John Wiley & Sons Drug Delivery Approaches Cover This book discusses drug delivery options to achieve target profiles and approaches as defined by ph.. Product #: 978-1-119-77273-6 Regular price: $195.33 $195.33 Auf Lager

Drug Delivery Approaches

Perspectives from Pharmacokinetics and Pharmacodynamics

Berner, Bret / Gordi, Toufigh / Benson, Heather A. E. / Roberts, Michael S. (Herausgeber)

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1. Auflage September 2021
464 Seiten, Hardcover
Fachbuch

ISBN: 978-1-119-77273-6
John Wiley & Sons

Kurzbeschreibung

This book discusses drug delivery options to achieve target profiles and approaches as defined by physical and pharmacokinetic models. Following an overview of drug absorption and physiological models, chapters on oral delivery routes (the most common route) focus on both PBPK and multiple dosage form options. In the case of systemic transdermal delivery, understanding the pharmacokinetics of the formulation and the drug is essential to guide formulation from earliest conception throughout development. Separate chapters discuss the biological and delivery approaches to pulmonary and mucosal delivery. For emergency care settings, authors discuss the relationship between parenteral infusion profiles and PK/PD. The book concludes with recent trends like virtual experiments to elucidate mechanisms and approaches to drug delivery and personalized medicine.

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In diesem Werk werden Möglichkeiten der Wirkstoffverabreichung dargestellt, wobei physikalische und pharmakokinetische Modelle zur Erzielung der gewünschten Profile und Ansätze herangezogen werden. Nach einem Überblick über die Wirkstoffaufnahme und die physiologischen Modelle werden in den Kapiteln über die oralen Verabreichungswege (die häufigste Form der Verabreichung) die PBPK und verschiedene mögliche Darreichungsformen beschrieben. Bei der systemischen transdermalen Verabreichung ist es notwendig, die Pharmakokinetik der Formulierung und des Wirkstoffs zu verstehen, um die Formulierung von der ersten Konzeption über die gesamte Entwicklung darauf auszurichten. In weiteren Kapiteln werden die biologischen und praktischen Ansätze bei der pulmonalen und mukosalen Verabreichung besprochen. Für den Fall der Notfallversorgung betrachten die Autoren die Beziehung zwischen parenteralen Infusionsprofilen und PK/PD. In den letzten Kapiteln werden aktuelle Trends dargestellt, darunter virtuelle Experimente zur Verdeutlichung von Mechanismen sowie moderne Ansätze in der Wirkstoffverabreichung und personalisierten Medizin.
Das Werk Drug Delivery Approaches: Perspectives from Pharmacokinetics and Pharmacodynamics eignet sich nicht nur perfekt für Wissenschaftler, Forscher in der Industrie, Doktoranden und Postdoktoranden in den Bereichen der Pharmawissenschaft und Pharmatechnik, sondern verdient auch einen Platz in den Bücherregalen von Experten, die sich mit Formulierungen, Pharmakokinetik und klinischer Pharmakologie beschäftigen.

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 ß-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
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.