Drug Delivery to the Brain

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 bloodbrain 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 anemphasis 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, drug industry perspectives, and a primer on neuroanatomy and physiological considerations written specifically for drug delivery scientists. 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.

Describes small and large drug delivery to the brain Contains methods for studying drug delivery, routes, and types ofadministration Cutting-edge, educationa,l and high-level

Autorentext

Elizabeth C.M. de Lange (PhD) 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 PKPD models on CNS drugs using advanced in vivo animal models and mathematical modeling techniques, with a number of recent successes. She is an Editorial Board member of the journal Fluids and Barriers of the CNS, and an Editorial Advisory Board member of the Journal of Pharmaceutical Sciences and of Pharmaceutical Research. She has been the cofounder and (co-)Chair at the 1st, 2nd and 5th International Symposia on Microdialysis, and has been the Chair of the 9th International Conference on Cerebral Vascular Biology (2011). Among many other functions within the American Association of Pharmaceutical Scientists, she is the 2014 Chair of the Annual Meeting Programming Committee. With her company "In Focus" she provides courses, training and advice on microdialysis, pharmacokinetics, BBB transport, intra-brain distribution and PKPD relationships.

Margareta Hammarlund-Udenaes (PhD) is a Professor in Pharmacokinetics and Pharmacodynamics (PKPD) at Uppsala University and the Head of the Translational PKPD Group. Her research is focused at studying pharmacokinetic aspects of BBB transport of drugs in relation to CNS effects, which has led to the development of new concepts and methods within the BBB transport area, focusing on unbound drug relationships. Dr. Hammarlund-Udenaes is an Associate Editor of Pharmaceutical Research and a member of the Editorial Advisory Board of Journal of Pharmaceutical Sciences and Fluids and Barriers of the CNS. She became an American Association of Pharmaceutical Scientists' Fellow in 2005. She is a frequent lecturer at conferences and in drug industry. Her company gives courses and advice in PKPD and BBB transport issues. She co-founded and has co-chaired several of the International Symposia on Microdialysis, and she is the Chair of the 'Barriers of the CNS' Gordon Conference in 2014.

Robert G. Thorne (PhD) is a Denali Fellow at Denali Therapeutics and an Adjunct Associate Professor in the Department of Pharmaceutics at the University of Minnesota. His research as a laboratory head has focused primarily on CNS barrier sites and diffusive and convective transport within the extracellular and perivascular spaces of the central nervous system. A consistent theme in his work has been to leverage knowledge of physiology, CNS structure, and the blood-brain and blood-cerebrospinal fluid barriers along with a variety of experimental methods in order to identify how best to deliver antibodies, oligonucleotides, and gene therapy vectors to the brain following administration to the circulation or via the various different central routes (e.g. intrathecal, intranasal and intraparenchymal). Prior to joining Denali, he worked full time for over 10 years as a member of the faculty at two academic institutions, first with the Department of Physiology and Neuroscience at New York University School of Medicine and next with the Division of Pharmaceutical Sciences at the University of Wisconsin-Madison. Now at Denali, his focus has broadened to encompass all potential strategies for large molecule delivery to the brain, including brain endothelial cell receptor-targeted approaches for crossing the blood-brain barrier after systemic administration. He was elected in 2017 to serve as the Vice President (President-elect) of the International Brain Barriers Society, a global organization responsible for leadership and directing worldwide initiatives related to the CNS barriers and drug delivery fields. Dr. Thorne previously chaired the 2016 'Barriers of the CNS' Gordon Research Conference and co-chaired the 2019 AAPS-IBBS Workshop on 'Novel Approaches Targeting Brain Barriers for Effective Delivery of Therapeutics.'

Inhalt
Part I-Physiology and Basic Principles of Drug Handling for the CNS.- Anatomy and Physiology of the Blood Brain Barriers.- Drug Delivery to the Brain: Integrating Neuroscience, Physiology, and Brain Barriers Science.- Brain Delivery of Therapeutics via Transcytosis: Types and Mechanisms of Vesicle-Mediated Transport Across the BBB.- Brain- Arachnoid Barrier as an Important Clearance Pathway from CSF.- BBB Pharmacoproteomics: Quantitative Targeted Absolute Proteomics (QTAP): Species Differences.- Drug Metabolism at the BBB and the BCFSB.- PART II-PK Concepts and Methods for Studying CNS Drug Delivery.- Pharmacokinetics Concepts in Brain Drug Delivery.- In Vitro Models of CNS Barriers.- Human In Vitro BBB Models Derived from Pluripotent Stem Cells.- In situ and In vivo Animal Models.- Principles of PET and Its Role in Understanding Drug Delivery to the Brain.- Prediction of CNS PK and PD Using Translational Research Approaches.- Part III-Industrial Approachesfor Investigation of Potential CNS Drugs.- Drug Discovery Methods for Studying Brain Drug Delivery and Distribution.- Prediction of Drug Exposure in the Brain From the Chemical Structure.- Integrated Approach to Optimizing CNS Penetration in Drug Discovery.- Part IV: Strategies for Improved CNS Drug Delivery.- Intranasal Drug Delivery to the Brain.- Blood to Brain Drug Delivery Using Nanocarriers.- Enhancing CNS Exposure Through Brain Endothelial Cell RMT-Exploiting the Transferrin Receptor at the BBB.- Therapeutic Osmotic Modification of the BBB in the Treatment of CNS Pathologies.- Biophysical Perspectives on BBB Permeability Enhancement by Ultrasound and Microbubbles for Targeted Drug Delivery in the Clinical Setting.- Optimization of Blood Brain Barrier Opening With Focused Ultrasound-The Animal Perspective.- CNS Gene Therapy Using Adeno-Associated Virus (AAV) Vectors .- Part V-CNS Drug Delivery in Disease Conditions.- Disease Influence on BBB Transport in Neurodegeneration and Neuroinflammation.- Enhancing Drug Delivery in the Setting of Stroke and Brain Inju…