Preface xv
1 Introduction: Utility of Mathematical Models in Drug Development and Delivery 1
Toufigh Gordi and Bret Berner
1.1 Introduction 1
1.2 Use of Mathematical Models in Drug Development 2
1.3 Noncompartmental Analysis 3
1.4 Pharmacokinetic (PK) Models 5
1.5 Physiologically Based Pharmacokinetic (PBPK) Models 7
1.6 Pharmacokinetic/Pharmacodynamic (PK/PD) Models 9
1.7 Systems Pharmacology Models 12
1.8 Utility of PK/PD Analysis and Models in Drug Development 14
1.8.1 Drug Delivery and PK/PD 26
1.8.2 Drug Properties and Mechanism of Release from the Dosage Form 27
1.8.2.1 Temporal Pattern of Delivery 30
1.9 Discussion 32
References 34
2 Physiologically Based Models: Techniques and Applications to Drug Delivery 43
Richard N. Upton, Ashley M. Hopkins, Ahmad Y. Abuhelwa, Jim H. Hughes and David J.R. Foster
2.1 Introduction 43
2.2 Types of Pharmacokinetic Models 43
2.3 Commercial vs. Bespoke PBPK Models 45
2.4 Data Sources 46
2.5 Applications of PBPK Models 46
2.6 Techniques of PBPK Modeling 48
2.6.1 The “Language” of PBPK Models 48
2.6.2 Oral Absorption Models 49
2.6.3 Drug Metabolism and Drug–Drug Interactions 56
2.6.4 Drug Transporters 58
2.6.5 Renal Elimination 59
2.6.6 Protein Binding 59
2.6.7 Accounting for Size 61
2.6.8 Accounting for Age 63
2.6.9 Interspecies Scaling 64
2.6.10 Between-Subject Variability 65
2.6.11 Sensitivity Analysis 66
2.6.12 Pharmacodynamics 66
2.7 Summary 68
References 68
3 Oral Delivery and Pharmacokinetic Models 75
Wojciech Krzyzanski
3.1 Introduction 75
3.2 Compartmental Models 76
3.2.1 First-Order Absorption 76
3.2.2 Zero-Order Absorption 78
3.2.3 Absorption Delay 78
3.2.4 Parallel Inputs 80
3.2.5 Discontinuous Absorption 81
3.2.6 Compartmental Absorption and Transit 81
3.2.7 Gastrointestinal Transit Time 82
3.2.8 Other Compartmental Models 82
3.3 Empirical Models 82
3.3.1 Gamma Model 83
3.3.2 Weibull Model 83
3.3.3 Inverse Gaussian Model 85
3.4 Physiologically Based Pharmacokinetic Models of Drug Absorption 85
3.4.1 Traditional and Segregated-Flow Models 86
3.5 Advanced PBPK Models 88
3.5.1 Advanced Compartmental Absorption and Transit Model 88
3.5.2 Advanced Dissolution Absorption and Metabolism Model 89
3.6 Intestinal First-pass Drug Metabolism 90
3.6.1 Well-stirred Gut Model 90
3.6.2 QGut Model 91
3.7 Spatiotemporal Models of Drug Absorption 91
3.7.1 Dispersion Model 92
3.7.2 Translocation Model 92
3.8 Conclusions 93
References 94
4 Oral Site-Directed Drug Delivery and Influence on PK 99
Peter Scholes, Vanessa Zann, Wu Lin, Chris Roe and Bret Berner
4.1 Introduction 99
4.2 GI Anatomy and Physiology 99
4.2.1 Anatomy 100
4.2.2 Regional Variations in Physiology Affecting Drug Delivery 101
4.2.2.1 Fluid Volume and pH 101
4.2.2.2 Enzymes, GutWall Metabolism, Tissue Permeability, and Transporters 102
4.2.2.3 Gender and Age Effects 111
4.2.2.4 GI Transit 112
4.2.2.5 Effect of Food 114
4.2.2.6 Enterohepatic Circulation 115
4.3 Biopharmaceutics Classification System (BCS) 116
4.3.1 Background and Regulatory Perspectives 116
4.3.2 Determining a Solubility Class 119
4.3.3 Determining a Permeability Class 123
4.3.4 Determining Dissolution of the Drug Product 125
4.3.5 GI Stability 126
4.3.6 Applications and Limitations of BCS Classification 126
4.3.7 “Developability Classification System” 129
4.4 Applications and Limitations of Characterization and Predictive Tools 131
4.4.1 In Silico Tools: Predictive Models, Molecular Descriptors, and ADMET 131
4.4.2 In Vitro Tools 133
4.4.2.1 PAMPA 133
4.4.2.2 Cell Lines 135
4.4.3 Ex Vivo Tools 137
4.4.3.1 Ussing Chambers 137
4.4.3.2 Everted Intestinal Sac/Ring 140
4.4.4 In Situ Tools 142
4.4.4.1 Closed Loop Intestinal Perfusion 143
4.4.4.2 Single-Pass Intestinal Perfusion 143
4.4.4.3 Intestinal Perfusion with Venous Sampling 143
4.4.4.4 Vascularly Perfused Intestinal Models 144
4.4.4.5 Other Animal Models 144
4.4.5 In Vivo Tools 145
4.4.6 In Silico Tools for Prediction of PK and PK/PD 146
4.4.7 Preclinical PK Models 150
4.5 Tools to Probe Regional Bioavailability in Humans: Case Studies 151
4.5.1 Site-Specific Delivery Devices 151
4.5.2 Gamma Scintigraphic Imaging 157
4.5.3 Magnetic Resonance Imaging (MRI) 159
4.6 Rational Formulation Design and Effective Clinical Evaluation: Case Studies Describing How to Achieve Desired Release Modality and Target PK 160
4.6.1 Formulation Strategies to Address BCS Classification Challenges 160
4.6.1.1 Solubilization 160
4.6.1.2 Permeability Enhancement 168
4.6.1.3 Concluding Remarks on Strategies for BCS Challenges 170
4.6.2 Formulation Strategies for Chronotherapeutic and Regional GI Delivery for Local or Systemic Delivery 170
4.6.2.1 Gastric Retention 170
4.6.2.2 Enteric-Coated Dosage Forms and Delayed Release to the Small Intestine 182
4.6.2.3 Delivery to the Jejunum and Ileum 185
4.6.2.4 Colonic Delivery 186
4.7 Conclusions 191
References 191
5 The Vasoconstrictor Assay (VCA): Then and Now 221
Isadore Kanfer and Howard Maibach
5.1 Introduction 221
5.1.1 Applications and Procedures 222
5.1.2 Visual Assessment 224
5.1.3 Chromameter Assessment 225
5.1.3.1 Comparison Between Visual and Chromameter Assessment 226
5.2 Issues and Controversies 228
5.2.1 Fitting of PD Response Data 228
5.2.2 Circadian Activity 229
5.2.3 BE Studies Performed Under Occlusion 230
5.2.4 Erythema Response at Application Sites 230
5.2.5 Use of VCA for Market Approval in the European Union 231
5.2.6 Potency Ranking of Topical Corticosteroid Products 232
5.2.7 Sensitive Region of the Dose–Response Curve 234
5.2.8 Correlation of ED50 with Potency Classification of a Product? 235
5.3 Conclusions 236
References 236
6 Topical Delivery: Toward an IVIVC 241
Sam G. Raney and Thomas J. Franz
6.1 Introduction 241
6.2 In Vitro–In Vivo Correlation: Validating the Model of Topical Delivery 241
6.3 In Vitro–In Vivo Correlation: Transdermal Delivery 244
6.4 In Vitro–In Vivo Correlation: Bioavailability and Bioequivalence 245
6.5 Summary 250
Disclaimer 250
References 250
7 Integrated Transdermal Drug Delivery and Pharmacokinetics in Development 253
Bret Berner and Gregory M. Kochak
7.1 Introduction 253
7.2 Fundamentals of Transdermal Delivery 254
7.2.1 Architecture of Skin 254
7.2.2 Skin Permeation and Transdermal Delivery 255
7.2.3 Basic Pharmacokinetics of Transdermal Delivery 262
7.3 In Vivo Assessment of Drug Input and Pharmacokinetic Disposition 266
7.3.1 Deconvolution 266
7.3.2 Convolution 267
7.3.3 Instability in Deconvolution 269
7.3.4 Generalized Input and Convolution 272
7.4 In Vitro Testing: Drug Release from Transdermal Systems 273
7.5 In Vitro/In Vivo Correlation 275
7.6 Clinical Safety and Efficacy Studies for Dermal Drug Development 280
7.6.1 Bioavailability and Bioequivalence 281
7.6.2 Skin Irritation and Sensitization Study 282
7.7 Dosage Form Proportionality Scaling and Dose Proportionality 283
7.7.1 Residual Content of the Dosage Form 283
7.7.2 Comparative Toxicity and Efficacy 283
7.8 Supporting In Vitro Studies 283
7.9 Safety Studies Related to Environmental Conditions Such as Heat and Storage Conditions 284
7.10 Active Transdermal Systems That Enhance Barrier Penetration 284
7.10.1 Microneedles 284
7.10.2 Thermal or Radio Frequency Ablation 287
7.10.3 Sonophoresis 288
7.10.4 Electrical 289
7.10.4.1 Electroporation 289
7.10.4.2 Iontophoresis 290
7.11 Conclusion 293
References 293
8 Formulation and Pharmacokinetic Challenges Associated with Targeted Pulmonary Drug Delivery 305
Tomoyuki Okuda and Hak-Kim Chan
8.1 Progress on Formulations and Devices for Inhaled Drugs 305
8.2 Challenges for Inhaled Formulations 308
8.2.1 High-Dose Drugs and Amorphous Powders 308
8.2.2 Generic DPI Formulations 309
8.2.3 Biologics and Macromolecules 310
8.2.4 Controlled Release Formulations 310
8.3 Factors Determining the Fate of Inhaled Drugs in the Body 311
8.3.1 Anatomical and Histological Characteristics of the Respiratory System 311
8.3.2 Physicochemical Characteristics of Inhaled Drugs 312
8.4 Pharmacokinetic/Pharmacodynamic Correlation of Inhaled Drugs 314
8.4.1 Desirable Pharmacokinetic Parameters of Inhaled Drugs for Local Action and Systemic Delivery 314
8.4.2 Pharmacokinetic/Pharmacodynamic Correlation of Clinically Approved Inhaled Drugs 315
8.4.2.1 Corticosteroids and Bronchodilators 315
8.4.2.2 Antimicrobials 316
8.4.2.3 Prostacyclin Analogs 317
8.4.2.4 Loxapine 318
8.4.2.5 Insulin 318
8.5 Application of Drug Delivery System for Improving Pharmacokinetic/Pharmacodynamic Parameters of Inhaled Drugs 320
8.5.1 Chemical Modification 320
8.5.2 Functional Micro/Nanoparticle Formulations 321
8.5.3 Active Targeting 322
8.6 Conclusion 323
References 324
9 Oral Transmucosal Drug Delivery 333
Mohammed Sattar and Majella E. Lane
9.1 Introduction 333
9.2 Structure and Physiology of the Oral Mucosa 334
9.2.1 Buccal Mucosa 334
9.2.2 Sublingual Mucosa 335
9.2.3 Gingiva and Palate 336
9.2.4 Saliva 336
9.2.5 Mucus 336
9.2.6 Permeation Routes 336
9.3 Drug Properties Which Influence OTMD 337
9.3.1 Molecular Weight 337
9.3.2 Lipid Solubility 338
9.3.3 Degree of Ionization 339
9.3.4 Potency 340
9.4 Buccal and Sublingual Formulations 340
9.4.1 Currently Used Technologies 340
9.4.2 Investigation of Iontophoresis for Oral Transmucosal Drug Delivery 342
9.5 Models to Study OTDD 342
9.5.1 Studies in Man and Human Tissue Models 342
9.5.2 Porcine Tissue Models 343
9.5.3 Dog, Monkey, and Rabbit Models 344
9.5.4 Chicken, Hamster, and Rat Models 345
9.5.5 Cell Culture Models 345
9.6 Feasibility of Systemic Delivery Based on In Vitro Permeation Studies 346
9.7 Conclusion 347
References 347
10 PK/PD and the Drug Delivery Regimen for Infusion in the Critical Care Setting 355
Fekade B. Sime and Jason A. Roberts
10.1 Introduction 355
10.2 PK/PD Properties and the Mode of Infusional Drug Delivery for Antibiotics 356
10.3 Changes in PK/PD and Infusional Drug Delivery Regimens in Critically Ill Patients 357
10.4 Short Intermittent Infusions 359
10.5 Extended Infusions 360
10.6 Continuous Infusion 361
10.6.1 Continuous Infusion of β-Lactam Antibiotics 361
10.6.2 Continuous Infusion of Vancomycin 366
10.7 Conclusions 367
References 367
11 Virtual Experiment Methods for Integrating Pharmacokinetic, Pharmacodynamic, and Drug Delivery Mechanisms: Demonstrating Feasibility for Acetaminophen Hepatotoxicity 375
Andrew K. Smith, Ryan C. Kennedy, Brenden K. Petersen, Glen E.P. Ropella and Carver Anthony Hunt
11.1 Introduction 375
11.1.1 Focus on Acetaminophen-Induced Liver Injury 376
11.2 Results 377
11.2.1 Engineering Parsimonious Fit for Purpose Virtual Mice 377
11.2.2 Concrete Lobule Location-Dependent Mechanisms 380
11.2.3 Falsifying Virtual Mechanisms 381
11.2.4 A Plausible Causal Cascade 383
11.2.5 Drug Delivery and a Therapeutic Intervention 385
11.3 Methods 386
11.3.1 Broad Requirements 386
11.3.2 Prediction 388
11.3.3 Iterative Refinement Protocol 388
11.3.4 Data Types, Reuse, and Sharing 390
11.3.5 Quality Assurance and Control 390
11.3.6 Building Mouse Analog Credibility 391
11.3.6.1 Validation 391
11.3.6.2 Verification 392
11.3.7 Liver and Lobular Form and Function 392
11.3.8 APAP Metabolism 393
11.3.9 PP-to-CV Gradients 394
11.3.10 GSH Depletion 394
11.3.11 Damage Products 395
11.3.12 Triggering Hepatocyte Death 395
11.3.13 Repair Events 395
11.3.14 Sensitivity Analyses and Uncertainty Quantification 396
11.3.15 Mouse Body 397
11.3.16 Death Delay 399
11.4 Discussion 399
References 402
12 Personalized Medicine: Drug Delivery and Pharmacokinetics 407
Melanie A. Felmlee and Xiaoling Li
12.1 Personalized Medicine 407
12.2 Drug Delivery in Personalized Medicine 409
12.2.1 Delivery Approaches to Alter Dose 410
12.2.2 Delivery Approaches That Alter Pharmacokinetic Parameters 412
12.2.3 Targeted Delivery Approaches 413
12.3 Pharmacokinetic Analysis for Personalized Drug Delivery 414
12.3.1 Pharmacokinetic Analysis for Non-targeted Delivery Approaches 414
12.3.2 Pharmacokinetic Analysis for Targeted Delivery Approaches 416
12.4 Challenges and Opportunities in Personalized Drug Delivery 417
12.5 Conclusions 418
References 419
Index 423
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