The handle http://hdl.handle.net/1887/67291 holds various files of this Leiden University
dissertation.
Author: Brussee, J.M.
Title: First-pass and systemic metabolism of cytochrome P450 3A substrates in neonates,
infants, and children
First-pass and systemic metabolism of cytochrome
P450 3A substrates in neonates, infants, and children
Drug Research.
Cover design: Dirk van Rijn, Paul Brussee, Jantine Brussee, and Proefschriften.nl Printed by Proefschriften.nl
ISBN: 978-94-6332-426-7 © J.M. Brussee, 2018
First-pass and systemic metabolism of cytochrome
P450 3A substrates in neonates, infants, and children
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 dinsdag 4 december 2018
klokke 16.15 uur door
Janneke Maria Brussee
prof. dr. M. Danhof
TABle oF conTenTs
section I General introduction and background 9
Chapter 1 First-pass and systemic metabolism of cytochrome P450 3A substrates in neonates, infants, and children – General introduction, Scope, and Outline
11
Chapter 2 Children in clinical trials: towards evidence-based pediatric pharmacotherapy using pharmacokinetic-pharmacodynamic modelling
23
section II systemic cYP3A-mediated metabolism in critically ill children
49
Chapter 3 Inflammation and organ failure severely affect midazolam clearance in critically ill children
51 Chapter 4 Predicting CYP3A-mediated midazolam metabolism in
critically ill neonates, infants, children and adults with inflammation and organ failure
75
section III First-pass cYP3A-mediated metabolism in children after oral drug administration
97
Chapter 5 First-pass CYP3A-mediated metabolism of midazolam in the gut wall and liver in preterm neonates
99 Chapter 6 Characterization of intestinal and hepatic CYP3A-mediated
metabolism of midazolam in children using a physiological population pharmacokinetic modelling approach
127
section IV Midazolam as probe drug for other cYP3A substrates 157
Chapter 7 A pediatric covariate function for CYP3A-mediated clearance can scale clearance of selected CYP3A substrates in children
159
section V summary, conclusions, and Perspectives 187
Chapter 8 First-pass and systemic metabolism of cytochrome P450 3A substrates in neonates, infants, and children – Summary, Conclusions, and Perspectives
189
Chapter 9 Nederlandse Samenvatting 213
Appendices 237
Appendix I Curriculum Vitae 239
Appendix II List of publications 241
