Explore the latest research in biopharmaceutics from leading contributors in the field
In Biopharmaceutics - From Fundamentals to Industrial Practice, distinguished Scientists from the UK's Academy of Pharmaceutical Sciences Biopharmaceutica Focus Group deliver a comprehensive examination of the tools used within the field of biopharmaceutics and their applications to drug development. This edited volume is an indispensable tool for anyone seeking to better understand the field of biopharmaceutics as it rapidly develops and evolves.
Beginning with an expansive introduction to the basics of biopharmaceutics and the context that underpins the field, the included resources go on to discuss how biopharmaceutics are integrated into product development within the pharmaceutical industry. Explorations of how the regulatory aspects of biopharmaceutics function, as well as the impact of physiology and anatomy on the rate and extent of drug absorption, follow.
Readers will find insightful discussions of physiologically based modeling as a valuable asset in the biopharmaceutics toolkit and how to apply the principles of the field to special populations. The book goes on to discuss:
- Thorough introductions to biopharmaceutics, basic pharmacokinetics, and biopharmaceutics measures
- Comprehensive explorations of solubility, permeability, and dissolution
- Practical discussions of the use of biopharmaceutics to inform candidate drug selection and optimization, as well as biopharmaceutics tools for rational formulation design
- In-depth examinations of biopharmaceutics classification systems and regulatory biopharmaceutics, as well as regulatory biopharmaceutics and the impact of anatomy and physiology
Perfect for professionals working in the pharmaceutical and biopharmaceutical industries, Biopharmaceutics - From Fundamentals to Industrial Practice is an incisive and up-to-date resource on the practical, pharmaceutical applications of the field.
Table of Contents
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
References 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 14
2.6 Volume of Distribution 15
2.7 Elimination 17
2.7.1 Metabolism 17
2.7.2 Excretion 17
2.8 Elimination Half- Life (t ½) 19
2.9 Elimination Rate Constant 19
2.9.1 Clearance 21
2.10 Area Under the Curve (AUC) 22
2.11 Bioequivalence 22
2.12 Steady State 23
2.13 Compartmental Concepts in Pharmacokinetics 25
2.14 Concept of Linearity in Pharmacokinetics 27
2.15 Conclusions 28
Further Reading 29
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 36
3.6.1 Molecular Weight 36
3.6.2 Lipophilicity 36
3.6.3 Hydrogen Bond Donors/Acceptors 37
References 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 46
4.9.3 Solubilisation by Surfactants 46
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
References 49
5 Permeability 51
Chris Roe and Vanessa Zann
5.1 Introduction 51
5.2 Enzymes, Gut Wall Metabolism, Tissue Permeability and Transporters 52
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 59
5.3 Applications and Limitations of Characterisation and Predictive Tools for Permeability Assessment 59
5.3.1 In Silico Tools: Predictive Models for Permeability 60
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 67
5.3.4.3 Intestinal Perfusion with Venous Sampling 67
5.3.4.4 Vascularly Perfused Intestinal Models 68
5.4 In Vivo Tools 68
5.5 Conclusion 69
References 69
6 Dissolution 73
Hannah Batchelor and James Butler
6.1 Introduction 73
6.2 Purpose of Dissolution Testing 73
6.2.1 Dissolution Versus Solubility 74
6.3 History of Dissolution Testing 75
6.4 Compendial (Pharmacopeial) Dissolution Apparatus 76
6.4.1 USP1 and 2 Apparatus 76
6.4.2 USP3 Apparatus 78
6.4.3 USP4 Apparatus 79
6.4.4 USP5 Apparatus 80
6.4.5 USP6 Apparatus 80
6.4.6 USP7 Apparatus 80
6.4.7 Intrinsic Dissolution Rate (IDR) Apparatus 80
6.4.8 Micro- dissolution Apparatus 81
6.5 Dissolution Media Selection 81
6.5.1 Biphasic Dissolution Media 82
6.6 Dissolution Agitation Rates 82
6.7 Reporting Dissolution Data 83
6.8 In Vitro In Vivo Relationships and Correlations (IVIVR/IVIVC) 84
6.8.1 Convolution and Deconvolution of Dissolution Data 85
6.9 Evolution of Biorelevant Dissolution Testing 86
6.9.1 Biorelevant Dissolution Media 86
6.9.2 Dissolution Testing to Mimic GI Transit 90
6.9.3 Dissolution Testing to Mimic Motility/Hydrodynamic Conditions 92
6.9.4 Dissolution Testing to Incorporate Permeability 93
6.10 Conclusions 93
References 94
7 Biopharmaceutics to Inform Candidate Drug Selection and Optimisation 99
Linette Ruston
7.1 Introduction 99
7.2 Oral Product Design Considerations During Early Development 100
7.3 Biopharmaceutics in Drug Discovery 101
7.3.1 Pre- Clinical Studies 102
7.4 Biopharmaceutics Assessment 103
7.4.1 Solubility 103
7.4.2 Permeability 104
7.4.3 Dissolution 104
7.4.4 Biopharmaceutics Classification System 104
7.4.5 Lipophilicity 104
7.4.6 pK a 105
7.4.7 Molecular Size 105
7.4.8 Crystallinity 105
7.4.9 In Vivo Pre-Clinical Studies 106
7.4.10 In Silico Modelling 106
7.4.11 Human Absorption/Dose Prediction 106
7.5 Output of Biopharmaceutics Assessment 107
7.5.1 New Modalities/Complex Delivery Systems Within Early Development 107
7.6 Influence/Optimise/Design Properties to Inform Formulation Development 108
7.6.1 Fraction Absorbed Classification System 110
7.7 Conclusion 110
References 110
8 Biopharmaceutics Tools for Rational Formulation Design 113
Panagiota Zarmpi, Mark McAllister, James Butler and Nikoletta Fotaki
8.1 Introduction 113
8.2 Formulation Development to Optimise Drug Bioavailability 115
8.3 Traditional Formulation Strategies 115
8.3.1 Decision Making for Conventional or Enabling Formulations 115
8.4 Decision Trees to Guide Formulation Development 115
8.4.1 Decision Trees Based on Biopharmaceutics Classification System (BCS) 115
8.4.2 Decision Trees Based on Developability Classification System (DCS) 117
8.4.3 Expanded Decision Trees 120
8.5 Computational Tools to Guide Formulation Strategies 120
8.5.1 Statistical Tools 120
8.5.2 Physiologically Based Pharmacokinetic/Biopharmaceutics Models 121
8.6 Decision- Making for Optimising Enabling Formulations 122
8.7 Decision Trees for Enabled Formulations 123
8.7.1 Statistical Tools 124
8.7.2 Physiologically Based Pharmacokinetic/Biopharmaceutics Models 124
8.8 System- Based Formulation Strategies 125
8.8.1 Quality by Design 125
8.8.2 Tools to Identify Quality Target Product Profile 125
8.9 Biopharmaceutics Risk Assessment Roadmap (BioRAM) 126
8.9.1 Tools to Identify Quality Target Product Profile 126
8.10 Conclusions 129
References 131
9 Biopharmaceutic Classification System 135
Hannah Batchelor and Talia Flanagan
9.1 Description and History of the BCS 135
9.2 BCS- Based Criteria for Solubility, Dissolution and Permeability 135
9.3 BCS- Based Biowaivers 137
9.4 Regulatory Development of BCS- Based Biowaivers 138
9.5 International Harmonisation of BCS- Based Biowaiver Criteria - ICH M 9 138
9.5.1 Application of BCS- Based Biowaivers 139
9.5.1.1 Drug Product Type 140
9.5.1.2 Composition 140
9.5.1.3 Dissolution Similarity 141
9.6 BCS as a Development Tool 141
9.6.1 Candidate Selection 142
9.6.2 Solid Form Selection 142
9.6.3 Product Development 142
9.7 Beyond the BCS 143
9.7.1 Biopharmaceutic Drug Disposition Classification System (bddcs) 143
9.7.2 Developability Classification System 144
9.7.3 Fraction Absorbed Classification System 144
9.7.4 BCS Applied to Special Populations 144
9.8 Conclusions 145
References 145
10 Regulatory Biopharmaceutics 147
Shanoo Budhdeo, Paul A. Dickinson and Talia Flanagan
10.1 Introduction 147
10.2 Clinical Bioequivalence Studies 148
10.3 Design of Clinical Bioequivalence (BE) Studies 150
10.4 Implication of Bioequivalence Metrics 151
10.5 Bioequivalence Regulatory Guidelines 152
10.6 Biowaivers 153
10.7 Biopharmaceutics in Quality by Design 153
10.8 Control of Drug Product and Clinically Relevant Specifications 155
10.9 Establishing Clinically Relevant Dissolution Methods and Specifications 156
10.10 Application of In Silico Physiologically Based Biopharmaceutics Modelling (PBBM) to Develop Clinically Relevant Specifications 159
10.11 Additional Considerations for Establishing Dissolution Methods and Specifications 159
10.12 Common Technical Document (CTD) 160
10.13 Other Routes of Administration and Locally Acting Drug Products 161
10.14 Conclusion 162
References 162
11 Impact of Anatomy and Physiology 165
Francesca K. H. Gavins, Christine M. Madla, Sarah J. Trenfield, Laura E. McCoubrey, Abdul W. Basit and Mark McAllister
11.1 Introduction 165
11.2 Influence of GI Conditions on Pharmacokinetic Studies 166
11.3 The Stomach 167
11.3.1 Gastric Anatomy 167
11.3.2 Gastric Motility and Mixing 168
11.3.3 Gastric Emptying 169
11.3.3.1 Gastric Fed State 170
11.3.4 Gastric Fluid Volume 170
11.3.5 Gastric Temperature 171
11.3.6 Gastric Fluid Composition 171
11.3.6.1 Gastric pH 171
11.3.6.2 Gastric Bile Salt Composition and Concentration 172
11.4 Small Intestine 172
11.4.1 Small Intestinal Anatomy 172
11.4.2 Small Intestinal Motility and Mixing 174
11.4.3 Small Intestinal Transit Time 174
11.4.4 Small Intestinal Volume 174
11.4.5 Small Intestinal Fluid Composition 175
11.4.5.1 Small Intestinal pH 176
11.4.5.2 Small Intestinal Buffer Capacity 176
11.4.5.3 Small Intestinal Surface Tension 176
11.4.5.4 Small Intestinal Osmolality 176
11.4.5.5 Bile Salt Composition and Concentration 177
11.5 The Colon/Large Intestine 177
11.5.1 Large Intestine Anatomy 178
11.5.2 Large Intestinal Motility and Mixing 178
11.5.3 Large Intestinal Transit Time 179
11.5.4 Large Intestinal Volume 179
11.5.5 Large Intestinal Fluid Composition 179
11.5.5.1 Large Intestinal pH 179
11.5.5.2 Large Intestinal Buffer Capacity 180
11.5.5.3 Large Intestinal Surface Tension 180
11.5.5.4 Large Intestinal Osmolality 180
11.5.5.5 Bile Salt Composition and Concentration 180
11.5.6 Impact of Microbiome on Oral Drug Delivery 181
11.6 Conclusions 182
References 182
12 Integrating Biopharmaceutics to Predict Oral Absorption Using PBPK Modelling 189
Konstantinos Stamatopoulos
12.1 Introduction 189
12.2 Mechanistic Models 190
12.3 Solubility Inputs 192
12.4 Dissolution Inputs 196
12.4.1 Fluid Dynamics and Dissolution 198
12.5 Permeability Inputs 198
12.6 Incorporation of Modelling and Simulation into Drug Development 200
12.6.1 Understanding the Effect of Formulation Modifications on Drug Pharmacokinetics 200
12.6.2 Model Verification/Validation 201
12.6.3 Using Modelling to Understand Bioequivalence 201
12.7 Conclusions 202
References 202
13 Special Populations 205
Christine M. Madla, Francesca K. H. Gavins, Sarah J. Trenfield and Abdul W. Basit
13.1 Introduction 205
13.2 Sex Differences in the Gastrointestinal Tract and Its Effect on Oral Drug Performance 206
13.3 Ethnic Differences in the Gastrointestinal Tract 208
13.4 Impact of Diet on Gastrointestinal Physiology 209
13.5 Pregnancy and Its Effect on Gastrointestinal Physiology 211
13.6 The Implication of Disease States on Gastrointestinal Physiology and Its Effect on Oral Drug Performance 212
13.7 Diseases that Affect the Gastrointestinal Tract 212
13.7.1 Irritable Bowel Syndrome 212
13.7.2 Inflammatory Bowel Disease 213
13.7.3 Celiac Disease 215
13.8 Infections in the Gastrointestinal Tract 216
13.8.1 Helicobacter pylori Infection 216
13.9 Systemic Diseases that Alter GI Physiology and Function 216
13.9.1 Cystic Fibrosis 217
13.9.2 Parkinson’s Disease 218
13.9.3 Diabetes 219
13.9.4 HIV Infection 221
13.10 Age- related Influences on Gastrointestinal Tract Physiology and Function 222
13.10.1 Gastrointestinal Physiology and Function in Paediatrics 222
13.10.2 Gastrointestinal Physiology and Function in Geriatrics 224
13.11 Conclusion 226
References 226
14 Inhalation Biopharmaceutics 239
Precious Akhuemokhan, Magda Swedrowska, and Ben Forbes
14.1 Introduction 239
14.2 Structure of the Lungs 240
14.2.1 Basic Anatomy 240
14.2.2 Epithelial Lining Fluid 241
14.2.3 Epithelium 241
14.3 Molecules, Inhalation Devices, Formulations 241
14.3.1 Inhaled Molecules 241
14.3.2 Inhalation Devices 242
14.3.2.1 Nebulisers 242
14.3.2.2 Pressurised Metered- Dose Inhalers 243
14.3.2.3 Dry Powder Inhalers 243
14.3.2.4 ‘Soft Mist’ Inhalers 243
14.3.3 Inhaled Medicine Formulation 243
14.4 Inhaled Drug Delivery and Models for Studying Inhalation Biopharmaceutics 244
14.4.1 Dosimetry and Deposition 244
14.4.2 Mucociliary Clearance 245
14.4.3 Dissolution 246
14.4.4 Lung Permeability, Absorption and Retention 247
14.4.5 Metabolism 248
14.4.6 Non- Clinical Inhalation Studies 248
14.4.7 Mechanistic Computer Modelling 249
14.5 Bioequivalence and an Inhalation Bioclassification System 249
14.6 Conclusion 249
References 250
15 Biopharmaceutics of Injectable Formulations 253
Wang Wang Lee and Claire M. Patterson
15.1 Introduction 253
15.2 Subcutaneous Physiology and Absorption Mechanisms 256
15.2.1 Physiology 256
15.2.2 Absorption Mechanisms 257
15.3 Intramuscular Physiology and Absorption Mechanisms 258
15.3.1 Physiology 258
15.3.2 Absorption Mechanisms 259
15.4 In Vitro Performance and IVIVC 259
15.4.1 In Silico Models 261
15.4.2 Preclinical Models 261
15.5 Bioequivalence of Injectable Formulations 261
15.6 Summary 262
References 262
16 Biopharmaceutics of Topical and Transdermal Formulations 265
Hannah Batchelor
16.1 Introduction 265
16.2 Skin Structure 266
16.2.1 Transport of Drugs Through Skin 267
16.2.2 Skin Metabolism 267
16.3 Active Pharmaceutical Ingredient Properties 267
16.4 Topical and Transdermal Dosage Forms 267
16.5 Measurement of In Vitro Drug Release 268
16.5.1 Diffusion Cells 268
16.5.2 Compendial Dissolution Apparatus 269
16.6 Measurement of Skin Permeation 269
16.6.1 Tape- Stripping ‘Dermatopharmacokinetics’ (DPK) 270
16.6.2 Confocal Laser Scanning Microscopy (CLSM) 270
16.6.3 Diffusion Cells Using Biorelevant Membranes to Model Permeation 270
16.6.3.1 Alternative Skin Substrates Used for Permeability Studies 270
16.6.4 Dermal Microdialysis 271
16.6.5 Skin Biopsy 271
16.6.6 In Silico Models of Dermal Absorption 271
16.6.7 Pre- Clinical Models 272
16.7 Bioequivalence Testing of Topical/Transdermal Products 273
16.8 Conclusions 274
References 274
17 Impact of the Microbiome on Oral Biopharmaceutics 277
Laura E. McCoubrey, Hannah Batchelor, Abdul W. Basit, Simon Gaisford and Mine Orlu
17.1 Introduction 277
17.2 Microbiome Distribution in the GI Tract 278
17.3 Key Causes of Microbiome Variability 280
17.4 Microbiome Influence on Key GI Parameters 281
17.4.1 pH 281
17.4.2 Bile Acid Concentration and Composition 281
17.4.3 Drug Transporters 283
17.4.4 Motility 283
17.4.5 Hepatic Drug Metabolism 283
17.4.6 Epithelial Permeability 284
17.5 Enzymatic Degradation of Drugs by GI Microbiota 284
17.6 Exploitation of the GI Microbiome for Drug Delivery 285
17.7 Models of the GI Microbiome 285
17.7.1 In Vitro Models 285
17.7.2 In Silico Models 289
17.8 Conclusion 289
References 290
Index 297
