Biopharmaceutics Modeling and Simulations
Theory, Practice, Methods, and Applications
Inbunden, Engelska, 2012
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Fri frakt för medlemmar vid köp för minst 249 kr.A comprehensive introduction to using modeling and simulation programs in drug discovery and developmentBiopharmaceutical 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 concentrationHow to simulate key drug absorption processesThe physiological and drug property data used for biopharmaceutical modelingReliable practices for reporting resultsWith 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.
Produktinformation
- Utgivningsdatum2012-09-28
- Mått163 x 241 x 31 mm
- Vikt857 g
- FormatInbunden
- SpråkEngelska
- Antal sidor528
- FörlagJohn Wiley & Sons Inc
- ISBN9781118028681
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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 xxvLIST OF ABBREVIATIONS xxix1 INTRODUCTION 11.1 An Illustrative Description of Oral Drug Absorption: The Whole Story 11.2 Three Regimes of Oral Drug Absorption 21.3 Physiology of the Stomach, Small Intestine, and Colon 51.4 Drug and API Form 61.4.1 Undissociable and Free Acid Drugs 61.4.2 Free Base Drugs 61.4.3 Salt Form Cases 61.5 The Concept of Mechanistic Modeling 7References 82 THEORETICAL FRAMEWORK I: SOLUBILITY 102.1 Definition of Concentration 102.1.1 Total Concentration 112.1.2 Dissolved Drug Concentration 112.1.3 Effective Concentration 122.2 Acid–Base and Bile-Micelle-Binding Equilibriums 132.2.1 Monoprotic Acid and Base 142.2.2 Multivalent Cases 162.2.3 Bile-Micelle Partitioning 172.2.4 Modified Henderson–Hasselbalch Equation 182.2.5 Kbm from Log Poct 192.3 Equilibrium Solubility 192.3.1 Definition of Equilibrium Solubility 192.3.2 pH–Solubility Profile (pH-Controlled Region) 212.3.3 Solubility in a Biorelevant Media with Bile Micelles (pH-Controlled Region) 232.3.4 Estimation of Unbound Fraction from the Solubilities with and without Bile Micelles 252.3.5 Common Ionic Effect 252.3.6 Important Conclusion from the pH–Equilibrium Solubility Profile Theory 272.3.7 Yalkowsky’s General Solubility Equation 272.3.8 Solubility Increase by Converting to an Amorphous Form 292.3.9 Solubility Increase by Particle Size Reduction (Nanoparticles) 302.3.10 Cocrystal 31References 313 THEORETICAL FRAMEWORK II: DISSOLUTION 333.1 Diffusion Coefficient 343.1.1 Monomer 343.1.2 Bile Micelles 353.1.3 Effective Diffusion Coefficient 363.2 Dissolution and Particle Growth 363.2.1 Mass Transfer Equations: Pharmaceutical Science Versus Fluid Dynamics 373.2.2 Dissolution Equation with a Lump Sum Dissolution Rate Coefficient (kdiss) 383.2.3 Particle Size and Surface Area 393.2.3.1 Monodispersed Particles 393.2.3.2 Polydispersed Particles 413.2.4 Diffusion Layer Thickness I: Fluid Dynamic Model 413.2.4.1 Reynolds and Sherwood Numbers 423.2.4.2 Disk (Levich Equation) 453.2.4.3 Tube (Graetz Problem) 453.2.4.4 Particle Fixed to Space (Ranz–Marshall Equation) 463.2.4.5 Floating Particle 473.2.4.6 Nonspherical Particle 493.2.4.7 Minimum Agitation Speed for Complete Suspension 513.2.4.8 Other Factors 523.2.5 Diffusion Layer Thickness II: Empirical Models for Particles 523.2.6 Solid Surface pH and Solubility 533.3 Nucleation 563.3.1 General Description of Nucleation and Precipitation Process 563.3.2 Classical Nucleation Theory 573.3.2.1 Concept of Classical Nucleation Theory 583.3.2.2 Mathematical Expressions 583.3.3 Application of a Nucleation Theory for Biopharmaceutical Modeling 61References 614 THEORETICAL FRAMEWORK III: BIOLOGICAL MEMBRANE PERMEATION 644.1 Overall Scheme 644.2 General Permeation Equation 664.3 Permeation Rate Constant, Permeation Clearance, and Permeability 664.4 Intestinal Tube Flatness and Permeation Parameters 684.5 Effective Concentration for Intestinal Membrane Permeability 704.5.1 Effective Concentration for Unstirred Water Layer Permeation 704.5.2 Effective Concentration for Epithelial Membrane Permeation: the Free Fraction Theory 704.6 Surface Area Expansion by Plicate and Villi 714.7 Unstirred Water Layer Permeability 734.7.1 Basic Case 734.7.2 Particles in the UWL (Particle Drifting Effect) 744.8 Epithelial Membrane Permeability (Passive Processes) 764.8.1 Passive Transcellular Membrane Permeability: pH Partition Theory 764.8.2 Intrinsic Passive Transcellular Permeability 774.8.2.1 Solubility–Diffusion Model 774.8.2.2 Flip-Flop Model 794.8.2.3 Relationship between Ptrans,0 and log Poct 804.8.3 Paracellular Pathway 834.8.4 Relationship between log Doct, MW, and Fa% 844.9 Enteric Cell Model 844.9.1 Definition of Papp 864.9.2 Enzymatic Reaction: Michaelis–Menten Equation 874.9.3 First-Order Case 1: No Transporter and Metabolic Enzymes 884.9.4 First-Order Case 2: Efflux Transporter in Apical Membrane 914.9.5 Apical Efflux Transporter with Km and Vmax 954.9.6 Apical Influx Transporter with Km and Vmax 1004.9.7 UWL and Transporter 1004.9.7.1 No Transporter 1014.9.7.2 Influx Transporter and UWL 1014.9.7.3 Efflux Transporter 1014.10 Gut Wall Metabolism 1034.10.1 The Qgut Model 1044.10.2 Simple Fg Models 1044.10.3 Theoretical Consideration on Fg 1044.10.3.1 Derivation of the Fg Models 1054.10.3.2 Derivation of the Anatomical Fg Model 1074.10.4 Interplay between CYP3A4 and P-gp 1084.11 Hepatic Metabolism and Excretion 114References 1155 THEORETICAL FRAMEWORK IV: GASTROINTESTINAL TRANSIT MODELS AND INTEGRATION 1225.1 GI Transit Models 1225.1.1 One-Compartment Model/Plug Flow Model 1225.1.2 Plug Flow Model 1235.1.3 Three-Compartment Model 1245.1.4 S1I7CX (X = 1–4) Compartment Models 1245.1.5 Convection–Dispersion Model 1265.1.6 Tapered Tube Model 1265.2 Time-Dependent Changes of Physiological Parameters 1275.2.1 Gastric Emptying 1275.2.2 Water Mass Balance 1285.2.3 Bile Concentration 1295.3 Integration 1: Analytical Solutions 1295.3.1 Dissolution Under Sink Condition 1305.3.1.1 Monodispersed Particles 1305.3.1.2 Polydispersed Particles 1315.3.2 Fraction of a Dose Absorbed (Fa%) 1325.3.3 Approximate Fa% Analytical Solutions 1: Case-by-Case Solution 1335.3.3.1 Permeability-Limited Case 1345.3.3.2 Solubility-Permeability-Limited Case 1355.3.3.3 Dissolution-Rate-Limited Case 1375.3.4 Approximate Fa% Analytical Solutions 2: Semi-General Equations 1375.3.4.1 Sequential First-Order Kinetics of Dissolution and Permeation 1375.3.4.2 Minimum Fa% Model 1385.3.5 Approximate Fa% Analytical Solutions 3: FaSS Equation 1395.3.5.1 Application Range 1405.3.5.2 Derivation of Fa Number Equation 1405.3.5.3 Refinement of the FaSS Equation 1415.3.5.4 Advantage of FaSS Equation 1465.3.5.5 Limitation of FaSS Equation 1465.3.6 Interpretations of Fa Equations 1465.3.7 Approximate Analytical Solution for Oral PK Model 1475.4 Integration 2: Numerical Integration 1475.4.1 Virtual Particle Bins 1495.4.2 The Mass Balance of Dissolved Drug Amount in Each GI Position 1495.4.3 Controlled Release of Virtual Particle Bin 1505.5 In Vivo FA From PK Data 1505.5.1 Absolute Bioavailability and Fa 1515.5.2 Relative Bioavailability Between Solid and Solution Formulations 1515.5.3 Relative Bioavailability Between Low and High Dose 1525.5.4 Convolution and Deconvolution 1525.5.4.1 Convolution 1535.5.4.2 Deconvolution 1545.6 Other Administration Routes 1565.6.1 Skin 156References 1576 PHYSIOLOGY OF GASTROINTESTINAL TRACT AND OTHER ADMINISTRATION SITES IN HUMANS AND ANIMALS 1606.1 Morphology of Gastrointestinal Tract 1606.1.1 Length and Tube Radius 1606.1.2 Surface Area 1616.1.2.1 Small Intestine 1616.1.2.2 Colon 1636.1.3 Degree of Flatness 1646.1.3.1 Small Intestine 1646.1.3.2 Colon 1646.1.4 Epithelial Cells 1656.1.4.1 Apical and Basolateral Lipid Bilayer Membranes 1656.1.4.2 Tight Junction 1686.1.4.3 Mucous Layer 1686.2 Movement of the Gastrointestinal Tract 1706.2.1 Transit Time 1706.2.1.1 Gastric Emptying Time (GET) 1706.2.1.2 Small Intestinal Transit Time 1706.2.1.3 Colon Transit Time 1716.2.2 Migrating Motor Complex 1716.2.3 Agitation 1736.2.3.1 Mixing Pattern 1736.2.3.2 Agitation Strength 1756.2.3.3 Unstirred Water Layer on the Intestinal Wall 1766.3 Fluid Character of the Gastrointestinal Tract 1786.3.1 Volume 1786.3.1.1 Stomach 1786.3.1.2 Small Intestine 1786.3.1.3 Colon 1796.3.2 Bulk Fluid pH and Buffer Concentration 1796.3.2.1 Stomach 1816.3.2.2 Small Intestine 1816.3.2.3 Colon 1816.3.3 Microclimate pH 1816.3.3.1 Small Intestine 1816.3.3.2 Colon 1826.3.4 Bile Micelles 1826.3.4.1 Stomach 1836.3.4.2 Small Intestine 1836.3.4.3 Colon 1856.3.5 Enzymes and Bacteria 1856.3.6 Viscosity, Osmolality, and Surface Tension 1856.4 Transporters and Drug-Metabolizing Enzymes in the Intestine 1866.4.1 Absorptive Drug Transporters 1866.4.1.1 PEP-T1 1866.4.1.2 OATP 1866.4.2 Efflux Drug Transporters 1866.4.2.1 P-gp 1866.4.3 Drug-Metabolizing Enzymes 1866.4.3.1 CYP3A4 1866.4.3.2 Glucuronyl Transferase and Sulfotransferase 1886.5 Intestinal and Liver Blood Flow 1886.5.1 Absorption Sites Connected to Portal Vein 1886.5.2 Villous Blood Flow (Qvilli) 1886.5.3 Hepatic Blood Flow (Qh) 1886.6 Physiology Related to Enterohepatic Recirculation 1896.6.1 Bile Secretion 1896.6.2 Mass Transfer into/from the Hepatocyte 1906.6.2.1 Sinusoidal Membrane (Blood to Hepatocyte) 1906.6.2.2 Canalicular Membrane (Hepatocyte to Bile Duct) 1916.7 Nasal 1916.8 Pulmonary 1936.8.1 Fluid in the Lung 1936.8.2 Mucociliary Clearance 1936.8.3 Absorption into the Circulation 1946.9 Skin 194References 1967 DRUG PARAMETERS 2067.1 Dissociation Constant (pKa) 2067.1.1 pH Titration 2077.1.2 pH–UV Shift 2077.1.3 Capillary Electrophoresis 2077.1.4 pH–Solubility Profile 2087.1.5 Calculation from Chemical Structure 2087.1.6 Recommendation 2087.2 Octanol–Water Partition Coefficient 2087.2.1 Shake Flask Method 2097.2.2 HPLC Method 2107.2.3 Two-Phase Titration Method 2107.2.4 PAMPA-Based Method 2107.2.5 In Silico Method 2107.2.6 Recommendation 2107.3 Bile Micelle Partition Coefficient (Kbm) 2117.3.1 Calculation from Solubility in Biorelevant Media 2117.3.2 Spectroscopic Method 2127.3.3 Recommendations 2127.4 Particle Size and Shape 2127.4.1 Microscope 2137.4.2 Laser Diffraction 2157.4.3 Dynamic Laser Scattering (DLS) 2157.4.4 Recommendations 2157.5 Solid Form 2157.5.1 Nomenclature 2157.5.1.1 Crystalline and Amorphous 2157.5.1.2 Salts, Cocrystals, and Solvates 2167.5.1.3 Hydrate 2177.5.2 Crystal Polymorph 2177.5.2.1 True Polymorph and Pseudopolymorph 2177.5.2.2 Kinetic Resolution versus Stable Form 2177.5.2.3 Dissolution Profile Advantages of Less Stable Forms 2187.5.2.4 Enantiotropy 2187.5.3 Solid Form Characterization 2197.5.3.1 Polarized Light Microscopy (PLM) 2197.5.3.2 Powder X-Ray Diffraction (PXRD) 2197.5.3.3 Differential Scanning Calorimeter (DSC) and Thermal Gravity (TG) 2207.5.3.4 High Throughput Solid Form Screening 2217.5.4 Wettability and Surface Free Energy 2227.5.5 True Density 2227.6 Solubility 2237.6.1 Terminology 2237.6.1.1 Definition of Solubility 2237.6.1.2 Intrinsic Solubility 2237.6.1.3 Solubility in Media 2237.6.1.4 Initial pH and Final pH 2247.6.1.5 Supersaturable API 2247.6.1.6 Critical Supersaturation Concentration and Induction Time 2247.6.1.7 Dissolution Rate and Dissolution Profile 2257.6.2 Media 2257.6.2.1 Artificial Stomach Fluids 2257.6.2.2 Artificial Small Intestinal Fluids 2257.6.3 Solubility Measurement 2257.6.3.1 Standard Shake Flask Method 2257.6.3.2 Measurement from DMSO Sample Stock Solution 2277.6.3.3 Solid Surface Solubility 2287.6.3.4 Method for Nanoparticles 2287.6.4 Recommendation 2287.6.4.1 Early Drug Discovery Stage (HTS to Early Lead Optimization) 2297.6.4.2 Late Lead Optimization Stage 2297.6.4.3 Transition Stage between Discovery and Development 2297.7 Dissolution Rate/Release Rate 2307.7.1 Intrinsic Dissolution Rate 2307.7.2 Paddle Method 2307.7.2.1 Apparatus 2317.7.2.2 Fluid Condition 2317.7.2.3 Agitation 2327.7.3 Flow-Through Method 2337.7.4 Multicompartment Dissolution System 2337.7.5 Dissolution Permeation System 2337.7.6 Recommendation 2357.8 Precipitation 2357.8.1 Kinetic pH Titration Method 2357.8.2 Serial Dilution Method 2367.8.3 Two-Chamber Transfer System 2367.8.4 Nonsink Dissolution Test 2367.9 Epithelial Membrane Permeability 2407.9.1 Back-Estimation from Fa% 2417.9.2 In Situ Single-Pass Intestinal Perfusion 2417.9.3 Cultured Cell Lines (Caco-2, MDCK, etc.) 2437.9.4 PAMPA 2447.9.5 Estimation of Ptrans,0 from Experimental Apparent Membrane Permeability 2467.9.6 Estimation of Ptrans,0 from Experimental log Poct 2477.9.7 Mechanistic Investigation 2477.9.8 Limitation of Membrane Permeation Assays 2477.9.8.1 UWL Adjacent to the Membrane 2497.9.8.2 Membrane Binding 2507.9.8.3 Low Solubility 2507.9.8.4 Differences in Paracellular Pathway 2517.9.8.5 Laboratory to Laboratory Variation 2517.9.8.6 Experimental Artifacts in Carrier-Mediated Membrane Transport 2517.9.9 Recommendation for Pep and Peff Estimation 2517.9.9.1 Hydrophilic Drugs 2517.9.9.2 Lipophilic Drugs 2527.9.9.3 Drugs with Medium Lipophilicity 2527.10 In Vivo Experiments 2527.10.1 P.O 2527.10.2 I.V 2537.10.3 Animal Species 2537.10.4 Analysis 254References 2548 VALIDATION OF MECHANISTIC MODELS 2668.1 Concerns Related to Model Validation Using In Vivo Data 2678.2 Strategy for Transparent and Robust Validation of Biopharmaceutical Modeling 2678.3 Prediction Steps 2688.4 Validation for Permeability-Limited Cases 2798.4.1 Correlation Between Fa% and Peff Data for Humans (Epithelial Membrane Permeability-Limited Cases PL-E) 2798.4.2 Correlation Between In Vitro Permeability and Peff and/or Fa% (PL-E Cases) 2838.4.2.1 Caco-2 2838.4.2.2 PAMPA 2858.4.2.3 Experimental log Poct and pKa 2858.4.3 Peff for UWL Limited Cases 2878.4.4 Chemical Structure to Peff, Fa%, and Caco-2 Permeability 2888.5 Validation for Dissolution-Rate and Solubility-Permeability-Limited Cases (without the Stomach Effect) 2908.5.1 Fa% Prediction Using In Vitro Dissolution Data 2908.5.2 Fa% Prediction Using In Vitro Solubility and Permeability Data 2928.6 Validation for Dissolution-Rate and Solubility-Permeability-Limited Cases (with the Stomach Effect) 3058.6.1 Difference Between Free Base and Salts 3058.6.2 Simulation Model for Free Base 3058.6.3 Simulation Results 3078.7 Salts 3078.8 Reliability of Biopharmaceutical Modeling 311References 3119 BIOEQUIVALENCE AND BIOPHARMACEUTICAL CLASSIFICATION SYSTEM 3229.1 Bioequivalence 3229.2 The History of BCS 3249.3 Regulatory Biowaiver Scheme and BCS 3269.3.1 Elucidation of BCS Criteria in Regulatory Biowaiver Scheme 3279.3.1.1 Congruent Condition of Bioequivalence 3289.3.1.2 Equivalence of Dose Number (Do) 3299.3.1.3 Equivalence of Permeation Number (Pn) 3299.3.1.4 Equivalence of Dissolution Number (Dn) 3299.3.2 Possible Extension of the Biowaiver Scheme 3319.3.2.1 Dose Number Criteria 3319.3.2.2 Permeability Criteria 3329.3.3 Another Interpretation of the Theory 3329.3.3.1 Another Assumption about Dissolution Test 3329.3.3.2 Assessment of Suitability of Dissolution Test Based on Rate-Limiting Process 3339.3.4 Validation of Biowaiver Scheme by Clinical BE Data 3339.3.5 Summary for Regulatory BCS Biowaiver Scheme 3349.4 Exploratory BCS 3359.5 In Vitro–In Vivo Correlation 3359.5.1 Levels of IVIVC 3359.5.2 Judgment of Similarity Between Two Formulations (f2 Function) 3369.5.3 Modeling the Relationship Between f2 and Bioequivalence 3369.5.4 Point-to-Point IVIVC 337References 33810 DOSE AND PARTICLE SIZE DEPENDENCY 34010.1 Definitions and Causes of Dose Nonproportionality 34010.2 Estimation of the Dose and Particle Size Effects 34110.2.1 Permeability-Limited Cases (PL) 34110.2.2 Dissolution-Rate-Limited (DRL) Cases 34110.2.3 Solubility–Epithelial Membrane Permeability Limited (SL-E) Cases 34210.2.4 Solubility-UWL-Permeability-Limited Cases 34410.3 Effect of Transporters 34410.4 Analysis of In Vivo Data 345References 34611 ENABLING FORMULATIONS 34711.1 Salts and Cocrystals: Supersaturating API 34711.1.1 Scenarios of Oral Absorption of Salt 34911.1.2 Examples 35011.1.2.1 Example 1: Salt of Basic Drugs 35011.1.2.2 Example 2: Salt of Acid Drugs 35211.1.2.3 Example 3: Other Supersaturable API Forms 35311.1.3 Suitable Drug for Salts 35311.1.3.1 pKa Range 35311.1.3.2 Supersaturability of Drugs 35511.1.4 Biopharmaceutical Modeling of Supersaturable API Forms 35711.2 Nanomilled API Particles 35811.3 Self-Emulsifying Drug Delivery Systems (Micelle/Emulsion Solubilization) 36011.4 Solid Dispersion 36311.5 Supersaturable Formulations 36411.6 Prodrugs to Increase Solubility 36511.7 Prodrugs to Increase Permeability 36511.7.1 Increasing Passive Permeation 36611.7.2 Hitchhiking the Carrier 36611.8 Controlled Release 36611.8.1 Fundamentals of CR Modeling 36711.8.2 Simple Convolution Method 36811.8.3 Advanced Controlled-Release Modeling 36811.8.4 Controlled-Release Function 36811.8.5 Sustained Release 36811.8.5.1 Objectives to Develop a Sustained-Release Formulation 36811.8.5.2 Suitable Drug Character for Sustained Release 36911.8.5.3 Gastroretentive Formulation 36911.8.6 Triggered Release 36911.8.6.1 Time-Triggered Release 36911.8.6.2 pH-Triggered Release 36911.8.6.3 Position-Triggered Release 37111.9 Communication with Therapeutic Project Team 371References 37312 FOOD EFFECT 37912.1 Physiological Changes Caused by Food 37912.1.1 Food Component 38012.1.2 Fruit Juice Components 38012.1.3 Alcohol 38212.2 Types of Food Effects and Relevant Parameters in Biopharmaceutical Modeling 38212.2.1 Delay in Tmax and Decrease in Cmax 38212.2.2 Positive Food Effect 38312.2.2.1 Bile Micelle Solubilization 38312.2.2.2 Increase in Hepatic Blood Flow 38812.2.2.3 Increase in Intestinal Blood Flow 38812.2.2.4 Inhibition of Efflux Transporter and Gut Wall Metabolism 38912.2.2.5 Desaturation of Influx Transporter 39112.2.3 Negative Food Effect 39112.2.3.1 Bile Micelle Binding/Food Component Binding 39112.2.3.2 Inhibition of Uptake Transporter 39212.2.3.3 Desaturation of First-Pass Metabolism and Efflux Transport 39412.2.3.4 Viscosity 39812.2.3.5 pH Change in the Stomach 39812.2.3.6 pH Change in the Small Intestine 39812.3 Effect of Food Type 39812.4 Biopharmaceutical Modeling of Food Effect 40112.4.1 Simple Flowchart and Semiquantitative Prediction 40112.4.2 More Complicated Cases 402References 40313 BIOPHARMACEUTICAL MODELING FOR MISCELLANEOUS CASES 41213.1 Stomach pH Effect on Solubility and Dissolution Rate 41213.1.1 Free Bases 41313.1.2 Free Acids and Undissociable Drugs 41313.1.3 Salts 41313.1.4 Chemical and Enzymatic Degradation in the Stomach and Intestine 41313.2 Intestinal First-Pass Metabolism 41413.3 Transit Time Effect 41513.3.1 Gastric Emptying Time 41513.3.2 Intestinal Transit Time 41513.4 Other Chemical and Physical Drug–Drug Interactions 41513.4.1 Metal Ions 41513.4.2 Cationic Resins 41613.5 Species Difference 41713.5.1 Permeability 41713.5.2 Solubility/Dissolution 41813.5.3 First-Pass Metabolism 41913.6 Validation of GI Site-Specific Absorption Models 42113.6.1 Stomach 42113.6.2 Colon 42213.6.3 Regional Difference in the Small Intestine: Fact or Myth? 42213.6.3.1 Transporter 42213.6.3.2 Bile-Micelle Binding and Bimodal Peak Phenomena 422References 42614 INTESTINAL TRANSPORTERS 43014.1 Apical Influx Transporters 43114.1.1 Case Example 1: Antibiotics 43114.1.2 Case Example 2: Valacyclovir 43314.1.3 Case Example: Gabapentin 43414.2 Efflux Transporters 43514.2.1 Effect of P-gp 43514.2.2 Drug–Drug Interaction (DDI) via P-gp 43714.3 Dual Substrates 43814.3.1 Talinolol 43814.3.2 Fexofenadine 44114.4 Difficulties in Simulating Carrier-Mediated Transport 44214.4.1 Absorptive Transporters 44214.4.1.1 Discrepancies Between In Vitro and In Vivo Km Values 44214.4.1.2 Contribution of Other Pathways 44314.4.2 Efflux Transporters 44314.5 Summary 445References 44615 STRATEGY IN DRUG DISCOVERY AND DEVELOPMENT 45215.1 Library Design 45215.2 Lead Optimization 45315.3 Compound Selection 45515.4 API Form Selection 45515.5 Formulation Selection 45515.6 Strategy to Predict Human Fa% 456References 45716 EPISTEMOLOGY OF BIOPHARMACEUTICAL MODELING AND GOOD SIMULATION PRACTICE 45916.1 Can Simulation be so Perfect? 45916.2 Parameter Fitting 46016.3 Good Simulation Practice 46116.3.1 Completeness 46116.3.2 Comprehensiveness 462References 463APPENDIX A GENERAL TERMINOLOGY 464A.1 Biopharmaceutic 464A.2 Bioavailability (BA% or F) 464A.3 Drug Disposition 465A.4 Fraction of a Dose Absorbed (Fa) 465A.5 Modeling/Simulation/In Silico 465A.6 Active Pharmaceutical Ingredient (API) 465A.7 Drug Product 465A.8 Lipophilicity 465A.9 Acid and Base 466A.10 Solubility 466A.11 Molecular Weight (MW) 466A.12 Permeability of a Drug 466APPENDIX B FLUID DYNAMICS 468B.1 Navier–Stokes Equation and Reynolds Number 468B.2 Boundary Layer Approximation 469B.3 The Boundary Layer and Mass Transfer 470B.4 The Thickness of the Boundary Layer 470B.4.1 99% of Main Flow Speed 471B.4.2 Displacement Thickness 471B.4.3 Momentum Thickness 471B.5 Sherwood Number 471B.6 Turbulence 473B.7 Formation of Eddies 474B.8 Computational Fluid Dynamics 474References 476INDEX 477
“This book serves as an invaluable source of information for the formulation scientist, the preclinical, translational or clinical pharmacokineticist, as well as the modeling and simulation scientist.” (ChemMedChem, 1 April 2013)