Description
A comprehensive introduction to using modeling and simulation programs in drug discovery and development Biopharmaceutical modeling has become integral to the design and development of new drugs. Influencing key aspects of the development process, including drug substance design, formulation design, and toxicological exposure assessment, biopharmaceutical modeling is now seen as the linchpin to a drug’s future success. And while there are a number of commercially available software programs for drug modeling, there has not been a single resource guiding pharmaceutical professionals to the actual tools and practices needed to design and test safe drugs. A guide to the basics of modeling and simulation programs, Biopharmaceutics Modeling and Simulations offers pharmaceutical scientists the keys to understanding how they work and are applied in creating drugs with desired medicinal properties. Beginning with a focus on the oral absorption of drugs, the book discusses: * The central dogma of oral drug absorption (the interplay of dissolution, solubility, and permeability of a drug), which forms the basis of the biopharmaceutical classification system (BCS) * The concept of drug concentration * How to simulate key drug absorption processes * The physiological and drug property data used for biopharmaceutical modeling * Reliable practices for reporting results With over 200 figures and illustrations and a peerless examination of all the key aspects of drug research–including running and interpreting models, validation, and compound and formulation selection–this reference seamlessly brings together the proven practical approaches essential to developing the safe and effective medicines of tomorrow. KIYOHIKO SUGANO has over seventeen years of experience as a pharmaceutical industrial researcher with Chugai in Japan and Pfizer in the United Kingdom. He has published extensively in peer-reviewed journals and book chapters, focusing on physicochemical profiling, drug permeability across biological membranes, oral drug delivery, and predictive and computational modeling. 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
