of Precipitation 48

4.11 Solubility and Link to Lipophilicity 49

4.12 Conclusions 49

5 Permeability 51
Chris Roe and Vanessa Zann

5.1 Introduction 51

5.2 Enzymes, Gut Wall Metabolism, Tissue Permeability and Transporters 51

5.2.1 Enzymes 52

5.2.2 Drug Transporters 54

5.2.3 Efflux Transporters 55

5.2.4 Transporters of Greatest Relevance to Oral Biopharmaceutics 56

5.2.5 Regulatory Overview of Transporter Effects on Biopharmaceutics 58

5.2.6 Regional Expression and Polymorphism of Intestinal Transporters and Impact of Drug Variability 58

5.3 Applications and Limitations of Characterisation and Predictive Tools for Permeability Assessment 59

5.3.1 In Silico Tools: Predictive Models for Permeability 59

5.3.2 in vitro Tools 60

5.3.2.1 PAMPA 60

5.3.2.2 Cell Lines 61

5.3.3 ex vivo Tools 63

5.3.3.1 Ussing Chambers 63

5.3.3.2 Everted Intestinal Sac/Ring 65

5.3.4 In Situ Tools 66

5.3.4.1 Closed-Loop Intestinal Perfusion 66

5.3.4.2 Single-Pass Intestinal Perfusion 66

5.3.4.3 Intestinal Perfusion with Venous Sampling 67

5.3.4.4 Vascularly Perfused Intestinal Models 67

5.4 in vivo Tools 67

5.5 Conclusion 69

6 Dissolution 75
Hannah Batchelor and James Butler

6.1 Introduction 75

6.2 Purpose of Dissolution Testing 75

6.2.1 Dissolution Versus Solubility 76

6.3 History of Dissolution Testing 77

6.4 Compendial (Pharmacopeial) Dissolution Apparatus 78

6.4.1 USP1 and 2 Apparatus 78

6.4.2 USP3 Apparatus 79

6.4.3 USP4 Apparatus 80

6.4.4 USP5 Apparatus 82

6.4.5 USP6 Apparatus 82

6.4.6 USP7 Apparatus 82

6.4.7 Intrinsic Dissolution Rate (IDR) Apparatus 83

6.4.8 Micro-dissolution Apparatus 83

6.5 Dissolution Media Selection 83

6.5.1 Biphasic Dissolution Media 84

6.6 Dissolution Agitation Rates 84

6.7 Reporting Dissolution Data 85

6.8 In Vitro In Vivo Relationships and Correlations (IVIVR/IVIVC) 86

6.8.1 Convolution and Deconvolution of Dissolution Data 87

6.9 Evolution of Biorelevant Dissolution Testing 88

6.9.1 Biorelevant Dissolution Media 88

6.9.2 Dissolution Testing to Mimic GI Transit 93

6.9.3 Dissolution Testing to Mimic Motility/Hydrodynamic Conditions 94

6.9.4 Dissolution Testing to Incorporate Permeability 95

6.10 Conclusions 96

7 Biopharmaceutics to Inform Candidate Drug Selection and Optimisation 103
Linette Ruston

7.1 Introduction 103

7.2 Oral Product Design Considerations During Early Development 103

7.3 Biopharmaceutics in Drug Discovery 105

7.3.1 Pre-Clinical Studies 106

7.4 Biopharmaceutics Assessment 107

7.4.1 Solubility 107

7.4.2 Permeability 107

7.4.3 Dissolution 108

7.4.4 Biopharmaceutics Classification System 108

7.4.5 Lipophilicity 109

7.4.6 pKa 109

7.4.7 Molecular Size 109

7.4.8 Crystallinity 109

7.4.9 In Vivo Pre-Clinical Studies 109

7.4.10 In Silico Modelling 110

7.4.11 Human Absorption/Dose Prediction 110

7.5 Output of Biopharmaceutics Assessment 110

7.5.1 New Modalities/Complex Delivery Systems Within Early Development 112

7.6 Influence/Optimise/Design Properties to Inform Formulation Development 112

7.6.1 Fraction Absorbed Classification System 113

7.7 Conclusion 114

8 Biopharmaceutics Tools for Rational Formulation Design 117
Panagiota Zarmpi, Mark McAllister, James Butler, and Nikoletta Fotaki

8.1 Introduction 117

8.2 Formulation Development to Optimise Drug Bioavailability 118

8.3 Traditional Formulation Strategies 119

8.3.1 Decision Making for Conventional or Enabling Formulations 119

8.4 Decision Trees to Guide Formulation Development 119

8.4.1 Decision Trees Based on Biopharmaceutics Classification System (BCS) 119

8.4.2 Decision Trees Based on Developability Classification System (DCS) 121

8.4.3 Expanded Decision Trees 122

8.5 Computational Tools to Guide Formulation Strategies 124

8.5.1 Statistical Tools 124

8.5.2 Physiologically Based Pharmacokinetic/Biopharmaceutics Models 125

8.6 Decision- Making for Optimising Enabling Formulations 125

8.7 Decision Trees for Enabled Formulations 127

8.7.1 Statistical Tools 128

8.7.2 Physiologically Based Pharmacokinetic/Biopharmaceutics Models 128

8.8 System-Based Formulation Strategies 128

8.8.1 Quality by Design 128

8.8.2 Tools to Identify Quality Target Product Profile 129

8.9 Biopharmaceutics Risk Assessment Roadmap (BioRAM) 131

8.9.1 Tools to Identify Quality Target Product Profile 131

8.10 Conclusions 132

9 Biopharmaceutic Classification System 139
Hannah Batchelor and Talia Flanagan

9.1 Description and History of the BCS 139

9.2 BCS-Based Criteria for Solubility, Dissolution and Permeability 139

9.3 BCS-Based Biowaivers 141

9.4 Regulatory Development of BCS-Based Biowaivers 142

9.5 International Harmonisation of BCS-Based Biowaiver Criteria - ICH M9 143

9.5.1 Application of BCS-Based Biowaivers 144

9.5.1.1 Drug Product Type 144

9.5.1.2 Composition 145

9.5.1.3 Dissolution Similarity 145

9.6 BCS as a Development Tool 146

9.6.1 Candidate Selection 146

9.6.2 Solid Form Selection 146

9.6.3 Product Development 146

9.7 Beyond the BCS 147

9.7.1 Biopharmaceutic Drug Disposition Classification System (BDDCS) 148

9.7.2 Developability Classification System 148

9.7.3 Fraction Absorbed Classification System 148

9.7.4 BCS Applied to Special Populations 149

9.8 Conclusions 149

10 Regulatory Biopharmaceutics 153
Shanoo Budhdeo, Paul A. Dickinson, and Talia Flanagan

10.1 Introduction 153

10.2 Clinical Bioequivalence Studies 154

10.3 Design of Clinical Bioequivalence (BE) Studies 156

10.4 Implication of Bioequivalence Metrics 157

10.5 Bioequivalence Regulatory Guidelines 159

10.6 Biowaivers 159

10.7 Biopharmaceutics in Quality by Design 159

10.8 Control of Drug Product and Clinically Relevant Specifications 162

10.9 Establishing Clinically Relevant Dissolution Methods and Specifications 162

10.10 Application of In Silico Physiologically Based Biopharmaceutics Modelling (PBBM) to Develop Clinically Relevant Specifications 165

10.11 Additional Considerations for Establishing Dissolution Methods and Specifications 165

10.12 Common Technical Document (CTD) 166

10.13 Other Routes of Administration and Locally Acting Drug Products 167

10.14 Conclusion 168

11 Impact of Anatomy and Physiology 171
Francesca K. H. Gavins, Christine M. Madla, Sarah J. Trenfield, Laura E. McCoubrey, Abdul W. Basit, and Mark McAllister

11.1 Introduction 171

11.2 Influence of GI Conditions on Pharmacokinetic Studies 172

11.3 The Stomach 172

11.3.1 Gastric Anatomy 172

11.3.2 Gastric Motility and Mixing 174

11.3.3 Gastric Emptying 175

11.3.3.1 Gastric Fed State 176

11.3.4 Gastric Fluid Volume 176

11.3.5 Gastric Temperature 177

11.3.6 Gastric Fluid Composition 177

11.3.6.1 Gastric pH 177

11.3.6.2 Gastric Bile Salt Composition and Concentration 178

11.4 Small Intestine 178

11.4.1 Small Intestinal Anatomy 178

11.4.2 Small Intestinal Motility and Mixing 180

11.4.3 Small Intestinal Transit Time 180

11.4.4 Small Intestinal Volume 180

11.4.5 Small Intestinal Fluid Composition 181

11.4.5.1 Small Intestinal pH 182

11.4.5.2 Small Intestinal Buffer Capacity 182

11.4.5.3 Small Intestinal Surface Tension 182

11.4.5.4 Small Intestinal Osmolality 182

11.4.5.5 Bile Salt Composition and Concentration 183

11.5 The Colon/Large Intestine 183

11.5.1 Large Intestine Anatomy 184

11.5.2 Large Intestinal Motility and Mixing 184

11.5.3 Large Intestinal Transit Time 185

11.5.4 Large Intestinal Volume 185

11.5.5 Large Intestinal Fluid Composition 185

11.5.5.1 Large Intestinal pH 186

11.5.5.2 Large Intestinal Buffer Capacity 186

11.5.5.3 Large Intestinal Surface Tension 186

11.5.5.4 Large Intestinal Osmolality 186

11.5.5.5 Bile Salt Composition and Concentration 186

11.5.6 Impact of Microbiome on Oral Drug Delivery 187

11.6 Conclusions 188

12 Integrating Biopharmaceutics to Predict Oral Absorption Using PBPK Modelling 197
Konstantinos Stamatopoulos

12.1 Introduction 197

12.2 Mechanistic Models 198

12.3 Solubility Inputs 200

12.4 Dissolution Inputs 203

12.4.1 Fluid Dynamics and Dissolution 205

12.5 Permeability Inputs 206

12.6 Incorporation of Modelling and Simulation into Drug Development 208

12.6.1 Understanding the Effect of Formulation Modifications on Drug Pharmacokinetics 208

12.6.2 Model Verification/Validation 209

12.6.3 Using Modelling to Understand Bioequivalence 209

12.7 Conclusions 210

13 Special Populations 213
Christine M. Madla, Francesca K. H. Gavins, Sarah J. Trenfield, and Abdul W. Basit

13.1 Introduction 213

13.2 Sex Differences in the Gastrointestinal Tract and Its Effect on Oral Drug Performance 213

13.3 Ethnic Differences in the Gastrointestinal Tract 216

13.4 Impact of Diet on Gastrointestinal Physiology 217

13.5 Pregnancy and Its Effect on Gastrointestinal Physiology 219

13.6 The Implication of Disease States on Gastrointestinal Physiology and Its Effect on Oral Drug Performance 220

13.7 Diseases that Affect the Gastrointestinal Tract 220

13.7.1 Irritable Bowel Syndrome 220

13.7.2 Inflammatory Bowel Disease 221

13.7.3 Celiac Disease 223

13.8 Infections in the Gastrointestinal Tract 224

13.8.1 Helicobacter pylori Infection 224

13.9 Systemic Diseases that Alter GI Physiology and Function 224

13.9.1 Cystic Fibrosis 225

13.9.2 Parkinson's Disease 226

13.9.3 Diabetes 227

13.9.4 HIV Infection 229

13.10 Age-related Influences on Gastrointestinal Tract Physiology and Function 230

13.10.1 Gastrointestinal Physiology and Function in Paediatrics 230

13.10.2 Gastrointestinal Physiology and Function in Geriatrics 232

13.11 Conclusion 234

14 Inhalation Biopharmaceutics 249
Precious Akhuemokhan, Magda Swedrowska and Ben Forbes

14.1 Introduction 249

14.2 Structure of the Lungs 250

14.2.1 Basic Anatomy 250

14.2.2 Epithelial Lining Fluid 251

14.2.3 Epithelium 251

14.3 Molecules, Inhalation Devices, Formulations 252

14.3.1 Inhaled Molecules 252

14.3.2 Inhalation Devices 252

14.3.2.1 Nebulisers 252

14.3.2.2 Pressurised Metered-Dose Inhalers 253

14.3.2.3 Dry Powder Inhalers 253

14.3.2.4 'Soft Mist' Inhalers 253

14.3.3 Inhaled Medicine Formulation 253

14.4 Inhaled Drug Delivery and Models for Studying Inhalation Biopharmaceutics 254

14.4.1 Dosimetry and Deposition 254

14.4.2 Mucociliary Clearance 256

14.4.3 Dissolution 256

14.4.4 Lung Permeability, Absorption and Retention 257

14.4.5 Metabolism 258

14.4.6 Non-Clinical Inhalation Studies 258

14.4.7 Mechanistic Computer Modelling 259

14.5 Bioequivalence and an Inhalation Bioclassification System 259

14.6 Conclusion 260

15 Biopharmaceutics of Injectable Formulations 263
Wang Wang Lee and Claire M. Patterson

15.1 Introduction 263

15.2 Subcutaneous Physiology and Absorption Mechanisms 266

15.2.1 Physiology 266

15.2.2 Absorption Mechanisms 266

15.3 Intramuscular Physiology and Absorption Mechanisms 268

15.3.1 Physiology 268

15.3.2 Absorption Mechanisms 269

15.4 In vitro Performance and IVIVC 269

15.4.1 In Silico Models 271

15.4.2 Preclinical Models 271

15.5 Bioequivalence of Injectable Formulations 271

15.6 Summary 272

16 Biopharmaceutics of Topical and Transdermal Formulations 275
Hannah Batchelor

16.1 Introduction 275

16.2 Skin Structure 275

16.2.1 Transport of Drugs Through Skin 276

16.2.2 Skin Metabolism 277

16.3 Active Pharmaceutical Ingredient Properties 277

16.4 Topical and Transdermal Dosage Forms 277

16.5 Measurement of Vitro Drug Release 278

16.5.1 Diffusion Cells 278

16.5.2 Compendial Dissolution Apparatus 279

16.6 Measurement of Skin Permeation 279

16.6.1 Tape-Stripping 'Dermatopharmacokinetics' (DPK) 279

16.6.2 Confocal Laser Scanning Microscopy (CLSM) 280

16.6.3 Diffusion Cells Using Biorelevant Membranes to Model Permeation 280

16.6.3.1 Alternative Skin Substrates Used for Permeability Studies 280

16.6.4 Dermal Microdialysis 281

16.6.5 Skin Biopsy 281

16.6.6 In Silico Models of Dermal Absorption 281

16.6.7 Pre-Clinical Models 282

16.7 Bioequivalence Testing of Topical/Transdermal Products 282

16.8 Conclusions 283

17 Impact of the Microbiome on Oral Biopharmaceutics 287
Laura E. McCoubrey, Hannah Batchelor, Abdul W. Basit, Simon Gaisford, and Mine Orlu

17.1 Introduction 287

17.2 Microbiome Distribution in the GI Tract 288

17.3 Key Causes of Microbiome Variability 290

17.4 Microbiome Influence on Key GI Parameters 292

17.4.1 pH 292

17.4.2 Bile Acid Concentration and Composition 292

17.4.3 Drug Transporters 292

17.4.4 Motility 293

17.4.5 Hepatic Drug Metabolism 293

17.4.6 Epithelial Permeability 294

17.5 Enzymatic Degradation of Drugs by GI Microbiota 294

17.6 Exploitation of the GI Microbiome for Drug Delivery 295

17.7 Models of the GI Microbiome 295

17.7.1 In vitro Models 295

17.7.2 In Silico Models 299

17.8 Conclusion 299

Index 000