Оглавление
Группа авторов. Biopharmaceutics
Table of Contents
List of Tables
List of Illustrations
Guide
Pages
Biopharmaceutics. From Fundamentals to Industrial Practice
List of Contributors
Foreword
1 An Introduction to Biopharmaceutics
1.1 Introduction
1.2 History of Biopharmaceutics
1.3 Key Concepts and Definitions Used Within Biopharmaceutics
1.4 The Role of Biopharmaceutics in Drug Development
1.5 Conclusions
References
2 Basic Pharmacokinetics
2.1 Introduction
2.2 What is ‘Pharmacokinetics’?
2.3 Pharmacokinetic Profile
2.4 Bioavailability
2.5 Drug Distribution
Box 2.1 Drug Concentration in blood is not the same as the drug concentration in plasma!
Box 2.2 Why measure drug concentrations?
2.6 Volume of Distribution
Box 2.3 Total body water
2.7 Elimination
2.7.1 Metabolism
2.7.2 Excretion
2.8 Elimination Half‐Life (t½)
2.9 Elimination Rate Constant
Box 2.4 How long it will take for the drug to eliminate completely from the body?
2.9.1 Clearance
Box 2.5 The elimination rate constant, k and the elimination half‐life (t½)
2.10 Area Under the Curve (AUC)
2.11 Bioequivalence
2.12 Steady State
Box 2.6 How long it takes to get to the steady state?
Box 2.7 Therapeutic drug monitoring (TDM)
2.13 Compartmental Concepts in Pharmacokinetics
2.14 Concept of Linearity in Pharmacokinetics
2.15 Conclusions
Further Reading
3 Introduction to Biopharmaceutics Measures
3.1 Introduction
3.2 Solubility
3.3 Dissolution
3.4 Permeability
3.5 Absorptive Flux
3.6 Lipinsky's Rule of 5
3.6.1 Molecular Weight
3.6.2 Lipophilicity
3.6.3 Hydrogen Bond Donors/Acceptors
References
4 Solubility
4.1 Definition of Solubility
4.2 The Importance of Solubility in Biopharmaceutics
4.3 What Level of Solubility Is Required?
4.4 Solubility‐Limited Absorption
4.5 Methods to Assess Solubility
4.6 Brief Overview of Forces Involved in Solubility
4.6.1 van der Waals Interactions
4.6.2 Hydrogen Bonding
4.6.3 Ionic Interactions
4.7 Solid‐State Properties and Solubility
4.8 pH and Drug Solubility
4.9 Solvents
4.9.1 Biorelevant Solubility
4.9.2 Buffer System – Phosphate vs Bicarbonate
4.9.3 Solubilisation by Surfactants
4.9.4 Solubilisation During Digestion
4.9.5 Excipients and Solubility
4.10 Risk of Precipitation
4.11 Solubility and Link to Lipophilicity
4.12 Conclusions
References
5 Permeability
5.1 Introduction
5.2 Enzymes, Gut Wall Metabolism, Tissue Permeability and Transporters
5.2.1 Enzymes
5.2.2 Drug Transporters
5.2.3 Efflux Transporters
5.2.4 Transporters of Greatest Relevance to Oral Biopharmaceutics
5.2.5 Regulatory Overview of Transporter Effects on Biopharmaceutics
5.2.6 Regional Expression and Polymorphism of Intestinal Transporters and Impact of Drug Variability
5.3 Applications and Limitations of Characterisation and Predictive Tools for Permeability Assessment
5.3.1 In Silico Tools: Predictive Models for Permeability
5.3.2 In Vitro Tools. 5.3.2.1 PAMPA
5.3.2.2 Cell Lines
5.3.3 Ex Vivo Tools
5.3.3.1 Ussing Chambers
5.3.3.2 Everted Intestinal Sac/Ring
5.3.4 In Situ Tools
5.3.4.1 Closed‐Loop Intestinal Perfusion
5.3.4.2 Single‐Pass Intestinal Perfusion
5.3.4.3 Intestinal Perfusion with Venous Sampling
5.3.4.4 Vascularly Perfused Intestinal Models
5.4 In Vivo Tools
5.5 Conclusion
References
6 Dissolution
6.1 Introduction
6.2 Purpose of Dissolution Testing
6.2.1 Dissolution Versus Solubility
6.3 History of Dissolution Testing
6.4 Compendial (Pharmacopeial) Dissolution Apparatus
6.4.1 USP1 and 2 Apparatus
6.4.2 USP3 Apparatus
6.4.3 USP4 Apparatus
6.4.4 USP5 Apparatus
6.4.5 USP6 Apparatus
6.4.6 USP7 Apparatus
6.4.7 Intrinsic Dissolution Rate (IDR) Apparatus
6.4.8 Micro‐dissolution Apparatus
6.5 Dissolution Media Selection
6.5.1 Biphasic Dissolution Media
6.6 Dissolution Agitation Rates
6.7 Reporting Dissolution Data
6.8 In Vitro In Vivo Relationships and Correlations (IVIVR/IVIVC)
6.8.1 Convolution and Deconvolution of Dissolution Data
6.9 Evolution of Biorelevant Dissolution Testing
6.9.1 Biorelevant Dissolution Media
6.9.2 Dissolution Testing to Mimic GI Transit
6.9.3 Dissolution Testing to Mimic Motility/Hydrodynamic Conditions
6.9.4 Dissolution Testing to Incorporate Permeability
6.10 Conclusions
References
7 Biopharmaceutics to Inform Candidate Drug Selection and Optimisation
7.1 Introduction
7.2 Oral Product Design Considerations During Early Development
7.3 Biopharmaceutics in Drug Discovery
7.3.1 Pre‐Clinical Studies
7.4 Biopharmaceutics Assessment
7.4.1 Solubility
7.4.2 Permeability
7.4.3 Dissolution
7.4.4 Biopharmaceutics Classification System
7.4.5 Lipophilicity
7.4.6 pKa
7.4.7 Molecular Size
7.4.8 Crystallinity
7.4.9 In Vivo Pre‐Clinical Studies
7.4.10 In Silico Modelling
7.4.11 Human Absorption/Dose Prediction
7.5 Output of Biopharmaceutics Assessment
7.5.1 New Modalities/Complex Delivery Systems Within Early Development
7.6 Influence/Optimise/Design Properties to Inform Formulation Development
7.6.1 Fraction Absorbed Classification System
7.7 Conclusion
References
8 Biopharmaceutics Tools for Rational Formulation Design
8.1 Introduction
8.2 Formulation Development to Optimise Drug Bioavailability
8.3 Traditional Formulation Strategies. 8.3.1 Decision Making for Conventional or Enabling Formulations
8.4 Decision Trees to Guide Formulation Development. 8.4.1 Decision Trees Based on Biopharmaceutics Classification System (BCS)
8.4.2 Decision Trees Based on Developability Classification System (DCS)
8.4.3 Expanded Decision Trees
8.5 Computational Tools to Guide Formulation Strategies
8.5.1 Statistical Tools
8.5.2 Physiologically Based Pharmacokinetic/Biopharmaceutics Models
8.6 Decision‐Making for Optimising Enabling Formulations
8.7 Decision Trees for Enabled Formulations
8.7.1 Statistical Tools
8.7.2 Physiologically Based Pharmacokinetic/Biopharmaceutics Models
8.8 System‐Based Formulation Strategies. 8.8.1 Quality by Design
8.8.2 Tools to Identify Quality Target Product Profile
8.9 Biopharmaceutics Risk Assessment Roadmap (BioRAM)
8.9.1 Tools to Identify Quality Target Product Profile
8.10 Conclusions
References
9 Biopharmaceutic Classification System
9.1 Description and History of the BCS
9.2 BCS‐Based Criteria for Solubility, Dissolution and Permeability
9.3 BCS‐Based Biowaivers
9.4 Regulatory Development of BCS‐Based Biowaivers
9.5 International Harmonisation of BCS‐Based Biowaiver Criteria – ICH M9
Box 9.1 Summary of BCS Classification and Biowaiver Requirements in the ICH M9 Guideline
9.5.1 Application of BCS‐Based Biowaivers
9.5.1.1 Drug Product Type
9.5.1.2 Composition
9.5.1.3 Dissolution Similarity
9.6 BCS as a Development Tool
9.6.1 Candidate Selection
9.6.2 Solid Form Selection
9.6.3 Product Development
9.7 Beyond the BCS
9.7.1 Biopharmaceutic Drug Disposition Classification System (BDDCS)
9.7.2 Developability Classification System
9.7.3 Fraction Absorbed Classification System
9.7.4 BCS Applied to Special Populations
9.8 Conclusions
References
10 Regulatory Biopharmaceutics
10.1 Introduction
10.2 Clinical Bioequivalence Studies
10.3 Design of Clinical Bioequivalence (BE) Studies
10.4 Implication of Bioequivalence Metrics
10.5 Bioequivalence Regulatory Guidelines
10.6 Biowaivers
10.7 Biopharmaceutics in Quality by Design
10.8 Control of Drug Product and Clinically Relevant Specifications
10.9 Establishing Clinically Relevant Dissolution Methods and Specifications
Box 10.1 Five step process to establishing clinically relevant specifications described by Dickinson et al. [13, 15]
10.10 Application of In Silico Physiologically Based Biopharmaceutics Modelling (PBBM) to Develop Clinically Relevant Specifications
10.11 Additional Considerations for Establishing Dissolution Methods and Specifications
10.12 Common Technical Document (CTD)
10.13 Other Routes of Administration and Locally Acting Drug Products
10.14 Conclusion
References
11 Impact of Anatomy and Physiology
11.1 Introduction
11.2 Influence of GI Conditions on Pharmacokinetic Studies
11.3 The Stomach. 11.3.1 Gastric Anatomy
11.3.2 Gastric Motility and Mixing
11.3.3 Gastric Emptying
11.3.3.1 Gastric Fed State
11.3.4 Gastric Fluid Volume
11.3.5 Gastric Temperature
11.3.6 Gastric Fluid Composition
11.3.6.1 Gastric pH
11.3.6.2 Gastric Bile Salt Composition and Concentration
11.4 Small Intestine. 11.4.1 Small Intestinal Anatomy
11.4.2 Small Intestinal Motility and Mixing
11.4.3 Small Intestinal Transit Time
11.4.4 Small Intestinal Volume
11.4.5 Small Intestinal Fluid Composition
11.4.5.1 Small Intestinal pH
11.4.5.2 Small Intestinal Buffer Capacity
11.4.5.3 Small Intestinal Surface Tension
11.4.5.4 Small Intestinal Osmolality
11.4.5.5 Bile Salt Composition and Concentration
11.5 The Colon/Large Intestine
11.5.1 Large Intestine Anatomy
11.5.2 Large Intestinal Motility and Mixing
11.5.3 Large Intestinal Transit Time
11.5.4 Large Intestinal Volume
11.5.5 Large Intestinal Fluid Composition
11.5.5.1 Large Intestinal pH
11.5.5.2 Large Intestinal Buffer Capacity
11.5.5.3 Large Intestinal Surface Tension
11.5.5.4 Large Intestinal Osmolality
11.5.5.5 Bile Salt Composition and Concentration
11.5.6 Impact of Microbiome on Oral Drug Delivery
11.6 Conclusions
References
12 Integrating Biopharmaceutics to Predict Oral Absorption Using PBPK Modelling
12.1 Introduction
12.2 Mechanistic Models
12.3 Solubility Inputs
12.4 Dissolution Inputs
12.4.1 Fluid Dynamics and Dissolution
12.5 Permeability Inputs
12.6 Incorporation of Modelling and Simulation into Drug Development
12.6.1 Understanding the Effect of Formulation Modifications on Drug Pharmacokinetics
12.6.2 Model Verification/Validation
12.6.3 Using Modelling to Understand Bioequivalence
12.7 Conclusions
References
13 Special Populations
13.1 Introduction
13.2 Sex Differences in the Gastrointestinal Tract and Its Effect on Oral Drug Performance
13.3 Ethnic Differences in the Gastrointestinal Tract
13.4 Impact of Diet on Gastrointestinal Physiology
13.5 Pregnancy and Its Effect on Gastrointestinal Physiology
13.6 The Implication of Disease States on Gastrointestinal Physiology and Its Effect on Oral Drug Performance
13.7 Diseases that Affect the Gastrointestinal Tract
13.7.1 Irritable Bowel Syndrome
13.7.2 Inflammatory Bowel Disease
13.7.3 Celiac Disease
13.8 Infections in the Gastrointestinal Tract. 13.8.1 Helicobacter pylori Infection
13.9 Systemic Diseases that Alter GI Physiology and Function
13.9.1 Cystic Fibrosis
13.9.2 Parkinson's Disease
13.9.3 Diabetes
13.9.4 HIV Infection
13.10 Age‐related Influences on Gastrointestinal Tract Physiology and Function. 13.10.1 Gastrointestinal Physiology and Function in Paediatrics
13.10.2 Gastrointestinal Physiology and Function in Geriatrics
13.11 Conclusion
References
14 Inhalation Biopharmaceutics
14.1 Introduction
14.2 Structure of the Lungs
14.2.1 Basic Anatomy
14.2.2 Epithelial Lining Fluid
14.2.3 Epithelium
14.3 Molecules, Inhalation Devices, Formulations. 14.3.1 Inhaled Molecules
14.3.2 Inhalation Devices
14.3.2.1 Nebulisers
14.3.2.2 Pressurised Metered‐Dose Inhalers
14.3.2.3 Dry Powder Inhalers
14.3.2.4 ‘Soft Mist’ Inhalers
14.3.3 Inhaled Medicine Formulation
14.4 Inhaled Drug Delivery and Models for Studying Inhalation Biopharmaceutics
14.4.1 Dosimetry and Deposition
14.4.2 Mucociliary Clearance
14.4.3 Dissolution
14.4.4 Lung Permeability, Absorption and Retention
14.4.5 Metabolism
14.4.6 Non‐Clinical Inhalation Studies
14.4.7 Mechanistic Computer Modelling
14.5 Bioequivalence and an Inhalation Bioclassification System
14.6 Conclusion
References
Note
15 Biopharmaceutics of Injectable Formulations
15.1 Introduction
15.2 Subcutaneous Physiology and Absorption Mechanisms. 15.2.1 Physiology
15.2.2 Absorption Mechanisms
15.3 Intramuscular Physiology and Absorption Mechanisms. 15.3.1 Physiology
15.3.2 Absorption Mechanisms
15.4 In Vitro Performance and IVIVC
15.4.1 In Silico Models
15.4.2 Preclinical Models
15.5 Bioequivalence of Injectable Formulations
15.6 Summary
References
16 Biopharmaceutics of Topical and Transdermal Formulations
16.1 Introduction
16.2 Skin Structure
16.2.1 Transport of Drugs Through Skin
16.2.2 Skin Metabolism
16.3 Active Pharmaceutical Ingredient Properties
16.4 Topical and Transdermal Dosage Forms
16.5 Measurement of In Vitro Drug Release
16.5.1 Diffusion Cells
16.5.2 Compendial Dissolution Apparatus
16.6 Measurement of Skin Permeation
16.6.1 Tape‐Stripping ‘Dermatopharmacokinetics’ (DPK)
16.6.2 Confocal Laser Scanning Microscopy (CLSM)
16.6.3 Diffusion Cells Using Biorelevant Membranes to Model Permeation
16.6.3.1 Alternative Skin Substrates Used for Permeability Studies
16.6.4 Dermal Microdialysis
16.6.5 Skin Biopsy
16.6.6 In Silico Models of Dermal Absorption
16.6.7 Pre‐Clinical Models
16.7 Bioequivalence Testing of Topical/Transdermal Products
16.8 Conclusions
References
17 Impact of the Microbiome on Oral Biopharmaceutics
17.1 Introduction
17.2 Microbiome Distribution in the GI Tract
17.3 Key Causes of Microbiome Variability
17.4 Microbiome Influence on Key GI Parameters. 17.4.1 pH
17.4.2 Bile Acid Concentration and Composition
17.4.3 Drug Transporters
17.4.4 Motility
17.4.5 Hepatic Drug Metabolism
17.4.6 Epithelial Permeability
17.5 Enzymatic Degradation of Drugs by GI Microbiota
17.6 Exploitation of the GI Microbiome for Drug Delivery
17.7 Models of the GI Microbiome
17.7.1 In Vitro Models
17.7.2 In Silico Models
17.8 Conclusion
References
Index
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