Bret Berner, PhD, is a pharmaceutical consultant in drug delivery, formulation, and pharmacokinetics. He was formerly Director of Basic Pharmaceutics Research at Ciba-Geigy, Vice President of Development at Cygnus Therapeutics, and Chief Scientific Officer at Depomed. Toufigh Gordi, PhD, is a Senior Director of clinical pharmacology at Rigel Pharmaceuticals, with extensive experience in using pharmacokinetic and pharmacodynamic modeling to advance candidate drug molecules from preclinical through late phase confirmatory clinical studies. Heather A. E. Benson, PhD, is Associate Professor in Curtin Medical School at Curtin University, Australia where she leads the Skin Delivery Research Group Michael S. Roberts, PhD, is Professor of Therapeutics and Pharmaceutical Science at the University of South Australia and Professor of Clinical Pharmacology and Therapeutics at the University of Queensland.

• Preface xv1 Introduction: Utility of Mathematical Models in Drug Development and Delivery 1Toufigh Gordi and Bret Berner1.1 Introduction 11.2 Use of Mathematical Models in Drug Development 21.3 Noncompartmental Analysis 31.4 Pharmacokinetic (PK) Models 51.5 Physiologically Based Pharmacokinetic (PBPK) Models 71.6 Pharmacokinetic/Pharmacodynamic (PK/PD) Models 91.7 Systems Pharmacology Models 121.8 Utility of PK/PD Analysis and Models in Drug Development 141.8.1 Drug Delivery and PK/PD 261.8.2 Drug Properties and Mechanism of Release from the Dosage Form 271.8.2.1 Temporal Pattern of Delivery 301.9 Discussion 32References 342 Physiologically Based Models: Techniques and Applications to Drug Delivery 43Richard N. Upton, Ashley M. Hopkins, Ahmad Y. Abuhelwa, Jim H. Hughes and David J.R. Foster2.1 Introduction 432.2 Types of Pharmacokinetic Models 432.3 Commercial vs. Bespoke PBPK Models 452.4 Data Sources 462.5 Applications of PBPK Models 462.6 Techniques of PBPK Modeling 482.6.1 The “Language” of PBPK Models 482.6.2 Oral Absorption Models 492.6.3 Drug Metabolism and Drug–Drug Interactions 562.6.4 Drug Transporters 582.6.5 Renal Elimination 592.6.6 Protein Binding 592.6.7 Accounting for Size 612.6.8 Accounting for Age 632.6.9 Interspecies Scaling 642.6.10 Between-Subject Variability 652.6.11 Sensitivity Analysis 662.6.12 Pharmacodynamics 662.7 Summary 68References 683 Oral Delivery and Pharmacokinetic Models 75Wojciech Krzyzanski3.1 Introduction 753.2 Compartmental Models 763.2.1 First-Order Absorption 763.2.2 Zero-Order Absorption 783.2.3 Absorption Delay 783.2.4 Parallel Inputs 803.2.5 Discontinuous Absorption 813.2.6 Compartmental Absorption and Transit 813.2.7 Gastrointestinal Transit Time 823.2.8 Other Compartmental Models 823.3 Empirical Models 823.3.1 Gamma Model 833.3.2 Weibull Model 833.3.3 Inverse Gaussian Model 853.4 Physiologically Based Pharmacokinetic Models of Drug Absorption 853.4.1 Traditional and Segregated-Flow Models 863.5 Advanced PBPK Models 883.5.1 Advanced Compartmental Absorption and Transit Model 883.5.2 Advanced Dissolution Absorption and Metabolism Model 893.6 Intestinal First-pass Drug Metabolism 903.6.1 Well-stirred Gut Model 903.6.2 QGut Model 913.7 Spatiotemporal Models of Drug Absorption 913.7.1 Dispersion Model 923.7.2 Translocation Model 923.8 Conclusions 93References 944 Oral Site-Directed Drug Delivery and Influence on PK 99Peter Scholes, Vanessa Zann, Wu Lin, Chris Roe and Bret Berner4.1 Introduction 994.2 GI Anatomy and Physiology 994.2.1 Anatomy 1004.2.2 Regional Variations in Physiology Affecting Drug Delivery 1014.2.2.1 Fluid Volume and pH 1014.2.2.2 Enzymes, GutWall Metabolism, Tissue Permeability, and Transporters 1024.2.2.3 Gender and Age Effects 1114.2.2.4 GI Transit 1124.2.2.5 Effect of Food 1144.2.2.6 Enterohepatic Circulation 1154.3 Biopharmaceutics Classification System (BCS) 1164.3.1 Background and Regulatory Perspectives 1164.3.2 Determining a Solubility Class 1194.3.3 Determining a Permeability Class 1234.3.4 Determining Dissolution of the Drug Product 1254.3.5 GI Stability 1264.3.6 Applications and Limitations of BCS Classification 1264.3.7 “Developability Classification System” 1294.4 Applications and Limitations of Characterization and Predictive Tools 1314.4.1 In Silico Tools: Predictive Models, Molecular Descriptors, and ADMET 1314.4.2 In Vitro Tools 1334.4.2.1 PAMPA 1334.4.2.2 Cell Lines 1354.4.3 Ex Vivo Tools 1374.4.3.1 Ussing Chambers 1374.4.3.2 Everted Intestinal Sac/Ring 1404.4.4 In Situ Tools 1424.4.4.1 Closed Loop Intestinal Perfusion 1434.4.4.2 Single-Pass Intestinal Perfusion 1434.4.4.3 Intestinal Perfusion with Venous Sampling 1434.4.4.4 Vascularly Perfused Intestinal Models 1444.4.4.5 Other Animal Models 1444.4.5 In Vivo Tools 1454.4.6 In Silico Tools for Prediction of PK and PK/PD 1464.4.7 Preclinical PK Models 1504.5 Tools to Probe Regional Bioavailability in Humans: Case Studies 1514.5.1 Site-Specific Delivery Devices 1514.5.2 Gamma Scintigraphic Imaging 1574.5.3 Magnetic Resonance Imaging (MRI) 1594.6 Rational Formulation Design and Effective Clinical Evaluation: Case Studies Describing How to Achieve Desired Release Modality and Target PK 1604.6.1 Formulation Strategies to Address BCS Classification Challenges 1604.6.1.1 Solubilization 1604.6.1.2 Permeability Enhancement 1684.6.1.3 Concluding Remarks on Strategies for BCS Challenges 1704.6.2 Formulation Strategies for Chronotherapeutic and Regional GI Delivery for Local or Systemic Delivery 1704.6.2.1 Gastric Retention 1704.6.2.2 Enteric-Coated Dosage Forms and Delayed Release to the Small Intestine 1824.6.2.3 Delivery to the Jejunum and Ileum 1854.6.2.4 Colonic Delivery 1864.7 Conclusions 191References 1915 The Vasoconstrictor Assay (VCA): Then and Now 221Isadore Kanfer and Howard Maibach5.1 Introduction 2215.1.1 Applications and Procedures 2225.1.2 Visual Assessment 2245.1.3 Chromameter Assessment 2255.1.3.1 Comparison Between Visual and Chromameter Assessment 2265.2 Issues and Controversies 2285.2.1 Fitting of PD Response Data 2285.2.2 Circadian Activity 2295.2.3 BE Studies Performed Under Occlusion 2305.2.4 Erythema Response at Application Sites 2305.2.5 Use of VCA for Market Approval in the European Union 2315.2.6 Potency Ranking of Topical Corticosteroid Products 2325.2.7 Sensitive Region of the Dose–Response Curve 2345.2.8 Correlation of ED50 with Potency Classification of a Product? 2355.3 Conclusions 236References 2366 Topical Delivery: Toward an IVIVC 241Sam G. Raney and Thomas J. Franz6.1 Introduction 2416.2 In Vitro–In Vivo Correlation: Validating the Model of Topical Delivery 2416.3 In Vitro–In Vivo Correlation: Transdermal Delivery 2446.4 In Vitro–In Vivo Correlation: Bioavailability and Bioequivalence 2456.5 Summary 250Disclaimer 250References 2507 Integrated Transdermal Drug Delivery and Pharmacokinetics in Development 253Bret Berner and Gregory M. Kochak7.1 Introduction 2537.2 Fundamentals of Transdermal Delivery 2547.2.1 Architecture of Skin 2547.2.2 Skin Permeation and Transdermal Delivery 2557.2.3 Basic Pharmacokinetics of Transdermal Delivery 2627.3 In Vivo Assessment of Drug Input and Pharmacokinetic Disposition 2667.3.1 Deconvolution 2667.3.2 Convolution 2677.3.3 Instability in Deconvolution 2697.3.4 Generalized Input and Convolution 2727.4 In Vitro Testing: Drug Release from Transdermal Systems 2737.5 In Vitro/In Vivo Correlation 2757.6 Clinical Safety and Efficacy Studies for Dermal Drug Development 2807.6.1 Bioavailability and Bioequivalence 2817.6.2 Skin Irritation and Sensitization Study 2827.7 Dosage Form Proportionality Scaling and Dose Proportionality 2837.7.1 Residual Content of the Dosage Form 2837.7.2 Comparative Toxicity and Efficacy 2837.8 Supporting In Vitro Studies 2837.9 Safety Studies Related to Environmental Conditions Such as Heat and Storage Conditions 2847.10 Active Transdermal Systems That Enhance Barrier Penetration 2847.10.1 Microneedles 2847.10.2 Thermal or Radio Frequency Ablation 2877.10.3 Sonophoresis 2887.10.4 Electrical 2897.10.4.1 Electroporation 2897.10.4.2 Iontophoresis 2907.11 Conclusion 293References 2938 Formulation and Pharmacokinetic Challenges Associated with Targeted Pulmonary Drug Delivery 305Tomoyuki Okuda and Hak-Kim Chan8.1 Progress on Formulations and Devices for Inhaled Drugs 3058.2 Challenges for Inhaled Formulations 3088.2.1 High-Dose Drugs and Amorphous Powders 3088.2.2 Generic DPI Formulations 3098.2.3 Biologics and Macromolecules 3108.2.4 Controlled Release Formulations 3108.3 Factors Determining the Fate of Inhaled Drugs in the Body 3118.3.1 Anatomical and Histological Characteristics of the Respiratory System 3118.3.2 Physicochemical Characteristics of Inhaled Drugs 3128.4 Pharmacokinetic/Pharmacodynamic Correlation of Inhaled Drugs 3148.4.1 Desirable Pharmacokinetic Parameters of Inhaled Drugs for Local Action and Systemic Delivery 3148.4.2 Pharmacokinetic/Pharmacodynamic Correlation of Clinically Approved Inhaled Drugs 3158.4.2.1 Corticosteroids and Bronchodilators 3158.4.2.2 Antimicrobials 3168.4.2.3 Prostacyclin Analogs 3178.4.2.4 Loxapine 3188.4.2.5 Insulin 3188.5 Application of Drug Delivery System for Improving Pharmacokinetic/Pharmacodynamic Parameters of Inhaled Drugs 3208.5.1 Chemical Modification 3208.5.2 Functional Micro/Nanoparticle Formulations 3218.5.3 Active Targeting 3228.6 Conclusion 323References 3249 Oral Transmucosal Drug Delivery 333Mohammed Sattar and Majella E. Lane9.1 Introduction 3339.2 Structure and Physiology of the Oral Mucosa 3349.2.1 Buccal Mucosa 3349.2.2 Sublingual Mucosa 3359.2.3 Gingiva and Palate 3369.2.4 Saliva 3369.2.5 Mucus 3369.2.6 Permeation Routes 3369.3 Drug Properties Which Influence OTMD 3379.3.1 Molecular Weight 3379.3.2 Lipid Solubility 3389.3.3 Degree of Ionization 3399.3.4 Potency 3409.4 Buccal and Sublingual Formulations 3409.4.1 Currently Used Technologies 3409.4.2 Investigation of Iontophoresis for Oral Transmucosal Drug Delivery 3429.5 Models to Study OTDD 3429.5.1 Studies in Man and Human Tissue Models 3429.5.2 Porcine Tissue Models 3439.5.3 Dog, Monkey, and Rabbit Models 3449.5.4 Chicken, Hamster, and Rat Models 3459.5.5 Cell Culture Models 3459.6 Feasibility of Systemic Delivery Based on In Vitro Permeation Studies 3469.7 Conclusion 347References 34710 PK/PD and the Drug Delivery Regimen for Infusion in the Critical Care Setting 355Fekade B. Sime and Jason A. Roberts10.1 Introduction 35510.2 PK/PD Properties and the Mode of Infusional Drug Delivery for Antibiotics 35610.3 Changes in PK/PD and Infusional Drug Delivery Regimens in Critically Ill Patients 35710.4 Short Intermittent Infusions 35910.5 Extended Infusions 36010.6 Continuous Infusion 36110.6.1 Continuous Infusion of β-Lactam Antibiotics 36110.6.2 Continuous Infusion of Vancomycin 36610.7 Conclusions 367References 36711 Virtual Experiment Methods for Integrating Pharmacokinetic, Pharmacodynamic, and Drug Delivery Mechanisms: Demonstrating Feasibility for Acetaminophen Hepatotoxicity 375Andrew K. Smith, Ryan C. Kennedy, Brenden K. Petersen, Glen E.P. Ropella and Carver Anthony Hunt11.1 Introduction 37511.1.1 Focus on Acetaminophen-Induced Liver Injury 37611.2 Results 37711.2.1 Engineering Parsimonious Fit for Purpose Virtual Mice 37711.2.2 Concrete Lobule Location-Dependent Mechanisms 38011.2.3 Falsifying Virtual Mechanisms 38111.2.4 A Plausible Causal Cascade 38311.2.5 Drug Delivery and a Therapeutic Intervention 38511.3 Methods 38611.3.1 Broad Requirements 38611.3.2 Prediction 38811.3.3 Iterative Refinement Protocol 38811.3.4 Data Types, Reuse, and Sharing 39011.3.5 Quality Assurance and Control 39011.3.6 Building Mouse Analog Credibility 39111.3.6.1 Validation 39111.3.6.2 Verification 39211.3.7 Liver and Lobular Form and Function 39211.3.8 APAP Metabolism 39311.3.9 PP-to-CV Gradients 39411.3.10 GSH Depletion 39411.3.11 Damage Products 39511.3.12 Triggering Hepatocyte Death 39511.3.13 Repair Events 39511.3.14 Sensitivity Analyses and Uncertainty Quantification 39611.3.15 Mouse Body 39711.3.16 Death Delay 39911.4 Discussion 399References 40212 Personalized Medicine: Drug Delivery and Pharmacokinetics 407Melanie A. Felmlee and Xiaoling Li12.1 Personalized Medicine 40712.2 Drug Delivery in Personalized Medicine 40912.2.1 Delivery Approaches to Alter Dose 41012.2.2 Delivery Approaches That Alter Pharmacokinetic Parameters 41212.2.3 Targeted Delivery Approaches 41312.3 Pharmacokinetic Analysis for Personalized Drug Delivery 41412.3.1 Pharmacokinetic Analysis for Non-targeted Delivery Approaches 41412.3.2 Pharmacokinetic Analysis for Targeted Delivery Approaches 41612.4 Challenges and Opportunities in Personalized Drug Delivery 41712.5 Conclusions 418References 419Index 423