Towards quantitative risk prediction in humans

Cover Page
The handle http://hdl.handle.net/1887/29414 holds various files of this Leiden University
dissertation
Author: Sahota, Tarjinder
Title: Pharmacology based toxicity assessment : towards quantitative risk prediction in
humans
Issue Date: 2014-10-30
Pharmacology based toxicity assessment:
Towards quantitative risk prediction in humans
Tarjinder Sahota
PhD. Thesis, Leiden University, October 2014
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Pharmacology based toxicity assessment:
Towards quantitative risk prediction in humans
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 donderdag 30 oktober 2014
klokke 11.15 uur
door
Tarjinder Sahota
geboren te Letchworth, United Kingdom
in 1982
Promotor
Prof. dr. M. Danhof
Co-promotor
Prof. dr. O.E. Della Pasqua
Referent
Prof. G. Tucker (Sheffield University, Verenigd Koninkrijk)
Overige Leden
Prof. dr. P.H. van der Graaf
Prof. dr. K. Burggraaf
Prof. dr. B. vd Water
Prof. dr. T Hankemeier
Dr. J.W. van der Laan
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The research leading to this thesis has received funding from GlaxoSmithKline (Worldwide
Product Development scholarship) and was performed at the Division of Pharmacology of
the Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
The printing of this thesis was financially supported by:
Leiden Academic Centre for Drug Research
GlaxoSmithKline
Cover and layout by Roweena Asgalari
Printed by GVO printers & designers B.V., Ede, The Netherlands
ISBN: 978-90-6464-821-2
©2014 Tarjinder Sahota ([email protected])
No part of this thesis may be reproduced or transmitted in any form or by any means
without written permission of the author
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CONTENTS
Section 1
General Introduction
7
Chapter 1
Challenges in the assessment and prediction of safety pharmacology
and drug toxicity in humans
9
Chapter 2
Scope and intent of investigation
55
Section 2
Conceptual framework
69
Chapter 3
The impact of composite AUC estimates on the prediction of systemic
exposure in toxicology experiments
71
Chapter 4
Application of optimal design concepts to experimental protocols for
the evaluation of toxicokinetics and safety thresholds
120
Chapter 5
Use of biomarkers for the characterisation of long-term safety:
advantages of a model-based approach for the analysis of toxicology
experiments
148
Chapter 6
Utility of model based approaches to predict the risk of adverse events
from preclinical toxicology protocols.
178
Section 3
Case study and practical application
211
Chapter 7
Model-based analysis of thromboxane B2 and prostaglandin E2 as
biomarkers in the safety evaluation of naproxen.
213
Chapter 8
Model-based prediction of the acute and long-term safety profile of
naproxen in rats
249
Section 4
Conclusions and Perspectives
280
Chapter 9
Pharmacology based toxicity assessment: Towards quantitative risk
prediction in humans
282
Chapter 10
Nederlandse Samenvatting (Synopsis in Dutch)
320
Acknowledgements
338
Curriculum Vitae
339
List of publications
340
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