Pharmaceutical chemistry and technology Books
Apple Academic Press Inc. Lipase: An Industrial Enzyme Through Metagenomics
Book SynopsisMicrobial lipases are industrially important and have gained attention due to their stability, selectivity, and broad substrate specificity. Lipases are used as medicine, and they also aid in indigestion, heartburn, allergy to gluten in wheat products (celiac disease), Crohn’s disease, and cystic fibrosis. This volume considers the industrial demand for new sources of lipases with different catalytic characteristics that stimulate the isolation, growth, and development of new microbial strains. The volume narrates the challenging metagenomic approach with the isolation of the lipase gene, its cloning into Escherichia coli, culture of the recombinant bacteria, and extraction and assessment of the lipase enzyme. Lipase-producing bacteria are available in different habitats, such as industrial wastes, vegetable oil processing factories, dairy plants, and soils contaminated with oil and oil seeds, among others. This volume is the effort of the authors to document the scientific findings carried out over the last eight years in the area of un-culturable soil microorganisms. The book presents the physic-chemical features of lipases and their specific applications in different commercial industries. The in-depth study looks at metagenomics for lipases from all angles and provides a truly informative resource. It describes the biochemical characterization of lipase enzymes with the high activity in the presence of 1% tributyrin. A wide review has been presented in the book on lipase enzymes purified from a large collection of microbes present in soil, seawater, waste-dumping sites, animal systems (including human beings), and the atmosphere. Stability of enzymes over changing environments of the industry is indeed a big issue, and the book deals at length with the changing temperatures and pH and metal ion concentrations. Table of ContentsIntroduction. Application of Lipases. Metagenomics and Unculturable Bacteria. Accessing Metagenomics. Metagenomics for Lipase. Functional Approach for Metagenomic Library Construction. Overexpression of Recombinant Protein. Biochemical Characterization of Purified Lipase. Genomic Study of Culture Dependent Bacteria. Genomic Study of Culturable Bacteria. Microbial Assay of Culture Supernatant Containing Crude Lipase. Critical Observations.
£110.20
Apple Academic Press Inc. Dendrimers for Drug Delivery
Book SynopsisWith chapters from highly skilled, experienced, and renowned scientists and researchers from around the globe, Dendrimers for Drug Delivery provides an abundance of information on dendrimers and their applications in the field of drug delivery.The volume begins with an introduction to dendrimers, summarizing dendrimer applications and the striking features of dendrimers. It goes on to present the details of usual properties, structure, classification, and methods of synthesis, with relevant examples. The toxicity of dendrimers is also discussed. The chapter authors provide an exhaustive amount of information about dendrimers and their biomedical applications, including biocompatibility and toxicity aspects, a very useful feature. This informative volume will be valuable resource that will help readers to create products derived from dendrimers and navigate through the regulatory, manufacturing, and quality control hurdles. It will be an important resource for researchers, scientists, upper-level students, and industry professionals. Table of ContentsDendrimers: Branched Nanoarchitectures and Drug Delivery. Dendrimers: A Tool for Advanced Drug Delivery. Dendrimers: General Features and Applications. Computational Approach to Elucidate Dendrimers. An Overview of Dendrimers and Their Biomedical Applications. Dendrimers for Controlled Release Drug Delivery. Dendrimers in Targeted Drug Delivery. Dendrimers in Oral Drug Delivery. Dendrimers in Gene Delivery. Dendrimers as Nanocarriers for Anticancer Drugs. Dendrimeric Architecture for Effective Antimicrobial Therapy.
£124.45
Apple Academic Press Inc. Nanoconjugate Nanocarriers for Drug Delivery
Book SynopsisThis new volume presents a plethora of new research on the use of nanoconjugate nanocarriers in drug delivery. Nanotechnology as drug carriers has been observed to increase the level of sophistication through a variety of ways. It helps to alleviate some of the pitfalls of conventional dosage forms, such as few pitfalls such as non-specific drug delivery, dose dumping, poor patient compliance, toxicities linked with higher doses, etc.With chapters from highly skilled, experienced, and renowned scientists and researchers, Nanoconjugate Nanocarriers for Drug Delivery is divided into four sections, providing an introduction to nanocarriers for drug delivery, physicochemical features of nanocarriers, and specific applications dealing with drug delivery in particular. The materials used as well as formulation and characterization have been discussed in detail. The nanocarriers covered in the book include nanoparticles, vesicular carriers, carriers having carbon as the core constituent, dispersed systems, etc. The book also delves into the interaction and associations between drug delivery research and its therapeutic applications in practice.The book integrates a wide variety of case studies, research, and theories in an attempt to reveal the diversity and capture the novel approaches of nanoconjugate nanocarriers for drug delivery employed by developers and content experts in the field. This timely publication will be an essential reference and current awareness source, building on the available literature in the field of pharmacy and biomedical science, while also providing ideas for further research opportunities in this dynamic field.Table of ContentsNanobiomaterials for Drug Delivery. Role of Surfactants in Nanotechnology-Based Drug Delivery. Smart Polymeric Nanocarriers for Drug Delivery. Gold Nanoconjugates for Smart Drug Delivery and Targeting. Vesicular Drug Carriers as Delivery Systems. siRNA Delivery with Liposomes as Platform Technology. Theranostic Application of Indocyanine Green Liposomes. Aquasomes: A Nanocarrier System. Quantum Dots for Drug Delivery. Graphene and Graphene-Based Materials: Synthesis, Characterization, Toxicity, and Biomedical Applications. Graphene for Drug Delivery: Focus on Antimicrobial Activity. Carbon Nanotubes for Drug Delivery. Nanoemulsion for Drug Delivery. Nanoconjugate Nanocarriers for Drug Delivery in Tropical Medicine. Nanocarrier-Assisted Drug Delivery for Neglected Tropical Diseases. Self-Assembly of Sucrose and Trehalose Alkyl Ethers into Nanoparticles and Nanorods under Aqueous Conditions.
£124.45
Apple Academic Press Inc. Natural Polymers for Pharmaceutical Applications:
Book SynopsisThis new volume, Natural Polymers for Pharmaceutical Applications, Volume 1: Plant-Derived Polymers, presents some of the latest research on the applications of natural polymers in drug delivery and therapeutics for healthcare benefits. Polymers and their applications from several plants are discussed in depth, including tamarind gum, gum Arabic, natural carbohydrate polymer gum tragacanth, pectin, guar gum and its derivatives, locust bean gum, sterculia gum, okra gum, and others. The use of the polymers derived from plants as potential pharmaceutical excipients is expanding day by day because of their stability in the biological system, drug-releasing capability, drug-targeting abilities, as well as their bioavailability. Trade Review“A well-engrossed concept on application of natural plant derivatives as pharmaceutical additives. . . . The superlative collection on the application of plant derivatives in design of novel drug delivery systems, such as micro and nanoparticles, throws an insight on the useful applications of plant-derived products. I would say with a definite certitude that the book will prove to be an exemplary reference for academicians and scientist working in the field of plant-derived products for pharmaceutical applications.” - Dr. Tahir Ansari, Assistant Professor, University of Kualalumpur, MalaysiaTable of ContentsVolume 1: Plant-Derived Polymers 1. Pharmaceutical Applications of Tamarind Gum 2. Pharmaceutical Applications of Gum Arabic 3. Recent Advances in Pharmaceutical Applications of Natural Carbohydrate Polymer Gum Tragacanth 4. Application Potential of Pectin in Drug Delivery 5. Guar Gum and Its Derivatives: Pharmaceutical Applications 6. Pharmaceutical Applications of Locust Bean Gum 7. Pharmaceutical Applications of Sterculia Gum 8. Pharmaceutical Applications of Okra Gum 9. Pharmaceutical Applications of Fenugreek Seed Gum
£117.80
Apple Academic Press Inc. Natural Polymers for Pharmaceutical Applications:
Book SynopsisMany polymers derived from various marine sources and microorganisms possess some important biological properties such as biocompatibility, biodegradability, and bioadhesivity that make them attractive as pharmaceutical excipients in various pharmaceutical dosage forms. Moreover, these polymers can be modified physically and/or chemically to improve their biomaterial properties.In this volume, Natural Polymers for Pharmaceutical Applications, Volume 2: Marine- and Microbiologically Derived Polymers, looks at how these polymers have been explored and exploited for pharmaceutical uses, such as in tablets, microparticles, nanoparticles, ophthalmic preparations, gels, emulsions, suspensions, etc. Some commonly used marine- and microbiologically derived polymers used as pharmaceutical excipients include alginates, agar-agar, gellan gum, carrageenan; chitosan, xanthan gum, and others. The book focuses on important recent advances from experts around the world on marine-derived polysaccharides and pharmaceutical applications of alginates, agar-agar, gellan gum, carrageenan, chitosan derivatives, xanthan gum. Table of ContentsVolume 2: Marine- and Microbiologically Derived Polymers 1. Marine-Derived Polysaccharides: Pharmaceutical Applications 2. Pharmaceutical Applications of Alginates 3. Pharmaceutical Applications of Agar-Agar 4. Pharmaceutical Applications of Gellan Gum 5. Pharmaceutical Applications of Carrageenan 6. Pharmaceutical Application of Chitosan Derivatives 7. Pharmaceutical Applications of
£117.80
de Gruyter Chemistry of Nucleic Acids
Book Synopsis
£73.80
De Gruyter Carbohydrates in Chemistry and Biology
Book Synopsis
£131.85
Harwood-Academic Publishers Advances in Oncology
Book SynopsisFirst Published in 1988. This is a collection of the Proceedings of a course held at the International School of Medical Sciences Ettore Majorana Centre for Scientific Culture, Italy 5-13 September 1986.Table of ContentsPreface, Biological Aspects, Clinical Aspects, Conclusions
£999.99
Harwood-Academic Publishers Growth and Hyperplasia of Cardiac Muscle Cells
Book SynopsisFirst Published in 1991. This Volume three of a set of a monograph series publishing versions of some of the research reviewed in its companion series, Section A (Cardiology Reviews) of Soviet Medical Reviews.Table of ContentsPreface PART I NORMAL GROWTH OF DEVELOPING CARDIAC MUSCLE Chapter 1 Differentiation of Cardiomyocytes Chapter 2 Reproduction of Cardiac Myocytes Developing In Vivo and its Relation to Processes of Differentiation PART 11 CELLULAR ASPECTS OF REGENERATIVE PROCESSES AND HYPERPLASIA IN THE INJURED AND OVERLOADED MYOCARDIUM Chapter 3 Regenerative Processes in the Myocardium of Cold-B1ooded Animals Chapter 4 Proliferation of Cardiac Myocytes in the Injured and Overloaded Myocardium du ring Early Ontogenesis of Warm-Blooded Animals and Man Reactive hyperplasia of cardiomyoeytes of the injured heart of embryos and neonatal animals Chapter 5 Regenerative Possibilities of the Ventricular Myocardium of Adult Mammals Chapter 6 Unusual Proliferative Behavior of Adult Mammalian Atrial Cardiomyocytes Chapter 7 On the Possibility of Reactivation of Proliferative Processes in Cardiomyocytes Of the Conducting System Chapter 8 A Paradoxical Capacity of Working Myocytes of the Overloaded Heart of Man and Primates for Polyploidization Chapter 9 Attempts to Stimulate Myocardial Regeneration PART III MODULATION OF PROCESSES OF CARDIOMYOCYTE DIFFERENTlATION AND PROLIFERATION IN VITRO AND IN TISSUE TRANSPLANTS Chapter 10 Modulations of Differentiation in Tissue Explants of the Myocardium In Vitra Chapter II Processes of Cardiomyocyte Proliferation and Differentiation in Cell Culture Chapter 12 Regenerative Morphogenesis du ring Auto- and Heterotransplantation of Myocardial Tissue Grafts
£308.75
CRC Press The Pharmaceutical Index: 2013 Worldwide NCEs
Book SynopsisAn ideal drug candidate should possess good pharmacological activity, absorption, distribution, metabolism, excretion and toxicity properties. Historically, there are around 6,000 drugs being used in humans and approximately 3,000 still in clinical use, not including herbal medicines. This Pharmaceutical Index series focuses on the profiles of 500 pharmaceutically marketed products from the past two decades. Professor Dr. K. Barry Sharpless is Honorary Editor-in-Chief of this first Index by Pharmacodia. The volume includes 24 NCEs worldwide approved drugs in 2013. Pharmacodia plan to publish two further volumes which will feature 2014 NCEs (32 drugs) and 2015 NCEs (25 drugs).
£380.00
Taylor & Francis Ltd Submicron Emulsions in Drug Targeting and
Book SynopsisIt is anticipated that submicron emulsion and lipid suspension will find numerous and novel medical applications in the near future. The purpose of this multi-authore book is to provide the reader with an up-to-date general overview of submicron emulsions and lipid suspensions (solid lipid nanoparticles) as well as to emphasize the various methods of preparation, characerization, evaluation and potential applications in various therapeutic areas.Leading authors have contributed to this unique book which contains all state of the art and detailed knowledge related to the physico-chemical, pharmaceutical and medical aspects of these most interesting but complex dosage forms, thus making this information easily available to the reader. This book will be of interest to scientists working in the field of drug delivery and targeting in universities as well as in the pharmaceutical, food, cosmetic, veterinary and chemical industries.Table of Contents1. Introduction and Overview Part 1. Intravenous Fat Emulsions 2. Perspectives on the Use of Intravenous Lipid Emulsions in Man 3. Particle-Sizing Technologies for Submicron Emulsions 4. Biofate of Fat Emulsions Part 2. Submicron Emulsions as Therapeutic Delivery Systems 5. Design and Evaluation of Submicron Emulsions as Colloidal Drug Carriers for Intravenous Administration 6. Submicron Emulsions as Drug Carriers for Tropical Administration 7. Emulsions of Supercooled Melts - A Novel Drug Delivery System 8. Submicron Lipid Suspensions (Solid Lipid Nanoparticles) Versus Lipid Nanoemulsions: Similarities and Differences 9. Solid Lipid Nanoparticles (SLN) for Controlled Drug Delivery Part 3. Perfluorochemical Submicron Emulsions 10. The Design and Engineering of Oxygen-Delivering Fluorocarbon Emulsions
£199.50
Pan Stanford Publishing Pte Ltd Dendrimer-Based Nanomedicine
Book SynopsisIn recent decades, dendrimers — free-shaped synthetic macromolecules — have garnered a great deal of scientific interest because of their unique molecular nanostructure. Used in a variety of scientific applications, dendrimers are now widely regarded as a safer, more precise and more effective way to practice medicine.This book compiles and details cutting-edge research in science and medicine from the interdisciplinary team of the Michigan Nanotechnology Institute for Medicine and Biological Sciences, which is currently revolutionizing drug delivery techniques through the development of engineered nanodevices. Edited by Istvan J. Majoros and James R. Baker Jr, two prominent nanotechnology researchers, this book will appeal to anyone involved in nanotechnology, macromolecular science, cancer therapy or drug delivery research. Trade Review"The authors' approach to fill in a little history with futuristic perspective will be a delight to all readers interested in the field. A must read."—Prof. George R. Newkome, The University of Akron, USATable of ContentsTargeted Drug Delivery in General, New Technology in Medicine. General Carriers for Drug Delivery. Poly(amidoamine) Dendrimer Synthesis and Characterization. Optical and Biophotonic Applications of Dendrimer Conjugate. Dendrimer Conjugates for Cancer Treatment. Biological Application of PAMAM Dendrimer Nanodevices in vitro and in vivo. Dendrimer-based Targeted Apoptosis Sensors for Medical Application. MRI Using Targeted Dendrimer Contrast Agents. Nanoparticle — Membrane Interactions: Mechanism for Enhanced Permeability. Computer Simulations of Dendrimers. Dendrimer-Entrapped and Dendrimer-Stabilized Metal Nanoparticles for Biomedical Applications.
£161.50
Pan Stanford Publishing Pte Ltd Bio-Inspired Regenerative Medicine: Materials,
Book SynopsisThis book presents a wide and interdisciplinary overview of the current state of the art in the development of biomimetic materials for tissue regeneration on the basis of relevant and high-impact clinical needs. It specifically emphasizes the regeneration of bone, cartilage, and osteochondral tissues as well as soft tissues such as nerves, heart, and endocrine organs. It brings together contributions from materials scientists, biologists, and surgeons with globally recognized experience in the field of regenerative medicine.The aim of the book is to highlight the relevance of biomimetics as an elective approach for the development of new scaffolds that can direct regenerative cascade by means of chemico-physical and topological nano-cues presented to cells and biologic tissues. Particularly, the book refers to emerging concepts in synthesis processes and scaffolds inspired by nature as well as to novel approaches for smart functionalization such as the use of magnetic signaling.Trade Review"This well-written book is essential reading for professionals and students from materials science, materials engineering, biology, or medicine who wish to know the state of the art on biomimetic-inspired materials for surgical applications. All fields are clearly presented, from powder synthesis to scaffold processing, tissue engineering, interaction between biomaterials and living cells, and biomechanical behavior. It is a good reference point for the foreseeable future."—Prof. Anne Leriche, University of Valenciennes, FranceTable of ContentsBio-Inspired Nanomaterials and Nano-Bio-Magnetism in Regenerative Medicine. Nano-Apatites. Biomorphic Scaffolds. Nanocomposites for Bone and Osteochondral Regeneration. Nerve Regeneration. Heart Regeneration. Triggering Cell-Biomaterial Interaction. Clinical Perspective of Bone Regeneration in Orthopaedics and Spine Surgery. Clinical Aspects Related to Osteochondral Regeneration. Organomorphic Approach to Bio-Artificial Endocrine Organs.
£104.50
Pan Stanford Publishing Pte Ltd Drug Delivery Across Physiological Barriers
Book SynopsisTransport of pharmaceutical agents in the body is paramount to therapeutic efficacy. Advances in the past decades have rendered a remarkable improvement of drug delivery strategies, which has helped to increase the bioavailability of therapeutic agents by protecting them from degradation, targeting them to diseased sites, and controlling their circulation time and release rate. Additionally, for most therapeutics, reaching the targets of action require penetration across tissues and/or entry within cells. The design of strategies to control the transport of therapeutic compounds through these physiological barriers has become an imperative and a challenging need in the quest for better therapeutics. This book provides an overview of the current advances in this field, including considerations on the biological regulation and natural mechanisms overcoming these barriers, as well as drug delivery strategies facilitating the transport of drugs and their carriers at the tissue, cell, and subcellular levels. Trade Review"This book combines a thorough overview of the barriers encountered and strategies employed to increase the delivery of therapeutics. It also provides a critical assessment of the merits and limitations of delivery approaches. Overall, this is a concentrate of the most recent scientific discoveries written by highly recognized authors in the field. It is an excellent reference for both students and seasoned scientists."—Dr. Mohamed ElSayed, University of Michigan, USA"Drug delivery across physiological barriers is a historic and challenging problem. This compelling book addresses this topic thoroughly, with detailed chapters ranging from descriptions of the composition of physiological barriers, through barrier-penetrating drug delivery strategies to how drugs are trafficked once inside cells. A must-have addition to any pharmaceutical scientist’s technical library." —Dr. John D. Higgins, Merck & Co., USA"Drug Delivery Across Physiological Barriers is a fundamental book in nanomedicine, particularly for those who start in the field of designing therapeutic strategies based on nano-drug delivery systems. It addresses the challenging anatomical and pathological barriers of the epithelia, endothelia, extracellular matrix, and cell endocytic pathways. It shows that a thorough understanding of the stepwise processing to which nanostructures are exposed throughout the body and intracellularly is a critical tool for a wise design of nanomedicines." —Dr. Eder L. Romero, National University of Quilmes, ArgentinaTable of ContentsIntroduction. Physiological Barriers Controlling Penetration and Transport of Substances in the Body. Structure and function of epithelial and endothelial barriers. The plasma membrane as a semipermeable barrier. Biology and regulation of protein sorting and vesicular transport. Pathogens and intracellular transport. Strategies for Drug Penetration across Tissue Compartments. Drug transport across the skin. Mucosal barriers. Transport of therapeutics across the gastrointestinal epithelium. Crossing the endothelial barrier. Nanoparticle-based drug delivery to solid tumors. Drug Transport into Cells and Subsequent Intracellular Trafficking. Membrane lipids and drug transport. Drug delivery systems that fuse with the plasmalemma. Endocytosis and the endolysosomal route in drug delivery. Endo-lysosomal escape. Intracellular transport to the mitochondria and other organelles.
£104.50
Pan Stanford Publishing Pte Ltd Tuning Innovation with Biotechnology
Book SynopsisThis book deals with evolving intelligence systems and their use in immune algorithm (IM), particle swarm optimization (PSO), bacterial foraging (BF), and hybrid intelligent system to improve plants, robots, etc. It discusses the motivation behind research on and background of evolving intelligence systems and illustrates IM-based approach for parameter estimation required for designing an intelligent system. It approaches optimal intelligent tuning using a hybrid genetic algorithm–particle swarm optimization (GA-PSO) and illustrates hybrid GA-PSO for intelligent tuning of vector system. Table of ContentsBackground. Immune Network–Based Parameter Estimation. Intelligent PID Controller Tuning Using a Hybrid GA-PSO Approach. GA-PSO-Based PI Controller Tuning for Indirect Vector Control of Three-Phase Induction Motor. Novel Hybrid System Based on GA and Bacteria Foraging. Conclusion.
£90.25
Pan Stanford Publishing Pte Ltd Embedding New Technologies into Society: A
Book SynopsisThe embedding of any new technologies in society is challenging. The evolving state of the scientific art, often-unquantifiable risks and ill-defined developmental trajectories have the potential to hinder innovation and/or the commercial success of a technology. The are, however, a number of tools that can now be utilized by stakeholders to bridge the chasm that exists between the science and innovation dimensions on the one hand, and the societal dimensions on the other. This edited volume will draw together leading researchers from the domains of law, philosophy, political science, public administration and the natural sciences in order to demonstrate how tools such as, for example, constructive technology assessment, regulatory governance and societal scenarios, may be employed by stakeholders to assist in successfully embedding new technologies into society. This volume will focus primarily on the embedding of two emergent and emerging technologies: nanotechnologies and synthetic biology. Government, industry and the epistemic community continue to struggle with how best to balance the promised benefits of an emerging technology with concerns about its potential impacts. There is a growing body of literature that has examined these challenges from various cultural, scientific and jurisdictional dimensions. There is, however, much work that still needs to be done; this includes articulating the successes and failures of attempts to the societal embedding of technologies and their associated products. This edited volume is significant and timely, as unlike other books currently on the market, it shall draw from real work experiences and experiments designed anticipate the societal embedding of emerging technologies. This empirical work shall be supported by robust theoretical underpinnings.Table of ContentsIntroduction - Foxes become hedgehogs. Reflexive co-evolution and governance patterns. Governance approaches for emerging technologies. Society as a laboratory to experiment with new technologies. Care and technoscience: re-embedding the future of innovation. Division of moral labour as an element in the governance of emerging technologies. Ethical reflexivity as capacity building: supportive tools and approaches. The demand side of innovation governance: Demand articulation processes in the case of nano-based sensor technologies. Evolving Patterns of Governance of and by Expectations. The Graphene Hype Wave. Transnational challenges of governing new technologies: The case of nanotechnology. Co-Regulation of Nanomaterials: On Collaborative Business Association Activities directed at Contributing to Occupational Health and Safety. The ‘Metamorphosis’ of the drone: the governance challenges of drone technology in border surveillance. On the disruptive potential of 3D printing. Modifying Materials, Mosquitoes and Measures: The Regulation of Nanotechnologies and Synthetic Biology. Conclusions.
£60.79
Pan Stanford Publishing Pte Ltd Capillary Electrophoresis: Trends and
Book SynopsisCapillary electrophoresis (CE) has become an established method with widespread recognition as an analytical technique of choice in numerous analytical laboratories, including industrial and academic sectors. Pharmaceutical and biochemical research and quality control are the most important CE applications. This book provides a comparative assessment of related techniques on mode selection, method development, detection, and quantitative analysis and estimation of pharmacokinetic parameters and broadens the understanding of modern CE applications, developments, and prospects. It introduces the fundamentals of CE and clearly outlines the procedures used to mitigate several barriers, such as detection limits, signal detection, changing capillary environment, resolution separation of analytes, and hyphenation of mass spectrometry with CE, for a range of analytical problems. Each chapter outlines a specific electrophoretic variant with detailed instructions and some standard operating procedures. In this respect, the book meets its desired goal of rendering assistance to lovers of electrophoresis.Trade Review"Decades after its introduction, capillary electrophoresis has evolved into a mature technique, especially in the field of pharmaceutical analysis. This book focuses on a number of fields in which this separation technique has proven its unique usefulness, such as chiral separations and the analysis of protein biopharmaceuticals. It highlights the current state of the art and offers high-quality general chapters and overviews as well as topical chapters. Recommended reading for all those involved in pharmaceutical analysis, albeit academically or industrially!"—Prof. Ann Van Schepdael, University of Leuven, BelgiumTable of ContentsCapillary Electrophoresis: A Versatile Technique in Pharmaceutical Analysis. Recent Applications of Chiral Capillary Electrophoresis in Pharmaceutical Analysis. A Mini-Review on Enantiomeric Separation of Ofloxacin using Capillary Electrophoresis: Pharmaceutical Applications. Nano-Stationary Phases for Capillary Electrophoresis Techniques. Capillary Electrophoresis Coupled to Mass Spectrometry for Enantiomeric Drugs Analysis. Enantioselective Drug–Plasma Protein-Binding Studies by Capillary Electrophoresis. Clinical Use of Capillary Zone Electrophoresis: New Insights into Parkinson’s Disease. Electrophoretically Mediated Microanalysis for Evaluation of Enantioselective Drug Metabolism. Capillary Electrophoresis for the Quality Control of Intact Therapeutic Monoclonal Antibodies. Molecular Simulation of Chiral Selector–Enantiomer Interactions through Docking: Antimalarial Drugs as Case Study.
£90.25
Indiana University Press Death to Beauty The Transformative History of
Book SynopsisTrade Review"A riveting text that bridges biography, history, and medicine, Death to Beauty is a must-read for anyone interested in the story of how Dr. Alan Scott, working almost independently and with few resources, transformed the world's deadliest toxin into a wonder drug that has not only become a multi-billion-dollar industry, but a medical and cultural phenomenon."—Dana Berkowitz, author of Botox Nation: Changing the Face of America"Expertly written and thoroughly researched, Dr. Helveston meticulously outlines the history of Botox and the pivotal role that Dr. Alan Scott played in bringing Botox safely to millions of people across the globe."—Christie L. Morse, MD, Concord Eye Center"Dr. Helveston has painstakingly researched the life and accomplishments of Alan B. Scott MD, one of the most brilliant minds in medicine and creator of botulinum toxin (Botox) for the treatment of many conditions. This book is a page burner, interesting, and still very thorough. I highly recommend it to clinicians and non-clinicians alike."—William Good, MD, Senior Scientist at Smith-Kettlewell Eye Research Institute"At the heart of this book is the curiosity and determination of one man, Alan Scott. Helveston's compelling narrative makes botulinum toxin understandable, all the while tracing the fine line that distinguishes poison from medicine. Death to Beauty is an important addition to the history of medicine."—Edward O'Malley, MD, Senior Staff Physician Emeritus, Henry Ford Health"Eugene Helveston, M.D. documents the amazing story of Botulinum toxin from a deadly problem to a very important therapeutic advance for patients with multiple types of neurological conditions, from various movement disorders' treatment to helping alleviating the misery of migraine headaches. Botulinum toxin has been a great advance for neurologists treating many needy patients."—David A. Josephson, M.D., Josephson-Wallack-Munshower Neurology, P.C."Dr. Scott would be proud and grateful."—C. William Hanke, MD, MPH, Former President, American Academy of Dermatology
£18.04
John Wiley & Sons Inc Comprehensive Quality by Design for
Book SynopsisThis book is a structured approach to designing a product and its associated manufacturing process. It shows pharmaceutical engineers and scientists involved in product and process development how to utilize QbD practices and applications effectively while complying with government regulations.Table of ContentsList of Contributors xiiiPreface xix1 Introduction 1Christine Seymour and Gintaras V. Reklaitis1.1 Quality by Design Overview 11.2 Pharmaceutical Industry 21.3 Quality by Design Details 31.4 Chapter Summaries 4References 72 An Overview of the Role of Mathematical Models in Implementation of Quality by Design Paradigm for Drug Development and Manufacture 9Sharmista Chatterjee, Christine M. V. Moore, and Moheb M. Nasr2.1 Introduction 92.2 Overview of Models 92.3 Role of Models in QbD 122.4 General Scientific Considerations for Model Development 202.5 Scientific Considerations for Maintenance of Models 222.6 Conclusion 23References 233 Role of Automatic Process Control in Quality by Design 25Mo Jiang, Nicholas C. S. Kee, Xing Yi Woo, Li May Goh, Joshua D. Tice, Lifang Zhou, Reginald B. H. Tan, Charles F. Zukoski, Mitsuko Fujiwara, Zoltan K. Nagy, Paul J. A. Kenis, and Richard D. Braatz3.1 Introduction 253.2 Design of Robust Control Strategies 313.3 Some Example Applications of Automatic Feedback Control 353.4 The Role of Kinetics Modeling 403.5 Ideas for a Deeper QbD Approach 423.6 Summary 44Acknowledgments 46References 474 Predictive Distributions for Constructing the ICH Q8 Design Space 55John J. Peterson, Mohammad Yahyah, Kevin Lief, and Neil Hodnett4.1 Introduction 554.2 Overlapping Means Approach 564.3 Predictive Distribution Approach 594.4 Examples 614.5 Summary and Discussion 68Acknowledgments 69References 695 Design of Novel Integrated Pharmaceutical Processes: A Model]Based Approach 71Alicia Román]Martínez, John M. Woodley, and Rafiqul Gani5.1 Introduction 715.2 Problem Description 735.3 Methodology 765.4 Application: Case Study 805.5 Conclusions 91References 916 Methods and Tools for Design Space Identification in Pharmaceutical Development 95Fani Boukouvala, Fernando J. Muzzio, and Marianthi G. Ierapetritou6.1 Introduction 956.2 Design Space: A Multidisciplinary Concept 986.3 Integration of Design Space and Control Strategy 1026.4 Case Studies 1026.5 Conclusions 119Acknowledgment 120References 1207 Using Quality by Design Principles as a Guide for Designing a Process Control Strategy 125Christopher L. Burcham, Mark LaPack, Joseph R. Martinelli, and Neil McCracken7.1 Introduction 1257.2 Chemical Sequence, Impurity Formation, and Control Strategy 1307.3 Mass Transfer and Reaction Kinetics 1407.4 Optimal Processing Conditions 1657.5 Predicted Product Quality under Varied Processing Conditions 1747.6 Conclusions 186Acknowledgments 187Notation 187Acronyms 187Symbols 187Notes 189References 1898 A Strategy for Tablet Active Film Coating Formulation Development Using a Content Uniformity Model and Quality by Design Principles 193Wei Chen, Jennifer Wang, Divyakant Desai, Shih]Ying Chang, San Kiang, and Olav Lyngberg8.1 Introduction 1938.2 Content Uniformity Model Development 1978.3 RSD Model Validation and Sensitivity Analysis for Model Parameters 2128.4 Model]Based Design Space Establishment for Tablet Active Film Coating 2198.5 Summary 229Notations 230References 2309 Quality by Design: Process Trajectory Development for a Dynamic Pharmaceutical Coprecipitation Process Based on an Integrated Real]Time Process Monitoring Strategy 235Huiquan Wu and Mansoor A. Khan9.1 Introduction 2359.2 Experimental 2379.3 Data Analysis Methods 2399.4 Results and Discussion 2409.5 Challenges and Opportunities for PCA]Based Data Analysis and Modeling in Pharmaceutical PAT and QbD Development 2509.6 Conclusions 252Acknowledgments 252References 25310 Application of Advanced Simulation Tools for Establishing Process Design Spaces Within the Quality by Design Framework 257Siegfried Adam, Daniele Suzzi, Gregor Toschkoff, and Johannes G. Khinast10.1 Introduction 25710.2 Computer Simulation]Based Process Characterization of a Pharmaceutical Blending Process 26110.3 Characterization of a Tablet Coating Process via CFD Simulations 27610.4 Overall Conclusions 294References 29511 Design Space Definition: A Case Study—Small Molecule Lyophilized Parenteral 301Linas Mockus, David LeBlond, Gintaras V. Reklaitis, Prabir K. Basu, Tim Paul, Nathan Pease, Steven L. Nail, and Mansoor A. Khan11.1 Introduction 30111.2 Case Study: Bayesian Treatment of Design Space for a Lyophilized Small Molecule Parenteral 30211.3 Results 30711.4 Conclusions 311Appendix 11.A Implementation Using WinBUGS and R 311Shelf Life 315Notation 316Acknowledgments 317References 31712 Enhanced Process Design and Control of a Multiple]Input Multiple]Output Granulation Process 319Rohit Ramachandran12.1 Introduction and Objectives 31912.2 Population Balance Model 32012.3 Simulation and Controllability Studies 32312.4 Identification of Existing “Optimal” Control]Loop Pairings 32712.5 Novel Process Design 33012.6 Conclusions 335References 33613 A Perspective on the Implementation of QbD on Manufacturing through Control System: The Fluidized Bed Dryer Control with MPC and NIR Spectroscopy Case 339Leonel Quiñones, Luis Obregón, and Carlos Velázquez13.1 Introduction 33913.2 Theory 34013.3 Materials and Methods 34413.4 Results and Discussion 34813.5 Continuous Fluidized Bed Drying 35513.6 Control Limitations 35613.7 Conclusions 357Acknowledgment 357References 35714 Knowledge Management in Support of QbD 361G. Joglekar, Gintaras V. Reklaitis, A. Giridhar, and Linas Mockus14.1 Introduction 36114.2 Knowledge Hierarchy 36314.3 Review of Existing Software 36414.4 Workflow]Based Framework 36514.5 Drug Substance Case Study 36814.6 Design Space 37414.7 Technical Challenges 38214.8 Conclusions 384References 385Index 387
£141.50
John Wiley & Sons Inc Continuous Manufacturing of Pharmaceuticals
Book SynopsisA comprehensive look at existing technologies and processes for continuous manufacturing of pharmaceuticals As rising costs outpace new drug development, the pharmaceutical industry has come under intense pressure to improve the efficiency of its manufacturing processes. Continuous process manufacturing provides a proven solution.Table of ContentsAbout the Editors xvii List of Contributors xix Series Preface xxv Preface xxvii 1 Continuous Manufacturing: Definitions and Engineering Principles 1 Johannes Khinast and Massimo Bresciani 1.1 Introduction 1 1.1.1 Definition of Continuous Manufacturing 1 1.1.2 Continuous Manufacturing in the Pharmaceutical Industry 2 1.1.3 Our View of Continuous Manufacturing 3 1.1.4 Regulatory Environment 8 1.2 Advantages of Continuous Manufacturing 8 1.2.1 Flexibility 8 1.2.2 Effect on the Supply Chain 8 1.2.3 Agility and Reduced Scale-up Efforts 9 1.2.4 Real-Time Quality Assurance and Better Engineered Systems 9 1.2.5 Decentralized Manufacturing 10 1.2.6 Individualized Manufacturing 10 1.2.7 Reduced Floor Space and Investment Costs 10 1.2.8 More Efficient Chemistries 10 1.2.9 Societal Benefits 11 1.3 Engineering Principles of Continuous Manufacturing 11 1.3.1 Pharmaceutical Unit Operations 11 1.3.2 Fundamentals of Process Modeling 15 1.3.3 Balance Equations for Mass, Species, Energy and Momentum 16 1.3.4 Residence Time Distribution 20 1.3.5 Classical Reactor Types as a Basis for Process Understanding 21 1.3.6 Process Control, Modeling and PAT 24 1.3.7 Scale-Up 26 1.3.8 Dimensioning 27 1.4 Conclusion 28 References 30 2 Process Simulation and Control for Continuous Pharmaceutical Manufacturing of Solid Drug Products 33 Marianthi Ierapetritou, M. Sebastian Escotet-Espinoza and Ravendra Singh 2.1 Introduction 33 2.1.1 Scope and Motivation 33 2.1.2 Process Simulation 34 2.1.3 Process Control 36 2.2 Pharmaceutical Solid Dosage Manufacturing Processes 38 2.2.1 Overview 38 2.2.2 Continuous Manufacturing Processes 38 2.2.3 Continuous Process Equipment 39 2.3 Mathematical Modeling Approaches 44 2.3.1 First Principle “Mechanistic” Models 44 2.3.2 Multi-dimensional Population Balance Models 44 2.3.3 Engineering or Phenomenological Models 46 2.3.4 Empirical and Reduced Order Models 47 2.4 Unit Operations Models 48 2.4.1 Feeders 48 2.4.2 Blenders (Mixers) 56 2.4.3 Tablet Press 63 2.4.4 Roller Compactor 67 2.4.5 Wet Granulation 71 2.4.6 Drying 75 2.4.7 Milling/Co-milling 76 2.4.8 Flowsheet Modeling 77 2.5 Process Control of Continuous Solid-based Drug Manufacturing 81 2.5.1 Process Control Basics 83 2.5.2 Control Design of Continuous Pharmaceutical Manufacturing Process 84 2.6 Summary 93 Acknowledgments 94 References 94 3 Regulatory and Quality Considerations for Continuous Manufacturing 107 Gretchen Allison, Yanxi Tan Cain, Charles Cooney, Tom Garcia, Tara Gooen Bizjak, Oyvind Holte, Nirdosh Jagota, Bekki Komas, Evdokia Korakianiti, Dora Kourti, Rapti Madurawe, Elaine Morefield, Frank Montgomery, Moheb Nasr, William Randolph, Jean-Louis Robert, Dave Rudd and Diane Zezza 3.1 Introduction 108 3.2 Current Regulatory Environment 108 3.3 Existing Relevant Regulations, Guidelines, and Standards Supporting Continuous Manufacturing 108 3.3.1 ICH Guidelines 108 3.3.2 United States Food and Drug Administration Guidances 109 3.3.3 US FDA Guidance on Process Validation 109 3.3.4 American Society for Testing and Materials Standards 109 3.3.5 European Union Guidelines 110 3.4 Regulatory Considerations 110 3.4.1 Development Considerations for Continuous Manufacturing 111 3.4.2 Special Considerations for Control Strategy in Continuous Manufacturing 112 3.4.3 Stability Considerations for Continuous Manufacturing 114 3.5 Quality/GMP Considerations 115 3.5.1 Pharmaceutical Quality Systems 115 3.5.2 Batch Release 115 3.5.3 Startup and Shutdown Procedures 116 3.5.4 State of Control: Product Collection and In-process Sampling 117 3.5.5 Process Validation and CPV 117 3.5.6 Material Traceability in Continuous Manufacturing 119 3.5.7 Handling of Raw Material and In-process Material 119 3.5.8 Detection and Treatment for Non-conformity 119 3.5.9 Personnel Procedures and Training 120 3.5.10 Material Carry-over 120 3.5.11 Material Diversion 120 3.5.12 Production Floor Product Monitoring 121 3.5.13 Raw Material Variability 121 3.5.14 Cleaning Validation 121 3.5.15 Equipment Failure 122 3.6 Quality Considerations for Bridging Existing Batch Manufacturing to Continuous Manufacturing 122 3.6.1 Physicochemical Equivalence Considerations 123 3.6.2 Bioequivalence Considerations 123 3.7 Glossary and Definitions 123 3.7.1 Batch Definition 123 3.7.2 21cfr 210.3 124 3.7.3 Cfr 211 124 3.7.4 Ich Q 7 124 3.7.5 Ich Q 10 124 3.8 General Regulatory References 124 3.8.1 cGMP Guidance 125 4 Continuous Manufacturing of Active Pharmaceutical Ingredients via Flow Technology 127 Svetlana Borukhova and Volker Hessel 4.1 Introduction 127 4.2 Micro Flow Technology 128 4.2.1 Micromixing 129 4.2.2 Flow Reactors 130 4.2.3 Reaction Activation Tools 130 4.2.4 Downstream Processing 139 4.2.5 Process Analytical Technology and Automation 142 4.3 Multi-step Synthesis of Active Pharmaceutical Ingredients in Micro Flow 150 4.3.1 Aliskiren 151 4.3.2 Artemisinin 151 4.3.3 Ibuprofen 153 4.3.4 Gleevec 154 4.3.5 Nabumetone 155 4.3.6 Quinolone Derivative as a Potent 5HT 1B Antagonist 155 4.3.7 Rufinamide 155 4.3.8 Thioquinazolinone 156 4.4 Larger-scale Syntheses 156 4.4.1 Hydroxypyrrolotriazine (Bristol–Myers–Squibb) 156 4.4.2 2,2-Dimethylchromenes (Bristol–Myers–Squibb) 156 4.4.3 Fused-Bycyclic Isoxazolidines (Eli Lilly and Company) 158 4.4.4 7-Ethyltryptophol on the Way to Etodolac 158 4.4.5 6-Hydroxybuspirone (Bristol-Myers-Squibb) 159 4.5 Current Industrial Applications 160 4.6 Conclusion and Outlook 161 References 162 5 Continuous Crystallisation 169 Cameron Brown, Thomas McGlone and Alastair Florence 5.1 Introduction 169 5.2 Principles of Crystallisation 173 5.2.1 Supersaturation 173 5.2.2 Nucleation and Growth 176 5.2.3 Conservation Equations 180 5.3 Crystallisation Process Development 180 5.4 Continuous Crystallisers and Applications 185 5.4.1 Mixed Suspension Mixed Product Removal 186 5.4.2 MSMPR Cascade 193 5.4.3 Plug Flow Reactors 198 5.4.4 Impinging Jet 206 5.4.5 Microfluidics 207 5.5 Process Monitoring, Analysis and Control 207 5.5.1 Process Monitoring and Analysis 207 5.5.2 Crystallisation Control Strategies 211 5.6 Particle Characterisation 213 5.7 Concluding Remarks 215 References 217 6 Continuous Fermentation for Biopharmaceuticals? 227 L. Mears, H. Feldman, F.C. Falco, C. Bach, M. Wu, A. Nørregaard and K.V. Gernaey 6.1 Introduction 227 6.1.1 Definition of Fermentation 227 6.1.2 Production of Biopharmaceuticals 228 6.1.3 Structure of Chapter 228 6.2 Operation of Fermentation Systems 229 6.2.1 Comparison of Different Cultivation Systems 229 6.2.2 Monitoring of Continuous Fermentation Processes 232 6.2.3 Control of Continuous Fermentation Processes 234 6.3 Continuous Fermentation Examples 238 6.3.1 Continuous Ethanol Fermentation 238 6.3.2 Continuous Lactic Acid Fermentation 239 6.3.3 Single Cell Protein Production 240 6.4 Discussion 241 6.5 Conclusions 243 References 244 7 Integrated Continuous Manufacturing of Biopharmaceuticals 247 Alois Jungbauer and Nikolaus Hammerschmidt 7.1 Background 247 7.1.1 Current Status of Manufacturing of Biopharmaceuticals 247 7.1.2 Challenges to Developing Continuous Processes 249 7.1.3 Rationale for Continuous Biomanufacturing 250 7.2 Continuous Upstream Processing 251 7.2.1 Cell Lines and Cell Line Stability 251 7.2.2 Perfusion Reactor 252 7.2.3 Cell Retention Devices 252 7.2.4 Chemostat and Turbidostat 254 7.2.5 Overview of Products Produced by Continuous Upstream Processing 254 7.3 Continuous Downstream Processing 257 7.3.1 Overview of Unit Operations 257 7.3.2 Continuous Centrifuges 257 7.3.4 Continuous Chromatography 260 7.3.5 Continuous Precipitation 263 7.3.6 Continuous Formulation 266 7.4 Process Integration and Single Use Technology 266 7.4.1 Disposable Bioreactors 268 7.4.2 Disposable Unit Operations in Downstream Processing 268 7.4.3 Full Process Train 270 7.5 Process Monitoring and Control 270 7.6 Process Economics of Continuous Manufacturing 274 7.7 Conclusions 275 Acknowledgments 276 References 276 8 Twin-screw Granulation Process Development: Present Approaches, Understanding and Needs 283 A. Kumar, K.V. Gernaey, I. Nopens and T. De Beer 8.1 Introduction 283 8.2 Continuous Wet-granulation using a TSG 284 8.3 Components of High Shear Wet Granulation in a TSG 287 8.4 Material Transport and Mixing in a TSG 287 8.4.1 Granulation Time in a TSG 288 8.4.2 Mixing in a TSG 291 8.5 Granule Size Evolution During Twin-screw Granulation 294 8.5.1 Granule Size and Shape Dynamics in a TSG 295 8.5.2 Link Between RTD, Liquid Distribution and GSD in a TSG 295 8.6 Model-based Analysis of Twin-screw Granulation 298 8.6.1 Modelling RTD in a TSG 298 8.6.2 Tracking GSD in a TSG using PBM 300 8.7 Towards Generic Twin-screw Granulation Knowledge 302 8.7.1 Regime Map Approach 303 8.7.2 Particle-scale Simulation using DEM 305 8.8 Strengths and Limitations of the Current Approaches in TSG Studies 307 8.9 Glossary 308 References 309 9 Continuous Line Roller Compaction 313 Ossi Korhonen 9.1 Roller Compaction 313 9.2 Main Components of a Roller Compactor 313 9.3 Theory of Powder Densification in Roller Compaction 315 9.4 Johanson Model 317 9.5 Modified Johanson Model 319 9.6 Experimental Observations of Pressure Distribution from Instrumented Roller Compactors 322 9.7 Off-line Characterization of Ribbon Quality 324 9.8 In-line Monitoring of Roller Compaction Process 326 9.9 Formulative Aspects of Roller Compaction 328 9.10 Roller Compaction as a Unit Operation in Continuous Manufacturing 330 9.11 Process Control of Continuous Roller Compaction 332 9.12 Conclusions 333 References 334 10 Continuous Melt Extrusion and Direct Pelletization 337 Stephan Laske, Theresa Hörmann, Andreas Witschnigg, Gerold Koscher, Patrick Wahl, Wen Kai Hsiao and Johannes Khinast 10.1 Introduction 337 10.2 The Extruder 338 10.3 Feeding 341 10.3.1 Solid Feeding 341 10.3.2 LIW Screw Feeders 342 10.4 Twin-screw Extrusion 345 10.4.1 Counter-rotating Twin-screw Extruder 346 10.4.2 Co-rotating Twin-screw Extruder 347 10.5 Operation Point 347 10.6 Downstream Processing 349 10.6.1 Direct Shaping of Final Product 350 10.6.2 Intermediate Products 352 10.7 Continuous Manufacturing with HME 356 10.7.1 Process Understanding 356 10.7.2 Control Strategy 356 10.7.3 State of Control 357 10.7.4 Diversion of Material 357 10.8 PAT for HME 360 10.8.1 Near-infrared Spectroscopy 360 10.8.2 Raman Spectroscopy 360 10.8.3 Chemical Imaging 361 10.8.4 Particle Size Analysis 361 10.8.5 Optical Coherence Tomography 361 10.8.6 Data Processing 362 10.9 Process Integration into Computerized Systems 362 10.9.1 IT Structure of Supervisory Control Systems 364 10.9.2 Real-time Release Testing 365 10.10 Conclusion 365 References 366 11 Continuous Processing in the Pharmaceutical Industry: Status and Perspective 369 Richard Steiner and Maik Jornitz 11.1 Industry Drivers for Continuous Processing: Competitive Advantages 369 11.2 Continuous Manufacturing in Bioprocessing 371 11.2.1 Continuous Bioprocessing Enablers and Guidance 371 11.2.2 Process Technologies 372 11.2.3 Examples of Continuous Manufacturing 376 11.2.4 Economic and Design Implications 377 11.3 Continuous Manufacturing for Oral Solid Dosage Forms 381 11.3.1 Industry Approaches to the Implementation of cm 381 11.3.2 Typical Installation Layouts 383 11.3.3 Economic Justification and Business Excellence 387 11.4 The Pharmaceutical Supply Chain of the Future 395 11.4.1 Portable, Continuous, Miniature and Modular 395 11.4.2 The PCMM Concept 396 11.4.3 Discussion 399 11.5 Conclusion 400 Acknowledgments 401 References 401 12 Design of an Integrated Continuous Manufacturing System 405 Sarang S. Oka, M. Sebastian Escotet-Espinoza, Ravendra Singh, James V. Scicolone, Douglas B. Hausner, Marianthi Ierapetritou and Fernando J. Muzzio 12.1 Introduction 405 12.2 Step 1: Rough Conceptual Design 406 12.2.1 Type of Product 406 12.2.2 Type of Manufacturing Route – Direct Compaction, Wet Granulation or Dry Granulation 407 12.2.3 Flexible or Dedicated 408 12.2.4 Feeding Multiple Ingredients, Including Pre-blends 408 12.2.5 Strategy for Sensing and Control 409 12.2.6 Regulatory Strategy 409 12.3 Step 2: Material Property Screening 410 12.4 Step 3: Characterizing Unit Operation Using Actual Process Materials 412 12.4.1 Loss in Weight Feeders 412 12.4.2 Continuous Blenders 415 12.5 Step 4: Develop and Calibrate Unit Operation Models Including Process Materials 422 12.5.1 Application of the Model Development Algorithm in Pharmaceutical Problems 422 12.5.2 Recommendations for Developing a Unit Operation Model that Incorporates the Effects of Material Properties 423 12.6 Step 5: Develop an Integrated Model of an Open Loop System 424 12.6.1 Model Integration Basics 425 12.6.2 General Algorithm for Building an Integrated Model 425 12.7 Step 6: Examine Open Loop Performance of the Process 427 12.8 Step 7: Develop/Fine Tune PAT Methods for Appropriate Unit Operations 429 12.9 Step 8: Implement Open Loop Kit with PAT and IPCs Enabled 430 12.10 Step 9: Design of the Control Architecture 432 12.11 Step 10: Develop Integrated Model of Closed Loop System 436 12.12 Step 11: Implementation and Verification of the Control Framework 438 12.13 Step 12: Characterize and Verify Closed Performance 440 12.14 Conclusions 442 References 443 13 End to End Continuous Manufacturing: Integration of Unit Operations 447 R. Lakerveld, P. L. Heider, K. D. Jensen, R. D. Braatz, K. F. Jensen, A. S. Myerson, and B. L. Trout 13.1 Introduction 447 13.2 Process Description 448 13.2.1 Specific Benefits Obtained as a Result of cm 452 13.3 System Dynamics 452 13.3.1 Model-based Design and Control are the Governing Concepts in cm 452 13.3.2 The Absence of True Steady-state Operation and the Implications for Product Quality Control 453 13.3.3 Plant-wide Control for CM: Disentanglement of Times Scales and Control Objectives 455 13.3.4 Residence Time Distribution of a CM Process: Impact of Recycling 456 13.3.5 Disturbances, Nonlinearities, and Delays: Implications for Control 460 13.3.6 Startup and Shutdown Procedures 464 13.3.7 Buffering 465 13.4 Process Monitoring and Control 468 13.4.1 PAT Use in the Integrated Continuous Manufacturing Process 468 13.4.2 Soft Sensors and Prediction of Future Performance 469 13.5 Outlook: Opportunities for Novel Unit Operations and System Configurations 471 13.6 Summary and Closing Thoughts 477 References 480 14 Methodology for Economic and Technical Comparison of Continuous and Batch Processes to Enhance Early Stage Decision-making 485 Isabella Aigner, Wen-Kai Hsiao, Diana Dujmovic, Sven Stegemann and Johannes Khinast 14.1 Introduction 485 14.2 Technical–Economic Evaluation Methodology 486 14.2.1 Definition of the System Boundaries and Performance Targets 488 14.2.2 Modeling of the Process Chains 489 14.2.3 Performing Technical Feasibility and Risk Assessment 490 14.2.4 Evaluation of the Process Options 492 14.2.5 Calculation of Process Costs, Cost Comparison and Interpretation 498 14.2.6 Technology–Economic Profiling and Interpretation of Results 498 14.2.7 Performing Scenario, Sensitivity and Uncertainty Analysis 502 14.3 Conclusion 502 References 504 15 Drivers for a Change – Manufacturing of Future Medicines for Personalized Drug Therapies 507 Jukka Rantanen and Jörg Breitkreutz 15.1 Introduction 507 15.2 Personalized Medicine 508 15.2.1 Therapy Based on Individualized Needs for Different Patient Groups 508 15.2.2 Point of Care Diagnostics 509 15.3 Flexible Dosing with Innovative Products 510 15.4 Future Health Care Scenario 513 15.4.1 Enabling Manufacturing Technologies and Materials Science 513 15.4.2 The Regulatory Environment 518 15.4.3 Supply Chain 520 References 521 16 Perspectives of Printing Technologies in Continuous Drug Manufacturing 525 Niklas Sandler and Petri Ihalainen 16.1 Introduction 525 16.1.1 Printing Technologies – Enablers of Continuous Drug Manufacturing Approaches 525 16.2 Inkjet (Microdrop Generation Techniques) 527 16.2.1 Inkjet – Technical Description 527 16.2.2 Ink Development and Printability 531 16.2.3 Pharmaceutical Applications of Inkjet Printing 533 16.3 Flexographic Printing 535 16.3.1 Flexography – Technique Description 535 16.3.2 Pharmaceutical Applications of Flexographic Printing 537 16.4 Formulation Approaches for Inkjet and Flexography 538 16.5 Process Control and Process Analytical Technology for Continuous Printing Applications 539 16.6 From Laboratory-scale Printing Towards an Industrial Scale 540 16.7 Three-dimensional Printing/Additive Manufacturing 541 16.7.1 From Prototyping to Large-scale Manufacturing 542 16.7.2 Fused Deposition Modeling or Fused Filament Fabrication 543 16.7.3 Feedstock Material for FDM Printing 544 16.7.4 3D Printing Techniques used in the Biomedical and Pharmaceutical Area 545 References 546 17 Development of Liquid Dispensing Technology for the Manufacture of Low Dose Drug Products 551 Allan Clarke and Dave Doughty 17.1 Introduction 551 17.2 Background 552 17.3 Goals for the LDT Program 554 17.4 Overview of LDT 555 17.4.1 Formulation Overview 555 17.4.2 LDT Platforms 557 17.5 LDT Machine Design Details 559 17.5.1 Commercial Line Operation 559 17.5.2 Liquid Dispensing Cell 560 17.5.3 Solvent Evaporation 563 17.5.4 Inspection Systems on the Commercial Machine for Critical Quality Attributes 563 17.5.5 Pad Printing Cell 565 17.6 Scale-independence of the LDT Technology 566 17.7 Real-time Release Potential 567 17.8 Occupational Health, Environmental and Cleaning Considerations 570 17.8.1 Occupational Health 570 17.8.2 Environmental Controls/Cleaning 572 17.9 Conclusion 573 Acknowledgments 574 References 574 Index 577
£147.56
John Wiley & Sons Inc Physiologically Based Pharmacokinetic PBPK
Book SynopsisPhysiologically Based Pharmacokinetic (PBPK) Modeling and Simulations The first book dedicated to the emerging field of physiologically based pharmacokinetic modeling (PBPK) Now in its second edition, Physiologically Based Pharmacokinetic (PBPK) Modelling and Simulations: Principles, Methods, and Applications in the Pharma Industry remains the premier reference book throughout the rapidly growing PBPK user community. Using clear and concise language, author Sheila Annie Peters connects theory with practice as she explores the vast potential of PBPK modeling for improving drug discovery and development. This fully updated new edition covers key developments in the field of PBPK modelling and simulations that have emerged in recent years. A brand-new section provides case studies in different application areas of PBPK modelling, including drug-drug interaction, genetic polymorphism, renal impairment, and pediatric extrapolation. Additional chapters address Table of ContentsPreface xix Acknowledgements xxi About the companion xxiii Section I. Principles, Methods, andBackground Information 1 1 A Review of Pharmacokinetic and Pharmacodynamic Principles 3 1.1 Introduction 4 1.2 Pharmacokinetic Principles 4 1.2.1 Routes of Drug Administration 4 1.2.2 Intravenous Bolus 4 1.2.3 Plasma Protein Binding and Blood–Plasma Ratio 9 1.2.4 Hepatic, Renal, and Biliary Clearances 12 1.2.5 Extravascular (Subcutaneous, Intramuscular, and Per Oral) Absorption 16 1.2.6 Absorption from Solid Dosage Forms 20 1.2.7 Role of Transporters in ADME 22 1.2.8 Linear and Non-Linear Pharmacokinetics 24 1.2.9 Intravenous Infusion, Repeated Dosing, Steady State Kinetics, and Accumulation 25 1.2.10 Active Metabolite and Prodrug Kinetics 28 1.3 Pharmacokinetic Variability 32 1.4 Pharmacokinetics Optimization in Drug Discovery 34 1.5 Pharmacodynamic Principles 34 1.5.1 Pharmacological Targets and Drug Action 35 1.5.2 Functional Adaptation Processes 39 1.5.3 Biomarkers, Surrogate Endpoints, and Clinical Endpoints 41 Keywords 47 References 48 2 A Review of Drug–Drug Interactions 51 2.1 Introduction 51 2.2 Drug Interactions Mediated by Enzymes and Transporters at Various Sites 54 2.3 Factors Affecting DDI 54 2.4 In Vitro Methods to Evaluate Drug–Drug Interactions 56 2.4.1 Candidate Drug as a Potential Perpetrator 57 2.4.2 Candidate Drug as a Potential Victim of Inhibition 58 2.5 Sources of Uncertainty 59 2.6 Therapeutic Protein–Drug Interaction 59 References 61 3 Modeling Pharmacokinetics, Pharmacodynamics, And Drug Interactions 65 3.1 Introduction 66 3.2 Modeling Pharmacokinetics 66 3.2.1 Compartmental Modeling of Linear and Nonlinear Pharmacokinetics (Enzyme and/or Transporter Capacity Limitation as Well as Target-Mediated Drug Disposition) 67 3.2.2 Population Pharmacokinetics 76 3.3 Pharmacokinetics/Pharmacodynamics and PK/Efficacy (Exposure/ Response) Modeling 80 3.3.1 PK/PD Models for Direct Effect: Sigmoid Emax Model 84 3.3.2 PK/PD Models for Direct Effect: Classical Receptor Theory 86 3.3.3 PK/PD Models Accommodating Delayed Pharmacological Response 89 3.3.4 PK/PD Models Accommodating Functional Adaptation Leading to Nonlinearity in Pharmacological Response with Respect to Time 96 3.3.5 PK/Efficacy Modeling 97 3.3.6 Translation of PK/PD and PK/Efficacy Modeling to Human 100 3.3.7 Average, Minimum, and Maximum Steady-State Concentrations 104 3.3.8 Estimation of Biologically Effective Dose in Human 107 3.3.9 Therapeutic Window 109 3.3.10 Static Models for Drug Interactions 109 3.4 Physiologically Based Pharmacokinetic (PBPK) Modeling and Its Integration with Pharmacodynamics and Efficacy Models 112 3.4.1 PK Modeling Compartmental vs PBPK 112 3.4.2 PK Variability: Population PK (popPK) Modeling vs PBPK 114 3.4.3 Integration of PBPK with PD, Quantitative Systems Pharmacology (QSP) Models or Quantitative Systems Toxicologyand Safety (QSTS) 114 3.4.4 PBPK Models to Evaluate Drug–Drug Interactions 115 3.4.5 DDI Risk Assessment with PBPK vs Static Models 118 Keywords 123 References 125 4 Physiological Model For Absorption 129 4.1 Introduction 130 4.2 Drug Absorption and Gut Bioavailability 130 4.2.1 Solubility and Dissolution Rate 130 4.2.2 Permeability: Transcellular, Paracellular, and Carrier-Mediated Pathways 136 4.2.3 Barriers to Membrane Transport – Luminal Degradation, Efflux, and Gut Metabolism 138 4.3 Factors Affecting Drug Absorption and Gut Bioavailability 140 4.3.1 Physiological Factors Affecting Oral Drug Absorption and Species Differences in Physiology 140 4.3.2 Compound-Dependent Factors 144 4.3.3 Formulation-Dependent Factors 144 4.4 In Silico Predictions of Passive Permeability and Solubility 147 4.4.1 In Silico Models for Permeability 147 4.4.2 In Silico Models for Solubility 147 4.5 Measurement of Permeability, Solubility, Luminal Stability, Efflux, Intestinal Metabolism 148 4.5.1 In Vitro, In Situ, and In Vivo Models for Effective Permeability 148 4.5.2 Measurement of Thermodynamic or Equilibrium Solubility 153 4.5.3 Luminal Stability 154 4.5.4 Efflux 154 4.5.5 In Vitro Models for Gut Metabolism and Estimation of Fraction Escaping Gut Metabolism 155 4.6 Absorption Modeling 156 Keywords 162 References 163 5 Physiological Model For Distribution 169 5.1 Introduction 170 5.2 Factors Affecting Tissue Distribution of Xenobiotics 170 5.2.1 Physiological Factors and Species Differences in Physiology 171 5.2.2 Compound-Dependent Factors 176 5.3 In Silico Models of Tissue Partition Coefficients 176 5.4 Measurement of Parameters Representing the Rate and Extent of Tissue Distribution 181 5.4.1 Assessment of Rate and Extent of Brain Penetration 181 5.5 Physiological Model for Drug Distribution 186 5.6 Drug Concentrations at the Site of Action 187 Keywords 189 References 189 6 Physiological Models For Drug Metabolism And Excretion 193 6.1 Introduction 193 6.2 Factors Affecting Drug Metabolism and Excretion of Xenobiotics 194 6.3 Models for Hepatobiliary and Renal Excretion 197 6.3.1 In Silico Models 197 6.3.2 In Vitro Models for Hepatic Metabolism 197 6.3.3 In Vitro Models for Transporters 200 6.4 Physiological Models 203 6.4.1 Hepato-Biliary Elimination of Parent Drug and Metabolites 205 6.4.2 Renal Excretion 208 References 211 7 Generic Whole-Body Physiologically Based Pharmacokinetic Modeling 217 7.1 Introduction 217 7.2 Structure of a Generic Physiologically-Based Pharmacokinetic (PBPK) Model 218 7.3 Somatic Compartments 220 7.3.1 Lungs (LU) 220 7.3.2 Arterial Blood (ART) 220 7.3.3 Venous Blood (VEN) 220 7.3.4 Stomach (ST) 220 7.3.5 Gut (GU) 220 7.4 Model Assumptions 221 7.5 PBPK Software 221 References 223 8 Pbpk Modeling Of Biotherapeutics 225 8.1 Introduction 226 8.2 Therapeutic Proteins 226 8.2.1 Peptides and Proteins 226 8.2.2 Antibodies and Antibody-Based Therapies 227 8.3 Pharmacokinetics of Therapeutic Proteins 234 8.3.1 Absorption 234 8.3.2 Renal Elimination 235 8.3.3 Immunogenicity 235 8.3.4 PEGylation 239 8.3.5 Transport by Convective and Transcytotic Extravasation 239 8.3.6 Catabolic Elimination (Proteolysis) 239 8.3.7 FcRn-Mediated Protection of IgGs Against Catabolism in FcRn-Rich Cells 241 8.3.8 Distribution and lymphatic elimination 242 8.3.9 Target-Mediated Drug Disposition and Receptor-Mediated Endocytosis 243 8.4 PBPK Modeling of Monoclonal Antibodies 244 8.4.1 Full PBPK Model for Monoclonal Antibodies 244 8.4.2 Minimal PBPK Model for Monoclonal Antibodies 253 8.5 Applications of PBPK Modeling of Monoclonal Antibodies 253 8.5.1 Pharmacokinetic Scaling 253 8.5.2 PBPK Integration with Pharmacodynamics of Monoclonal Antibodies 255 Keywords 156 References 258 9 Uncertainty And Population Variability 263 9.1 Introduction 264 9.2 Distinguishing Uncertainty and Variability 264 9.3 Sources of Uncertainty in Drug-related Parameters 264 9.4 Sources of Variability in System Parameters 266 9.5 Handling Population Variability 269 9.5.1 A POSTERIORI and A PRIORI Approaches to Handling Population Variability 269 9.5.2 Correlations Between Parameters 271 9.6 Uncertainty and Sensitivity Analysis 272 9.6.1 Local Sensitivity Analysis (One-at-a-time (OAT) and Derivative-based Methods) 272 9.6.2 Parameter Interactions and Global Sensitivity Analysis (GSA) 275 9.6.3 Global Sensitivity Analysis for Correlated Parameters (cGSA) 278 9.6.4 Applications of Sensitivity Analysis for PBPK Models 280 9.6.5 Limitations of Global Sensitivity Analysis 281 9.7 Uncertainty and Population Variability in Clinical Efficacy and Safety 282 Keywords 285 References 285 10 Nonclinical, Clinical, and Model-Informed Drug Development 293 10.1 Introduction: An Overview of Different Phases of Drug Development 294 10.2 Nonclinical Development 295 10.2.1 Preclinical Pharmacology, PK/PD Modeling, and Human Dose Prediction 297 10.2.2 Safety and Toxicology Studies 297 10.2.3 Studies with Radiolabeled Compound 298 10.3 Clinical Pharmacology Studies 302 10.3.1 First-in-Human, Single, and Multiple Ascending Dose Studies 302 10.3.2 Biopharmaceutics – Absolute Oral Bioavailability and Bioequivalence Study 304 10.3.3 Food Effect Study 304 10.3.4 Organ (Hepatic and Renal) Impairment Study 305 10.3.5 Pediatric Assessment 306 10.3.6 Mass Balance Study 307 10.3.7 Drug Interaction Study 307 10.3.8 Pharmacogenomics Study 308 10.3.9 Thorough QT (TQT) and Concentration QT (C-QT) Study 308 10.3.10 Immunogenicity Assays and Comparability Study for Biologics 309 10.3.11 Drug Labelling 309 10.4 Clinical Development in Oncology 310 10.5 Fast Track Routes to Address Unmet Medical Need in the Treatment of Serious Conditions 311 10.6 Model-Informed Drug Development 312 10.7 Physiologically Based Pharmacokinetic Models Complementing Clinical Pharmacology Studies 314 10.8 PBPK in Oncology 315 Regulatory Guidelines 316 References 319 Section II. Applications In The Pharmaceutical Industry 323 11 Overview Of Pbpk Applications 325 11.1 Introduction 325 11.2 PBPK Applications for Internal Decisions 326 11.3 PBPK Applications for Regulatory Filing 328 11.4 PBPK Modeling and Simulations Along the Value Chain 332 References 335 12 Applications Of Hypothesis Generation And Testing With Pbpk Models 337 12.1 Introduction 338 12.2 Hypothesis Generation and Testing with PBPK Models 338 12.2.1 Parameter Estimation from Intravenous Pharmacokinetic Profiles 338 12.2.2 Simulation of Oral PK Profile 341 12.2.3 Sensitivity Analysis 342 12.2.4 Verification of Hypotheses 346 12.2.5 Auto-inhibition of Drug-Metabolizing Enzymes, Uptake and Efflux Transporters 347 12.3 Hypothesis Generation and Testing Along the Value Chain 348 12.4 Conclusions 351 References 351 13 Applications of Physiologically Based Pharmacokinetic Models Integrated With Drug Effect Models (Pbpk/Pd) 353 13.1 Introduction: Integration of PBPK with Drug Effect Models 354 13.2 Dosing in Specific Populations 355 13.3 PBPK/PD for Bottom-Up Prediction of Inter-Patient Variability in Drug Response 357 13.4 PBPK/PD for Predicting the Inter-Patient Variability in Response to Prodrugs and Active Metabolites 358 13.5 PBPK/PD When Systemic Concentrations are not the Driver forDrug Response 359 13.5.1 Pre-Systemic Drug Target 359 13.5.2 Effect-Site Drug Concentration Different from Systemic Concentration 360 13.6 PBPK/PD for Monoclonal Antibodies 362 13.7 PBPK Models Linked to Quantitative Systems Pharmacology and Toxicology Models 363 13.7.1 PBPK–QST Models to Predict Drug-Induced Liver Injury 363 13.7.2 PBPK–QST Models to Predict Drug-Induced Cardiotoxicity 367 13.8 Conclusions 371 References 371 14 Pbpk Modeling and Simulations to Evaluate Clinical Drug-Drug Interactions 375 14.1 Introduction 376 14.2 Clinical DDI Studies and Modeling Approaches to Address Key Questions Related to Drug–Drug Interactions 376 14.2.1 Dedicated Clinical DDI Studies 378 14.2.2 Investigation of Phenotypic Effects for NMEs Predominantly Cleared by Polymorphic Enzyme or Transporter 379 14.2.3 Prospective Nested DDI Study 380 14.2.4 Cocktail DDI Study 381 14.2.5 PBPK Modeling and Simulations 381 14.2.6 Claims Relating to Results of DDI Studies 381 14.2.7 Impact on Label 382 14.3 PBPK Modeling of Different Types of Drug Interactions 382 14.3.1 PBPK Modeling Strategy: New Molecular Entity as Victim of CYP-Based Drug Interactions 382 14.3.2 PBPK Modeling Strategy: New Molecular Entity as Perpetrator of CYP-Based Drug Interactions 383 14.3.3 Non-CYP Based Drug Interactions 384 14.3.4 Transporter-Mediated Drug Interactions 385 14.4 DDI Predictions with PBPK Modeling and Simulations in Clinical Drug Development and Regulatory Submissions 387 14.4.1 DDI Predictions Along the Value Chain (Figure 14.5) 387 14.4.2 Possible Regulatory Outcomes, Based on the Predictions from a Verified and Validated PBPK Model 389 14.4.3 Regulatory Acceptance of PBPK Analyses Included in Regulatory Submissions 390 14.4.4 Predictive Performance of PBPK Models 391 14.5 Comparison of DDI Prediction Using Static and Dynamic Models 392 14.6 Conclusions 393 References 394 15 Dose Extrapolation Across Populations (Healthy Adult Caucasian To Pediatric, Pregnant Women, Different Ethnicities, Geriatric, Smokers And Obese Populations) 397 15.1 Introduction 398 15.2 PBPK Modeling Strategy for Dose Extrapolation to Specific Populations 398 15.3 Potential Benefits of PBPK Modeling for Dose Extrapolations to Specific Populations 399 15.4 Dose Extrapolations to Specific populations 404 15.4.1 Pediatric Starting Dose Selection 404 15.4.2 Pregnancy 406 15.4.3 Ethnicity – Japanese Population 407 15.4.4 Geriatric Population 408 15.4.5 Obese 409 15.4.6 Smokers 410 15.5 Conclusions 410 References 411 16 Dose Extrapolation Across Populations: Healthy Adult To Hepatic And Renal Impairment Populations 417 16.1 Introduction 418 16.2 Pathophysiological Changes in Organ Impairment 419 16.2.1 Hepatic Impairment 419 16.2.2 Renal Impairment 420 16.3 PBPK Modeling Strategy: Model Development, Verification, Validation, and Application 420 16.4 Benefits of Applying Validated PBPK Models to Organ-Impaired Populations 421 16.4.1 Enhancing Regulatory Confidence in the Application of PBPK Modeling for the Prediction of Exposure in the Organ-Impaired Population 421 16.4.2 Contribution of PBPK to the Totality of Evidence in Evaluating the Effect of Renal Impairment on Drug Exposure to Inform Labelling 424 16.5 Conclusions 425 References 426 17 Absorption-Related Applications Of Pbpk Modeling 429 17.1 Introduction 429 17.2 In Vitro – In Vivo Disconnect, Parameter Non-Identifiability and the Importance of Identifying Factors Limiting Absorption Through a Deconvolution of the Mechanisms Contributing to Gut Bioavailability 431 17.3 Non-Regulatory Internal Applications of PBPK Modeling and Simulations 433 17.3.1 Prediction of Fraction Absorbed 433 17.3.2 Oral Formulation Development 433 17.4 Regulatory Applications of PBPK Modeling and Simulations 438 17.4.1 Food–Drug Interactions 438 17.4.2 Interactions of a Poorly Soluble Weak Base with Acid Reducing Agents (ARAs) 444 17.4.3 In Vitro – In Vivo Correlations (IVIVCs) to Serve as Surrogate for Bioequivalence Testing (Case Study 12) 445 17.4.4 Biowaivers Based on Virtual Bioequivalence 449 17.4.5 Virtual Bioequivalence of Locally Acting Products (LAPs) 450 17.5 Conclusions 450 References 452 18 Regulatory Guidelines On The Reporting Of Physiologically Based Pharmacokinetic (Pbpk) Modeling Analysis 457 18.1 Introduction 457 18.2 Food and Drug Administration (FDA) Guidelines 458 18.3 European Medicines Agency (EMA) Guidelines 459 18.4 Comparison of FDA and EMA Guidelines 461 18.5 Risk-Informed Evidentiary Framework to Assess PBPK Model Credibility 463 18.6 Drug Model Verification of Locally Acting Products (LAPs) 464 References 466 19 Resolving The Challenges To Establishing Confidence In Pbpk Models 469 19.1 Introduction 470 19.2 Requirements for Developing Mechanistically Credible PBPK Models for the Three Broad Categories of Applications 470 19.3 Challenges to Developing Mechanistically Credible PBPK Models and Consequences 473 19.3.1 Model Building 473 19.3.2 Model Verification of Predicted Exposure and Validation of Predictive Performance 476 19.4 Resolving the Challenges to Developing Mechanistically Credible PBPK Models 476 19.5 Totality of Evidence 478 19.6 Conclusions 480 References 481 20 Epilogue 483 20.1 PBPK Modeling Successes 483 20.2 Challenges 484 20.2.1 Drug Model Parameterization 484 20.2.2 Knowledge Gaps in Physiological Parameters 485 20.2.3 Prospective Validation of Prediction Performance 485 20.3 Meeting the Challenges 485 20.4 Future Directions for PBPK Modeling 486 References 488 Section III. Case Studies Of Pbpk Applications In The Pharmaceutical Industry 491 Case Study 1 Hypothesis Testing (Solubility) 493 Case Study 2 Hypothesis Testing (Gastric Emptying) 499 Case Study 3 Hypothesis Testing (Intestinal Loss) 505 Case Study 4 Pbpk/Pd 509 Case Study 5 Drug–Drug Interaction (Inhibition) 515 Case Study 6 Drug–Drug Interaction (Induction) 521 Case Study 7 Genetic Polymorphism 527 Case Study 8 Pediatric Extrapolation 535 Case Study 9 Pregnancy 541 Case Study 10 Hepatic Impairment 547 Case Study 11 Renal Impairment 555 Case Study 12 Absorption – Ivivc 561 Appendices 567 Index 579
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