1. Proof-of-Concept Study of Drug Brain Permeability Between in Vivo Human Brain and an in Vitro iPSCs-Human Blood-Brain Barrier Model
- Author
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Anne-Cécile Guyot, Serena Pavoni, Frank Yates, Oliver Langer, Jean-Philippe Deslys, Frédéric Théodoro, Yulia Kiyan, Narciso Costa, Ferid Nassor, Gwenaëlle Le Roux, Nicolas Tournier, Rafika Jarray, Alain Pruvost, Aloïse Mabondzo, Service de Pharmacologie et d'Immunoanalyse (SPI), Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Service d'Etude des Prions et des Infections Atypiques, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Sup'Biotech, Imagerie Moléculaire in Vivo (IMIV - U1023 - ERL9218), Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Medizinische Hochschule Hannover (MHH), Department of Clinical Pharmacology, Medizinische Universität Wien = Medical University of Vienna, Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, French National Research Agency (ANR), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Lallemant, Christopher
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0301 basic medicine ,Drug Evaluation, Preclinical ,lcsh:Medicine ,Pharmacology ,Positron-emission-tomography ,Mice ,[SPI]Engineering Sciences [physics] ,0302 clinical medicine ,Endothelial-cells ,Medicine ,Abcb1 ,lcsh:Science ,Induced pluripotent stem cell ,Cells, Cultured ,media_common ,Inhibition ,Multidisciplinary ,Brain ,Cell Differentiation ,Human brain ,medicine.anatomical_structure ,Drug development ,Blood-Brain Barrier ,Abcg2 ,Strategies ,Neuroglia ,Delivery ,Drug ,[SPI] Engineering Sciences [physics] ,media_common.quotation_subject ,Induced Pluripotent Stem Cells ,Central nervous system ,Transport ,Models, Biological ,Proof of Concept Study ,Permeability ,Article ,03 medical and health sciences ,Pharmacokinetics ,In vivo ,Animals ,Humans ,business.industry ,lcsh:R ,In vitro ,Rats ,030104 developmental biology ,Pet ,Positron-Emission Tomography ,lcsh:Q ,business ,030217 neurology & neurosurgery - Abstract
The development of effective central nervous system (CNS) drugs has been hampered by the lack of robust strategies to mimic the blood-brain barrier (BBB) and cerebrovascular impairments in vitro. Recent technological advancements in BBB modeling using induced pluripotent stem cells (iPSCs) allowed to overcome some of these obstacles, nonetheless the pertinence for their use in drug permeation study remains to be established. This mandatory information requires a cross comparison of in vitro and in vivo pharmacokinetic data in the same species to avoid failure in late clinical drug development. Here, we measured the BBB permeabilities of 8 clinical positron emission tomography (PET) radioligands with known pharmacokinetic parameters in human brain in vivo with a newly developed in vitro iPSC-based human BBB (iPSC-hBBB) model. Our findings showed a good correlation between in vitro and in vivo drug brain permeability (R2 = 0.83; P = 0.008) which contrasted with the limited correlation between in vitro apparent permeability for a set of 18 CNS/non-CNS compounds using the in vitro iPSCs-hBBB model and drug physicochemical properties. Our data suggest that the iPSC-hBBB model can be integrated in a flow scheme of CNS drug screening and potentially used to study species differences in BBB permeation.
- Published
- 2019