Cover Page
The following handle holds various files of this Leiden University dissertation:
http://hdl.handle.net/1887/59461
Author: Yamamoto, Y.
Title: Systems pharmacokinetic models to the prediction of local CNS drug concentrations in human
Issue Date: 2017-11-21
SYSTEMS PHARMACOKINETIC
MODELS TO THE PREDICTION OF LOCAL CNS DRUG CONCENTRATIONS IN HUMAN
Yumi Yamamoto
Ph.D. Thesis, Leiden University, November 2017
no. D2-501 of the former Dutch Top Institute Pharma, currently Lygature (Leiden, the Netherlands) at the Division of Pharmacology of the Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
Financial support for the printing of this thesis was provided by:
Leiden Academic Centre for Drug Research (LACDR)
Cover and Layout: Design Your Thesis, Rotterdam, the Netherlands Printing: Ridderprint B.V., Ridderkerk, the Netherlands
ISBN: 978-94-6299-684-7
©2017 Yumi Yamamoto. No part of this thesis may be reproduced or transmitted in
SYSTEMS PHARMACOKINETIC
MODELS TO THE PREDICTION OF LOCAL CNS DRUG CONCENTRATIONS IN HUMAN
P R O E F S C H R I F T
ter verkrijging van
de graad van Doctor aan de Universiteit Leiden op gezag van Rector Magnificus prof.mr. C.J.J.M. Stolker,
volgens besluit van het College voor Promoties te verdedigen op dinsdag 21 november 2017
klokke 13:45 uur
door
Yumi Yamamoto geboren te Tokio, Japan
in 1980
Co-promotor: Dr. E.C.M. de Lange
Promotiecommissie: Prof. Dr. H. Irth, voorzitter Prof. Dr. J.A. Bouwstra, secretaris
Prof. Dr. A. Rostami, University of Manchester Prof. Dr. R. Masereeuw, Universiteit Utrecht Prof. Dr. J. Burggraaf, Universiteit Leiden Prof. Dr. O.C. Meijer, Universiteit Leiden Prof. Dr. T. Hankemeier, Universiteit Leiden
Everything that humans can imagine is a possibility in reality - Willy Karen-
Aan allen die mij dierbaar zijn
TABLE OF CONTENTS
CHAPTER 1 Scope and intent of investigations 9
CHAPTER 2 Microdialysis: the key to physiologically based model prediction of human CNS target site concentrations
19
CHAPTER 3 A generic multi-compartmental CNS distribution model structure for 9 drugs allows prediction of human brain target site concentrations
57
CHAPTER 4 Predicting drug concentration-time profiles in multiple CNS compartments using a comprehensive physiologically based pharmacokinetic model
105
CHAPTER 5 Prediction of human CNS pharmacokinetics using a physiologically based pharmacokinetic modeling approach
141
CHAPTER 6 General discussion and future perspectives 181
APPENDIX English summary 197
Nederlandse samenvatting 205
Acknowledgements 215
Curriculum vitae 217
List of publications 219
