Drug Delivery to the Brain: Physiological Concepts, Methodologies and Approaches (AAPS Advances in the Pharmaceutical Sciences Series Book 10)

The development of new CNS drugs is notoriously difficult. Drugs must reach CNS target sites for action and these sites are protected by a number of barriers, the most important being the blood –brain barrier (BBB). Many factors are therefore critical to consider for CNS drug delivery, e.g. active/passive transport across the BBB, intra-brain distribution, and central/systemic pharmacokinetics, to name a few. Neurological disease and trauma conditions add further complexity because CNS barriers, drug distribution and pharmacokinetics are dynamic and often changed by disease/trauma. Knowledge of all these factors and their interplay in different conditions is of utmost importance for proper CNS drug development and disease treatment. In recent years much information has become available for a better understanding of the many factors important for CNS drug delivery and how they interact to affect drug action. This book describes small and large drug delivery to the brain with an emphasis on the physiology of the BBB and the principles and concepts for drug delivery across the BBB and distribution within the brain. It contains methods descriptions for studying drug delivery, routes and approaches of administering drugs into the brain, the influence of disease, and drug industry perspectives. Therewith, it contributes to an in-depth understanding of the interplay between brain (patho)-physiology and drug characteristics. Furthermore, the content is designed to be both cutting-edge and educational, so that the book can be used in high-level training of academic and industry scientists with full references to original publications. ​ This book describes the different approaches for drug delivery to the brain with an emphasis on the physiology of the blood-brain barrier (BBB) and the governing principles and concepts for drug delivery across the BBB. It contains cutting-edge methods for studying drug delivery and administering drugs into the brain. The book also explores different approaches for predicting human brain concentrations as well as the influence of disease and drug industry perspectives. In addition to wide-ranging coverage of physiological concepts relevant to central nervous system (CNS) drug delivery, a detailed review of brain structure, function, blood supply and fluids is also provided. In each chapter, descriptions of future challenges and unresolved questions are combined with points for discussion. This unique combination of material makes this book a valuable resource for students and for established academic and industry scientists looking to learn about state-of-the-art drug delivery research. It is also a source for stimulating new ideas among experts already performing CNS drug delivery research or working in related areas. Margareta Hammarlund-Udenaes (Ph. D.) is a Professor in Pharmacokinetics and Pharmacodynamics (PK/PD) at Uppsala University and the Head of the Translational PK/PD Group. Her research is focused on studying pharmacokinetic aspects of BBB transport of drugs in relation to CNS effects, and it has led to the development of new concepts and methods within the BBB transport area, focusing on unbound drug relationships. Elizabeth C.M. de Lange (Ph. D.) is Head of the Target Site Equilibration Group at the Division of Pharmacology of the Leiden Academic Center for Drug Research (LACDR). Her research program focuses on the development of generally applicable predictive PK/PD models on CNS drugs using advanced in vivo animal models and mathematical modeling techniques, with a number of recent successes. Robert G. Thorne (Ph. D.) is an Assistant Professor in Pharmaceutical Sciences at the University of Wisconsin-Madison School of Pharmacy. He was previously a research scientist and faculty member in the Department of Physiology & Neuroscience at the New York University School of Medicine. His research focuses on diffusive and convective transport within the CNS and the development, refinement and optimization of strategies for delivering biologics into the brain Front Matter....Pages i-xx Front Matter....Pages 1-1 Anatomy and Physiology of the Blood–Brain Barriers....Pages 3-21 Recent Progress in Blood–Brain Barrier and Blood–CSF Barrier Transport Research: Pharmaceutical Relevance for Drug Delivery to the Brain....Pages 23-62 Blood–Brain Barrier (BBB) Pharmacoproteomics: A New Research Field Opened Up by Quantitative Targeted Absolute Proteomics (QTAP)....Pages 63-100 Drug Metabolism at the Blood–Brain and Blood–CSF Barriers....Pages 101-124 Front Matter....Pages 125-125 Pharmacokinetic Concepts in Brain Drug Delivery....Pages 127-161 In Vitro Models of CNS Barriers....Pages 163-197 In Situ and In Vivo Animal Models....Pages 199-211 Principles of PET and Its Role in Understanding Drug Delivery to the Brain....Pages 213-232 PKPD Aspects of Brain Drug Delivery in a Translational Perspective....Pages 233-268 Front Matter....Pages 269-269 Drug Discovery Methods for Studying Brain Drug Delivery and Distribution....Pages 271-316 Prediction of Drug Exposure in the Brain from the Chemical Structure....Pages 317-338 Integrated Approach to Optimizing CNS Penetration in Drug Discovery: From the Old to the New Paradigm and Assessment of Drug–Transporter Interactions....Pages 339-374 Pharmacoeconomic Considerations in CNS Drug Development....Pages 375-397 Front Matter....Pages 399-399 Intranasal Drug Delivery to the Brain....Pages 401-431 Blood-to-Brain Drug Delivery Using Nanocarriers....Pages 433-454 Development of New Protein Vectors for the Physiologic Delivery of Large Therapeutic Compounds to the CNS....Pages 455-484 CNS Gene Therapy Utilizing Intravenously Administered Viral Vectors....Pages 485-499 Neurosurgical Approaches: Drug Infusion Directly into the Parenchyma or the Cerebrospinal Fluid....Pages 501-518 Osmotic Opening of the BBB for Drug Treatment of Brain Tumors (Focus on Methodological Issues)....Pages 519-543 Emerging Engineering Technologies for Opening the BBB....Pages 545-570 Front Matter....Pages 571-571 Disease Influence on BBB Transport in Inflammatory Disorders....Pages 573-589 Disease Influence on BBB Transport in Neurodegenerative Disorders....Pages 591-634 Drug Delivery in the Context of Stroke and Brain Trauma....Pages 635-656 Which Drug or Drug Delivery Method Can Change Clinical Practice for Brain Tumor Therapy?....Pages 657-682 Back Matter....Pages 683-731