Blood-Brain Barrier in Drug Discovery

Li Di is an associate research fellow in the Pharmacokinetics, Dynamics, and Drug Metabolism Department at Pfizer Global Research and Development and has extensive experience in the pharmaceutical industry. She has over 100 publications, presented over 70 invited lectures, and teaches an American Chemical Society short course on drug-like properties.Edward Kerns worked in pharmaceutical research and development for over 30 years, was associate director at Wyeth and Bristol-Myers Squibb, then was at the NIH-National Center for Advancing Translational Sciences. He published over 90 journal papers or book chapters and 3 books, and teaches an American Chemical Society short course on drug-like properties.

• Contributors ixPreface xiii1 Introduction and Overview 1li di and Edward H. KernsPart 1 Pharmacokinetics of Brain Exposure 52 Pharmacokinetics of CNS Penetration 7Andreas Reichel3 Free Drug Hypothesis for CNS Drug Candidates 42Xingrong Liu and Cuiping Chen4 Species Differences and Impact of Disease State on BBB 66Jean-Marie NicolasPart 2 Mechanisms of Drugs Across the Blood–Brain Barrier 955 Passive Diffusion Permeability of the BBB—Examples and SAR 97Scott Summerfield, Phil Jeffrey, Jasminder Sahi, and Liangfu Chen6 Establishment of P-Glycoprotein Structure–Transport Relationships to Optimize CNS Exposure in Drug Discovery 113Jerome H. Hochman, Sookhee N. Ha, and Robert P. Sheridan7 Uptake Transport at the BBB—Examples and SAR 125Ziqiang Cheng and Qian Liu8 Transport of Protein and Antibody Therapeutics across the Blood–Brain Barrier 146William M. PardridgePart 3 Predicting and Measuring Brain Exposure of Drugs 1679 In Silico Tools for Predicting Brain Exposure of Drugs 169Hongming Chen, Susanne Winiwarter, and Ola Engkvist10 In Vitro Assays for Assessing BBB Permeability: Artificial Membrane and Cell Culture Models 188Alex Avdeef, Mária A. Deli, and Winfried Neuhaus11 Human-Based In Vitro Brain Endothelial Cell Models 238Hannah K. Wilson and Eric V. Shusta12 Methods for Assessing Brain Binding 274li di and Cheng Chang13 In Vivo Studies of Brain Exposure in Drug Discovery 284Edward H. Kerns14 PBPK Modeling Approach for Predictions of Human CNS Drug Brain Distribution 296Elizabeth C.M. de Lange15 PK/PD Modeling of CNS Drug Candidates 324Johan Gabrielsson, Stephan Hjorth, and Lambertus A. Peletier16 Microdialysis to Assess Free Drug Concentration in Brain 351William Kielbasa and Robert E. Stratford, Jr.17 Imaging Techniques for Central Nervous System (CNS) Drug Discovery 365Lei Zhang and Anabella VillalobosPart 4 Modulating Brain Penetration of Leads During Drug Discovery 38518 Designing CNS Drugs for Optimal Brain Exposure 387Zoran Rankovic19 Case Studies of CNS Drug Optimization—Medicinal Chemistry and CNS Biology Perspectives 425Kevin J. Hodgetts20 Designing Peripheral Drugs for Minimal Brain Exposure 446Peter Bungay, Sharan Bagal, and Andy Pike21 Case Studies of Non-CNS Drugs to Minimize Brain Penetration—Nonsedative Antihistamines 463Andrew CrowePart 5 Case Studies in CNS Drug Discovery 48322 Case Study 1: The Discovery and Development of Perampanel 485Antonio Laurenza, Jim Ferry, Haichen Yang, Shigeki Hibi, Takahisa Hanada, and Andrew Satlin23 Case Study 2: The Discovery and Development of the Multimodal Acting Antidepressant Vortioxetine 505Christoffer Bundgaard, Alan L. Pehrson, Connie Sánchez, and Benny Bang-AndersenPart 6 Drug Delivery Techniques to CNS 52124 Brain Delivery Using Nanotechnology 523Huile Gao and Xinguo Jiang25 Intranasal Delivery to the Central Nervous System 535Lisbeth IllumPart 7 Future Prospects in Blood-Brain Barrier Understanding and Drug Discovery 56726 Future Perspectives 569N. Joan AbbottIndex 580