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The handle http://hdl.handle.net/1887/58472 holds various files of this Leiden University dissertation.
Author: Witte, W.E.A. de
Title: Mechanistic modelling of drug target binding kinetics as determinant of the time course of drug action in vivo
Issue Date: 2017-12-19
Mechanistic modelling of drug target binding kinetics as determinant of the time course of drug action in vivo
Wilhelmus E. A. de Witte
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The research described in this thesis is part of the K4DD (Kinetics for Drug Discovery) consortium which is supported by the Innovative Medicines Initiative Joint Undertaking (IMI JU) under grant agreement no 115366. The IMI JU is a project supported by the European Union’s Seventh Framework Programme (FP7/2007–2013) and the European Federation of Pharmaceutical Industries and Associations (EFPIA).
The research was performed at the division of Pharmacology of the Leiden Academic Center for Drug Research, Leiden University, The Netherlands.
Publication of this thesis was financially supported by Cisbio and Greiner Bio-One.
Printed by GVO Printers and Designers B.V., Ede, The Netherlands
ISBN: 978-94-6332-278-2
©2017 Wilhelmus E.A. de Witte (WilbertdeW@gmail.com)
Copyright left-hand cover figure: Alex Antonio Ramirez Arias © 123RF.com Copyright right-hand cover figure: molekuul © 123RF.com
No part of this thesis may be reproduced or transmitted in any form or by any means without
written permission of the author and the publisher holding the copyright of the published articles
Mechanistic modelling of drug target binding kinetics as determinant of the time course of drug action in vivo
Proefschrift 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 19 december 2017
klokke 15.00 uur door
Wilhelmus Egbertus Arnout de Witte Geboren te Harderwijk, Nederland
op 25 maart 1989
4
Promotoren: Prof. Dr. M. Danhof
Prof. Dr. P. H. van der Graaf
Co-promotor: Dr. E. C. M. de Lange
Promotie commissie: Prof. Dr. H. Irth (voorzitter) Prof. Dr. J.A. Bouwstra (secretaris)
Prof. Dr. S. J. Charlton, University of Nottingham Prof. Dr. A. Vermeulen, Universiteit Gent Prof. Dr. A. P. IJzerman
Dr. M. van der Stelt Dr. J. H. Proost
Table of contents
Section I: General introduction 6
Chapter 1. Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients 6
Chapter 2. The long residing negligence of target saturation 30
Chapter 3. Mechanistic modelling of drug target binding kinetics as determinant of drug effect kinetics: Scope and intent of the investigations 39
Section II: Simulations, model analysis and experimental validation of the influence of binding kinetics on the time course of target occupancy 46
Chapter 4. In vivo target residence time and kinetic selectivity: the association rate constant as determinant. 46
Chapter 5. The influence of drug distribution and drug-target binding on target occupancy: The rate-limiting step approximation 77
Chapter 6. Target and tissue selectivity prediction by integrated mechanistic pharmacokinetic-target binding and quantitative structure activity modelling 88
SECTION III. Simulations, model analysis and experimental validation of the influence of binding kinetics on the time course of drug action 119
Chapter 7. Modelling the delay between PK and EEG effects of morphine in rats; binding kinetic versus effect compartment models 119
Chapter 8. In vitro and in silico analysis of the influence of D2 antagonist target binding kinetics on the cellular response to fluctuating dopamine concentrations 159
SECTION IV. Discussion, perspectives and conclusion 194
Chapter 9. Mechanistic modelling of drug target binding kinetics as determinant of the time course of drug action in vivo: Discussion, perspectives and conclusion 194
Acknowledgements 207
Curriculum Vitae 208
List of publications 209
Chapter 1. Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients
Wilhelmus E.A. de Witte1 , Yin Cheong Wong1, Indira Nederpelt2, Laura H. Heitman2, Meindert Danhof1, Piet H. van der Graaf1, Ron A.H.J. Gilissen3, Elizabeth C.M. de Lange1*
1 Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
2 Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
3 Janssen Research and Development, A Division of Janssen Pharmaceutica N.V., Turnhoutseweg 30, Beerse 2340, Belgium
*corresponding author: ecmdelange@lacdr.leidenuniv.nl
Expert Opin Drug Discov 2016;11(1):45–63
Abstract
Introduction: Drug-target binding kinetics are major determinants of the time course of drug action for several drugs, as clearly described for the irreversible binders omeprazole and aspirin. This supports the increasing interest to incorporate newly developed high-throughput assays for drug-target binding kinetics in drug discovery. A meaningful application of in vitro drug-target binding kinetics in drug discovery requires insight in the relation between in vivo drug effect and in vitro measured drug-target binding kinetics.
Areas covered: In this review, the authors discuss both the relation between in vitro and in vivo measured binding kinetics and the relation between in vivo binding kinetics, target occupancy and effect profiles.
We conclude that more scientific evidence is required for the rational selection and development of drug- candidates on basis of in vitro estimates of drug-target binding kinetics.
Expert opinion: To elucidate the value of in vitro binding kinetics measurements, it is necessary to obtain information on system-specific properties which influence the kinetics of target occupancy and drug effect.
Mathematical integration of this information enables the identification of drug-specific properties which lead to optimal target occupancy and drug effect in patients.
Abbreviations: GPCR: G-Protein Coupled Receptor, HTRF: Homogeneous Time-Resolved Fluorescence, NA:
Not Available, PET: Positron Emission Tomography, SAW: Surface Acoustic Wave, SPECT: Single Photon
