Edited by

Hannah Batchelor, Strathclyde Institute of Pharmacy and Biomedical Sciences.

List of Contributors xv Foreword xvii 1 An Introduction to Biopharmaceutics 1Hannah 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 9Hamid 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 ¿) 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 31Hannah 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 39Hannah 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 51Chris 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 73Hannah 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 99Linette 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 113Panagiota 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 135Hannah 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 147Shanoo 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 165Francesca 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 189Konstantinos 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...