Biopharmaceutics

Edited byHannah Batchelor, Strathclyde Institute of Pharmacy and Biomedical Sciences.

• List of Contributors xvForeword xvii1 An Introduction to Biopharmaceutics 1Hannah Batchelor1.1 Introduction 11.2 History of Biopharmaceutics 11.3 Key Concepts and Definitions Used Within Biopharmaceutics 31.4 The Role of Biopharmaceutics in Drug Development 61.5 Conclusions 8References 82 Basic Pharmacokinetics 9Hamid A. Merchant2.1 Introduction 92.2 What is ‘Pharmacokinetics’? 92.3 Pharmacokinetic Profile 102.4 Bioavailability 122.5 Drug Distribution 142.6 Volume of Distribution 152.7 Elimination 172.7.1 Metabolism 172.7.2 Excretion 172.8 Elimination Half- Life (t ½) 192.9 Elimination Rate Constant 192.9.1 Clearance 212.10 Area Under the Curve (AUC) 222.11 Bioequivalence 222.12 Steady State 232.13 Compartmental Concepts in Pharmacokinetics 252.14 Concept of Linearity in Pharmacokinetics 272.15 Conclusions 28Further Reading 293 Introduction to Biopharmaceutics Measures 31Hannah Batchelor and Pavel Gershkovich3.1 Introduction 313.2 Solubility 313.3 Dissolution 333.4 Permeability 343.5 Absorptive Flux 353.6 Lipinsky’s Rule of 5 363.6.1 Molecular Weight 363.6.2 Lipophilicity 363.6.3 Hydrogen Bond Donors/Acceptors 37References 374 Solubility 39Hannah Batchelor4.1 Definition of Solubility 394.2 The Importance of Solubility in Biopharmaceutics 394.3 What Level of Solubility Is Required? 404.4 Solubility- Limited Absorption 414.5 Methods to Assess Solubility 414.6 Brief Overview of Forces Involved in Solubility 424.6.1 van der Waals Interactions 424.6.2 Hydrogen Bonding 424.6.3 Ionic Interactions 434.7 Solid- State Properties and Solubility 434. 8 pH and Drug Solubility 434.9 Solvents 444.9.1 Biorelevant Solubility 454.9.2 Buffer System – Phosphate vs Bicarbonate 464.9.3 Solubilisation by Surfactants 464.9.4 Solubilisation During Digestion 474.9.5 Excipients and Solubility 474.10 Risk of Precipitation 484.11 Solubility and Link to Lipophilicity 494.12 Conclusions 49References 495 Permeability 51Chris Roe and Vanessa Zann5.1 Introduction 515.2 Enzymes, Gut Wall Metabolism, Tissue Permeability and Transporters 525.2.1 Enzymes 525.2.2 Drug Transporters 545.2.3 Efflux Transporters 555.2.4 Transporters of Greatest Relevance to Oral Biopharmaceutics 565.2.5 Regulatory Overview of Transporter Effects on Biopharmaceutics 585.2.6 Regional Expression and Polymorphism of Intestinal Transporters and Impact of Drug Variability 595.3 Applications and Limitations of Characterisation and Predictive Tools for Permeability Assessment 595.3.1 In Silico Tools: Predictive Models for Permeability 605.3.2 In Vitro Tools 605.3.2.1 Pampa 605.3.2.2 Cell Lines 615.3.3 Ex Vivo Tools 635.3.3.1 Ussing Chambers 635.3.3.2 Everted Intestinal Sac/Ring 655.3.4 In Situ Tools 665.3.4.1 Closed- Loop Intestinal Perfusion 665.3.4.2 Single- Pass Intestinal Perfusion 675.3.4.3 Intestinal Perfusion with Venous Sampling 675.3.4.4 Vascularly Perfused Intestinal Models 685.4 In Vivo Tools 685.5 Conclusion 69References 696 Dissolution 73Hannah Batchelor and James Butler6.1 Introduction 736.2 Purpose of Dissolution Testing 736.2.1 Dissolution Versus Solubility 746.3 History of Dissolution Testing 756.4 Compendial (Pharmacopeial) Dissolution Apparatus 766.4.1 USP1 and 2 Apparatus 766.4.2 USP3 Apparatus 786.4.3 USP4 Apparatus 796.4.4 USP5 Apparatus 806.4.5 USP6 Apparatus 806.4.6 USP7 Apparatus 806.4.7 Intrinsic Dissolution Rate (IDR) Apparatus 806.4.8 Micro- dissolution Apparatus 816.5 Dissolution Media Selection 816.5.1 Biphasic Dissolution Media 826.6 Dissolution Agitation Rates 826.7 Reporting Dissolution Data 836.8 In Vitro In Vivo Relationships and Correlations (IVIVR/IVIVC) 846.8.1 Convolution and Deconvolution of Dissolution Data 856.9 Evolution of Biorelevant Dissolution Testing 866.9.1 Biorelevant Dissolution Media 866.9.2 Dissolution Testing to Mimic GI Transit 906.9.3 Dissolution Testing to Mimic Motility/Hydrodynamic Conditions 926.9.4 Dissolution Testing to Incorporate Permeability 936.10 Conclusions 93References 947 Biopharmaceutics to Inform Candidate Drug Selection and Optimisation 99Linette Ruston7.1 Introduction 997.2 Oral Product Design Considerations During Early Development 1007.3 Biopharmaceutics in Drug Discovery 1017.3.1 Pre- Clinical Studies 1027.4 Biopharmaceutics Assessment 1037.4.1 Solubility 1037.4.2 Permeability 1047.4.3 Dissolution 1047.4.4 Biopharmaceutics Classification System 1047.4.5 Lipophilicity 1047.4.6 pK a 1057.4.7 Molecular Size 1057.4.8 Crystallinity 1057.4.9 In Vivo Pre-Clinical Studies 1067.4.10 In Silico Modelling 1067.4.11 Human Absorption/Dose Prediction 1067.5 Output of Biopharmaceutics Assessment 1077.5.1 New Modalities/Complex Delivery Systems Within Early Development 1077.6 Influence/Optimise/Design Properties to Inform Formulation Development 1087.6.1 Fraction Absorbed Classification System 1107.7 Conclusion 110References 1108 Biopharmaceutics Tools for Rational Formulation Design 113Panagiota Zarmpi, Mark McAllister, James Butler and Nikoletta Fotaki8.1 Introduction 1138.2 Formulation Development to Optimise Drug Bioavailability 1158.3 Traditional Formulation Strategies 1158.3.1 Decision Making for Conventional or Enabling Formulations 1158.4 Decision Trees to Guide Formulation Development 1158.4.1 Decision Trees Based on Biopharmaceutics Classification System (BCS) 1158.4.2 Decision Trees Based on Developability Classification System (DCS) 1178.4.3 Expanded Decision Trees 1208.5 Computational Tools to Guide Formulation Strategies 1208.5.1 Statistical Tools 1208.5.2 Physiologically Based Pharmacokinetic/Biopharmaceutics Models 1218.6 Decision- Making for Optimising Enabling Formulations 1228.7 Decision Trees for Enabled Formulations 1238.7.1 Statistical Tools 1248.7.2 Physiologically Based Pharmacokinetic/Biopharmaceutics Models 1248.8 System- Based Formulation Strategies 1258.8.1 Quality by Design 1258.8.2 Tools to Identify Quality Target Product Profile 1258.9 Biopharmaceutics Risk Assessment Roadmap (BioRAM) 1268.9.1 Tools to Identify Quality Target Product Profile 1268.10 Conclusions 129References 1319 Biopharmaceutic Classification System 135Hannah Batchelor and Talia Flanagan9.1 Description and History of the BCS 1359.2 BCS- Based Criteria for Solubility, Dissolution and Permeability 1359.3 BCS- Based Biowaivers 1379.4 Regulatory Development of BCS- Based Biowaivers 1389.5 International Harmonisation of BCS- Based Biowaiver Criteria – ICH M 9 1389.5.1 Application of BCS- Based Biowaivers 1399.5.1.1 Drug Product Type 1409.5.1.2 Composition 1409.5.1.3 Dissolution Similarity 1419.6 BCS as a Development Tool 1419.6.1 Candidate Selection 1429.6.2 Solid Form Selection 1429.6.3 Product Development 1429.7 Beyond the BCS 1439.7.1 Biopharmaceutic Drug Disposition Classification System (bddcs) 1439.7.2 Developability Classification System 1449.7.3 Fraction Absorbed Classification System 1449.7.4 BCS Applied to Special Populations 1449.8 Conclusions 145References 14510 Regulatory Biopharmaceutics 147Shanoo Budhdeo, Paul A. Dickinson and Talia Flanagan10.1 Introduction 14710.2 Clinical Bioequivalence Studies 14810.3 Design of Clinical Bioequivalence (BE) Studies 15010.4 Implication of Bioequivalence Metrics 15110.5 Bioequivalence Regulatory Guidelines 15210.6 Biowaivers 15310.7 Biopharmaceutics in Quality by Design 15310.8 Control of Drug Product and Clinically Relevant Specifications 15510.9 Establishing Clinically Relevant Dissolution Methods and Specifications 15610.10 Application of In Silico Physiologically Based Biopharmaceutics Modelling (PBBM) to Develop Clinically Relevant Specifications 15910.11 Additional Considerations for Establishing Dissolution Methods and Specifications 15910.12 Common Technical Document (CTD) 16010.13 Other Routes of Administration and Locally Acting Drug Products 16110.14 Conclusion 162References 16211 Impact of Anatomy and Physiology 165Francesca K. H. Gavins, Christine M. Madla, Sarah J. Trenfield, Laura E. McCoubrey, Abdul W. Basit and Mark McAllister11.1 Introduction 16511.2 Influence of GI Conditions on Pharmacokinetic Studies 16611.3 The Stomach 16711.3.1 Gastric Anatomy 16711.3.2 Gastric Motility and Mixing 16811.3.3 Gastric Emptying 16911.3.3.1 Gastric Fed State 17011.3.4 Gastric Fluid Volume 17011.3.5 Gastric Temperature 17111.3.6 Gastric Fluid Composition 17111.3.6.1 Gastric pH 17111.3.6.2 Gastric Bile Salt Composition and Concentration 17211.4 Small Intestine 17211.4.1 Small Intestinal Anatomy 17211.4.2 Small Intestinal Motility and Mixing 17411.4.3 Small Intestinal Transit Time 17411.4.4 Small Intestinal Volume 17411.4.5 Small Intestinal Fluid Composition 17511.4.5.1 Small Intestinal pH 17611.4.5.2 Small Intestinal Buffer Capacity 17611.4.5.3 Small Intestinal Surface Tension 17611.4.5.4 Small Intestinal Osmolality 17611.4.5.5 Bile Salt Composition and Concentration 17711.5 The Colon/Large Intestine 17711.5.1 Large Intestine Anatomy 17811.5.2 Large Intestinal Motility and Mixing 17811.5.3 Large Intestinal Transit Time 17911.5.4 Large Intestinal Volume 17911.5.5 Large Intestinal Fluid Composition 17911.5.5.1 Large Intestinal pH 17911.5.5.2 Large Intestinal Buffer Capacity 18011.5.5.3 Large Intestinal Surface Tension 18011.5.5.4 Large Intestinal Osmolality 18011.5.5.5 Bile Salt Composition and Concentration 18011.5.6 Impact of Microbiome on Oral Drug Delivery 18111.6 Conclusions 182References 18212 Integrating Biopharmaceutics to Predict Oral Absorption Using PBPK Modelling 189Konstantinos Stamatopoulos12.1 Introduction 18912.2 Mechanistic Models 19012.3 Solubility Inputs 19212.4 Dissolution Inputs 19612.4.1 Fluid Dynamics and Dissolution 19812.5 Permeability Inputs 19812.6 Incorporation of Modelling and Simulation into Drug Development 20012.6.1 Understanding the Effect of Formulation Modifications on Drug Pharmacokinetics 20012.6.2 Model Verification/Validation 20112.6.3 Using Modelling to Understand Bioequivalence 20112.7 Conclusions 202References 20213 Special Populations 205Christine M. Madla, Francesca K. H. Gavins, Sarah J. Trenfield and Abdul W. Basit13.1 Introduction 20513.2 Sex Differences in the Gastrointestinal Tract and Its Effect on Oral Drug Performance 20613.3 Ethnic Differences in the Gastrointestinal Tract 20813.4 Impact of Diet on Gastrointestinal Physiology 20913.5 Pregnancy and Its Effect on Gastrointestinal Physiology 21113.6 The Implication of Disease States on Gastrointestinal Physiology and Its Effect on Oral Drug Performance 21213.7 Diseases that Affect the Gastrointestinal Tract 21213.7.1 Irritable Bowel Syndrome 21213.7.2 Inflammatory Bowel Disease 21313.7.3 Celiac Disease 21513.8 Infections in the Gastrointestinal Tract 21613.8.1 Helicobacter pylori Infection 21613.9 Systemic Diseases that Alter GI Physiology and Function 21613.9.1 Cystic Fibrosis 21713.9.2 Parkinson’s Disease 21813.9.3 Diabetes 21913.9.4 HIV Infection 22113.10 Age- related Influences on Gastrointestinal Tract Physiology and Function 22213.10.1 Gastrointestinal Physiology and Function in Paediatrics 22213.10.2 Gastrointestinal Physiology and Function in Geriatrics 22413.11 Conclusion 226References 22614 Inhalation Biopharmaceutics 239Precious Akhuemokhan, Magda Swedrowska, and Ben Forbes14.1 Introduction 23914.2 Structure of the Lungs 24014.2.1 Basic Anatomy 24014.2.2 Epithelial Lining Fluid 24114.2.3 Epithelium 24114.3 Molecules, Inhalation Devices, Formulations 24114.3.1 Inhaled Molecules 24114.3.2 Inhalation Devices 24214.3.2.1 Nebulisers 24214.3.2.2 Pressurised Metered- Dose Inhalers 24314.3.2.3 Dry Powder Inhalers 24314.3.2.4 ‘Soft Mist’ Inhalers 24314.3.3 Inhaled Medicine Formulation 24314.4 Inhaled Drug Delivery and Models for Studying Inhalation Biopharmaceutics 24414.4.1 Dosimetry and Deposition 24414.4.2 Mucociliary Clearance 24514.4.3 Dissolution 24614.4.4 Lung Permeability, Absorption and Retention 24714.4.5 Metabolism 24814.4.6 Non- Clinical Inhalation Studies 24814.4.7 Mechanistic Computer Modelling 24914.5 Bioequivalence and an Inhalation Bioclassification System 24914.6 Conclusion 249References 25015 Biopharmaceutics of Injectable Formulations 253Wang Wang Lee and Claire M. Patterson15.1 Introduction 25315.2 Subcutaneous Physiology and Absorption Mechanisms 25615.2.1 Physiology 25615.2.2 Absorption Mechanisms 25715.3 Intramuscular Physiology and Absorption Mechanisms 25815.3.1 Physiology 25815.3.2 Absorption Mechanisms 25915.4 In Vitro Performance and IVIVC 25915.4.1 In Silico Models 26115.4.2 Preclinical Models 26115.5 Bioequivalence of Injectable Formulations 26115.6 Summary 262References 26216 Biopharmaceutics of Topical and Transdermal Formulations 265Hannah Batchelor16.1 Introduction 26516.2 Skin Structure 26616.2.1 Transport of Drugs Through Skin 26716.2.2 Skin Metabolism 26716.3 Active Pharmaceutical Ingredient Properties 26716.4 Topical and Transdermal Dosage Forms 26716.5 Measurement of In Vitro Drug Release 26816.5.1 Diffusion Cells 26816.5.2 Compendial Dissolution Apparatus 26916.6 Measurement of Skin Permeation 26916.6.1 Tape- Stripping ‘Dermatopharmacokinetics’ (DPK) 27016.6.2 Confocal Laser Scanning Microscopy (CLSM) 27016.6.3 Diffusion Cells Using Biorelevant Membranes to Model Permeation 27016.6.3.1 Alternative Skin Substrates Used for Permeability Studies 27016.6.4 Dermal Microdialysis 27116.6.5 Skin Biopsy 27116.6.6 In Silico Models of Dermal Absorption 27116.6.7 Pre- Clinical Models 27216.7 Bioequivalence Testing of Topical/Transdermal Products 27316.8 Conclusions 274References 27417 Impact of the Microbiome on Oral Biopharmaceutics 277Laura E. McCoubrey, Hannah Batchelor, Abdul W. Basit, Simon Gaisford and Mine Orlu17.1 Introduction 27717.2 Microbiome Distribution in the GI Tract 27817.3 Key Causes of Microbiome Variability 28017.4 Microbiome Influence on Key GI Parameters 28117.4.1 pH 28117.4.2 Bile Acid Concentration and Composition 28117.4.3 Drug Transporters 28317.4.4 Motility 28317.4.5 Hepatic Drug Metabolism 28317.4.6 Epithelial Permeability 28417.5 Enzymatic Degradation of Drugs by GI Microbiota 28417.6 Exploitation of the GI Microbiome for Drug Delivery 28517.7 Models of the GI Microbiome 28517.7.1 In Vitro Models 28517.7.2 In Silico Models 28917.8 Conclusion 289References 290Index 297