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The handle http://hdl.handle.net/1887/19939 holds various files of this Leiden University dissertation.
Author: Chain, Anne S.Y.
Title: Mind the gap : predicting cardiovascular risk during drug development Date: 2012-10-09
MIND THE GAP
PREDICTING CARDIOVASCULAR RISK DURING DRUG DEVELOPMENT
ANNE S.Y.CHAIN
The research presented in this thesis was performed within the framework of project D2-104 of the Dutch Top Institute Pharma at the Division of Pharmacology of the Leiden-Amsterdam Center for Drug Research (LACDR), Leiden University, Leiden, The Netherlands
Cover design by Omar Duragos, Creative Artist Nomad Creative, Toronto, Canada Nomad.Creative@rogers.com Printing by Ipskampdrukkers,
Enschede, The Netherlands ISBN:
Copyright ©2012 by Anne S. Y. Chain
All rights reserved. No part of this thesis may be reproduced, distributed, stored in a retrieval system, or transmitted in any form or by any means, without the written permission of the author and the publisher holding the copyright of the published articles.
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MIND THE GAP
PREDICTING CARDIOVASCULAR RISK DURING DRUG DEVELOPMENT
P
ROEFSCHRIFTter verkrijging van
de graad van Doctor aan de Universiteit Leiden,
op gezag van Rector Magnificus prof. mr. P. F. van der Heijden, volgens besluit van het College voor Promoties
te verdedigen op dinsdag 9 oktober 2012 klokke 15.00 uur
door
ANNE S.Y.CHAIN geboren te Hong Kong
in 1982
Promotiecommissie:
Promotoren: Prof. dr. M. Danhof
Prof. dr. M.C.J.M. Sturkenboom, Eramus Universiteit Rotterdam Co-promotor: Dr. O.E. Della Pasqua
Leden: Prof. dr. L. Aarons, The University of Manchester, Manchester, UK.
Prof. dr. J. Burggraaf, CHDR, Leiden
Prof dr. A.C.G.. Egberts, Universiteit van Utrecht, Utrecht Prof dr. T. Hankemeier, Universiteit Leiden, Leiden Prof dr. A.P. IJzerman, Universiteit Leiden, Leiden
To Nai-Nai and Yeh-Yeh wishing you were here...
C ONTENTS
SECTION I GENERAL INTRODUCTION 11
Chapter 1 An introduction to Mind the Gap: predicting
cardiovascular risk during drug development 13 Chapter 2 Scope and intent of investigation 59
SECTION II BAYESIAN METHODOLOGY 75
Chapter 3 Assessing the probability of QTc-interval
prolongation in clinical drug development 77 Chapter 4 Translational pharmacology of QTc-interval
prolongation 103
SECTION III FROM PHARMACOLOGY TO EPIDEMIOLOGY - ABRIDGING STRATEGY FOR RISK MANAGEMENT
137
Chapter 5 Not-in-Trial Simulation I:
bridging cardiovascular risk from clinical trials to real life conditions
139
Chapter 6 Not-In-Trial Simulation II:
predicting cardiovascular risk from clinical trial data
159
Chapter 7 Validation of Not-In-Trial-Simulation:
predicting cardiovascular risk from clinical trial data
181
Chapter 8 Can QTc prolongation >10 msec predict sudden
cardiac death? 201
SECTION IV CLINICAL TRIAL SIMULATION IN THE EVALUATION OF CARDIOVASCULAR SAFETY
219
Chapter 9 Model-Based Simulation of QT and RR Intervals for
the Evaluation of QTc-interval Prolongation 221 Chapter 10 Model-Based Analysis of Thorough QT Studies 237 Chapter 11 Can First-Time-In-Human Trials Replace Thorough
QT Studies? 257
SECTION V CONCLUSIONS &PERSPECTIVE 281 Chapter 12 Mind the Gap: Predicting Cardiovascular Risk
During Drug Development -
Summary, Conclusion and Perspectives
283
Chapter 13 Nederlandse Samenvatting (Synopsis in Dutch) 307
EPILOGUE 331
Acknowledgement PhD Portfolio List of Publications About the Author List of Abbreviations
Stellingen / Propositions to this dissertation
i iv viii iv x xii
