|  | Sugano, Kiyohiko
Biopharmaceutics Modeling and Simulations
Theory, Practice, Methods, and Applications
 1. Auflage September 2012
109,- Euro
2012. 520 Seiten, Hardcover
- Praktikerbuch -
ISBN 978-1-118-02868-1 - John Wiley & Sons
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| Kurzbeschreibung
This book provides pharmaceutical professionals with essential tools for modeling biopharmaceutics. The author uses illustrations and practical problems rather than heavy math to explain the basics of modeling and simulation programs and how to apply them to different biopharmaceutical properties. Readers will find critical guidance on the design of drug formulations for achieving desired medicinal effects, including practical applications examples in drug research such as running and interpreting models, compound and formulation selection, mechanisms, and virtual clinical trials.
Aus dem Inhalt
PREFACE xxv
LIST OF ABBREVIATIONS xxix
1 INTRODUCTION 1
1.1 An Illustrative Description of Oral Drug Absorption: The Whole Story 1
1.2 Three Regimes of Oral Drug Absorption 2
1.3 Physiology of the Stomach, Small Intestine, and Colon 5
1.4 Drug and API Form 6
1.5 The Concept of Mechanistic Modeling 7
References 8
2 THEORETICAL FRAMEWORK I: SOLUBILITY 10
2.1 Definition of Concentration 10
2.2 Acid-Base and Bile-Micelle-Binding Equilibriums 13
2.3 Equilibrium Solubility 19
References 31
3 THEORETICAL FRAMEWORK II: DISSOLUTION 33
3.1 Diffusion Coefficient 34
3.2 Dissolution and Particle Growth 36
3.3 Nucleation 56
References 61
4 THEORETICAL FRAMEWORK III: BIOLOGICAL MEMBRANE PERMEATION 64
4.1 Overall Scheme 64
4.2 General Permeation Equation 66
4.3 Permeation Rate Constant, Permeation Clearance, and Permeability 66
4.4 Intestinal Tube Flatness and Permeation Parameters 68
4.5 Effective Concentration for Intestinal Membrane Permeability 70
4.6 Surface Area Expansion by Plicate and Villi 71
4.7 Unstirred Water Layer Permeability 73
4.8 Epithelial Membrane Permeability (Passive Processes) 76
4.9 Enteric Cell Model 84
4.10 Gut Wall Metabolism 103
4.11 Hepatic Metabolism and Excretion 114
References 115
5 THEORETICAL FRAMEWORK IV: GASTROINTESTINAL TRANSIT MODELS AND INTEGRATION 122
5.1 GI Transit Models 122
5.2 Time-Dependent Changes of Physiological Parameters 127
5.3 Integration 1: Analytical Solutions 129
5.4 Integration 2: Numerical Integration 147
5.5 In Vivo FA From PK Data 150
5.6 Other Administration Routes 156
References 157
6 PHYSIOLOGY OF GASTROINTESTINAL TRACT AND OTHER ADMINISTRATION SITES IN HUMANS AND ANIMALS 160
6.1 Morphology of Gastrointestinal Tract 160
6.2 Movement of the Gastrointestinal Tract 170
6.3 Fluid Character of the Gastrointestinal Tract 178
6.4 Transporters and Drug-Metabolizing Enzymes in the Intestine 186
6.5 Intestinal and Liver Blood Flow 188
6.6 Physiology Related to Enterohepatic Recirculation 189
6.7 Nasal 191
6.8 Pulmonary 193
6.9 Skin 194
References 196
7 DRUG PARAMETERS 206
7.1 Dissociation Constant (pKa) 206
7.2 Octanol-Water Partition Coefficient 208
7.3 Bile Micelle Partition Coefficient (Kbm) 211
7.4 Particle Size and Shape 212
7.5 Solid Form 215
7.6 Solubility 223
7.7 Dissolution Rate/Release Rate 230
7.8 Precipitation 235
7.9 Epithelial Membrane Permeability 240
7.10 In Vivo Experiments 252
References 254
8 VALIDATION OF MECHANISTIC MODELS 266
8.1 Concerns Related to Model Validation Using In Vivo Data 267
8.2 Strategy for Transparent and Robust Validation of Biopharmaceutical Modeling 267
8.3 Prediction Steps 268
8.4 Validation for Permeability-Limited Cases 279
8.5 Validation for Dissolution-Rate and Solubility-Permeability-Limited Cases (without the Stomach Effect) 290
8.6 Validation for Dissolution-Rate and Solubility-Permeability-Limited Cases (with the Stomach Effect) 305
8.7 Salts 307
8.8 Reliability of Biopharmaceutical Modeling 311
References 311
9 BIOEQUIVALENCE AND BIOPHARMACEUTICAL CLASSIFICATION SYSTEM 322
9.1 Bioequivalence 322
9.2 The History of BCS 324
9.3 Regulatory Biowaiver Scheme and BCS 326
9.4 Exploratory BCS 335
9.5 In Vitro-In Vivo Correlation 335
References 338
10 DOSE AND PARTICLE SIZE DEPENDENCY 340
10.1 Definitions and Causes of Dose Nonproportionality 340
10.2 Estimation of the Dose and Particle Size Effects 341
10.3 Effect of Transporters 344
10.4 Analysis of In Vivo Data 345
References 346
11 ENABLING FORMULATIONS 347
11.1 Salts and Cocrystals: Supersaturating API 347
11.2 Nanomilled API Particles 358
11.3 Self-Emulsifying Drug Delivery Systems (Micelle/Emulsion Solubilization) 360
11.4 Solid Dispersion 363
11.5 Supersaturable Formulations 364
11.6 Prodrugs to Increase Solubility 365
11.7 Prodrugs to Increase Permeability 365
11.8 Controlled Release 366
11.9 Communication with Therapeutic Project Team 371
References 373
12 FOOD EFFECT 379
12.1 Physiological Changes Caused by Food 379
12.2 Types of Food Effects and Relevant Parameters in Biopharmaceutical Modeling 382
12.3 Effect of Food Type 398
12.4 Biopharmaceutical Modeling of Food Effect 401
References 403
13 BIOPHARMACEUTICAL MODELING FOR MISCELLANEOUS CASES 412
13.1 Stomach pH Effect on Solubility and Dissolution Rate 412
13.2 Intestinal First-Pass Metabolism 414
13.3 Transit Time Effect 415
13.4 Other Chemical and Physical Drug-Drug Interactions 415
13.5 Species Difference 417
13.6 Validation of GI Site-Specific Absorption Models 421
References 426
14 INTESTINAL TRANSPORTERS 430
14.1 Apical Influx Transporters 431
14.2 Efflux Transporters 435
14.3 Dual Substrates 438
14.4 Difficulties in Simulating Carrier-Mediated Transport 442
14.5 Summary 445
References 446
15 STRATEGY IN DRUG DISCOVERY AND DEVELOPMENT 452
15.1 Library Design 452
15.2 Lead Optimization 453
15.3 Compound Selection 455
15.4 API Form Selection 455
15.5 Formulation Selection 455
15.6 Strategy to Predict Human Fa% 456
References 457
16 EPISTEMOLOGY OF BIOPHARMACEUTICAL MODELING AND GOOD SIMULATION PRACTICE 459
16.1 Can Simulation be so Perfect? 459
16.2 Parameter Fitting 460
16.3 Good Simulation Practice 461
References 463
APPENDIX A GENERAL TERMINOLOGY 464
A.1 Biopharmaceutic 464
A.2 Bioavailability (BA% or F) 464
A.3 Drug Disposition 465
A.4 Fraction of a Dose Absorbed (Fa) 465
A.5 Modeling/Simulation/In Silico 465
A.6 Active Pharmaceutical Ingredient (API) 465
A.7 Drug Product 465
A.8 Lipophilicity 465
A.9 Acid and Base 466
A.10 Solubility 466
A.11 Molecular Weight (MW) 466
A.12 Permeability of a Drug 466
APPENDIX B FLUID DYNAMICS 468
B.1 Navier-Stokes Equation and Reynolds Number 468
B.2 Boundary Layer Approximation 469
B.3 The Boundary Layer and Mass Transfer 470
B.4 The Thickness of the Boundary Layer 470
B.5 Sherwood Number 471
B.6 Turbulence 473
B.7 Formation of Eddies 474
B.8 Computational Fluid Dynamics 474
References 476
INDEX 477
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