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Pharmacokinetics in Children with Liver Disease

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Pharmacokinetics in Children with Liver Disease Ghent University Faculty of Pharmaceutical Sciences Department of Bioanalysis Laboratory of Medical Biochemistry and Clinical Analysis PHARMACOKINETICS IN CHILDREN WITH LIVER DISEASE: CAN EX VIVO OBTAINED POPULATION-SPECIFIC CYP450 CHARACTERISTICS BRIDGE THE KNOWLEDGE GAP? Lies De Bock Pharmacist Thesis submitted to obtain the degree of Doctor in Pharmaceutical Sciences 2014 Promotors: Prof. Dr. Jan Van Bocxlaer Prof. Dr. Koen Boussery COPYRIGHT COPYRIGHT The author and the promotors give the authorization to consult and to copy parts of this thesis for personal use only. Any other use is limited by the Laws of Copyright, especially concerning the obligation to refer to the source whenever results are cited from this thesis. De auteur en de promotoren geven de toelating dit proefschrift voor consultatie beschikbaar te stellen en delen ervan te kopiëren voor persoonlijk gebruik. Elk ander gebruik valt onder de beperkingen van het auteursrecht, in het bijzonder met betrekking tot de verplichting uitdrukkelijk de bron te vermelden bij het aanhalen van resultaten uit dit proefschrift. Gent, 2014, The promotors, The author, Prof. Dr. Apr. Jan Van Bocxlaer Prof. Dr. Apr. Koen Boussery Apr. Lies De Bock I Voor Mamie ACKNOWLEDGEMENTS - DANKWOORD ACKNOWLEDGEMENTS - DANKWOORD Ik denk dat ik mijn dankwoord zo’n 50 keer herschreven heb.. En toch heb ik nog steeds het gevoel dat ik niet 100% correct kan verwoorden wat ik voel of denk. Dus als je je naam ziet verschijnen, en je vindt dat ik je bijdrage onvoldoende bejubel, denk er gerust zelf nog wat lovende commentaren voor jezelf bij.. Die heb je ongetwijfeld verdiend! Eerst en vooral een welgemeende dank u voor mijn promotoren Prof Jan Van Bocxlaer en Prof Koen Boussery. In oktober 2008 gaven jullie mij het vertrouwen te starten met dit uitdagende project. De wegen lagen niet altijd overal even glad, maar jullie leidden mij er toch telkens overheen. Om dit project te doen slagen had ik hulp nodig uit de klinische wereld, want zonder stalen geen analyses natuurlijk! Prof Myriam Van Winckel en Prof Peter De Paepe, bedankt voor jullie inbreng en ideeën bij het opstarten van het project. Prof Van Winckel en Dr Ruth De Bruyne, bedankt voor het aanleveren van de stalen. Eveneens een woord van dank voor de leden van transplantatiecentrum van het UZ Gent (Luc Colenbie, Nelly Mauws, Ivo Haentjens en Marc Van der Vennet). Zonder jullie telefoontjes was ik niet op de hoogte geweest! Prof Xavier Rogiers, bedankt mij toe te laten in uw OK om de stalen te nemen. Le soutien incontestable du Prof. Dr. Sokal, chef de service du Laboratoire d’Hépatologie Pédiatrique des Cliniques Universitaires Saint-Luc (Université Catholique de Louvain-la- Neuve), nous a permis d’inclure un nombre considérable de patients. J’aimerais remercier spécialement le Prof. Dr. Stephenne qui par son aide logistique, nous a informé des moments de transplantation et nous a procuré les foies explantés, et par son aide scientifique a contribué à nos résumés et publications. Je remercie également Mmes Ilse van Elewyck et Magda Janssen, ainsi que les autres collègues de l’équipe qui nous ont apporté leur aide. Voor mijn genotyperingsexperimenten kon ik terecht op het Labo Farmaceutische Technologie van Prof Dieter Deforce. Bedankt, Filip, om mij wegwijs te maken in de TaqMan analyses. Verder een woord van dank voor Dr Geert Mannens en Mr Jos Van Houdt van DMPK van Janssen Farmaceutica in Beerse. Mijn eerste kennismaking en tips and tricks voor het maken van microsomen en het uitvoeren van incubaties kreeg ik van jullie. Naast onderzoek naar CYP450 bij kinderen met leverlijden, had ik een succesvolle samenwerking met Prof Croubels van de vakgroep farmacologie, toxicologie en biochemie van de faculteit diergeneeskunde naar CYP450 in lever en darm bij kippen en varkens. V ACKNOWLEDGEMENTS - DANKWOORD Hieruit kwamen niet enkel 3 A1 publicaties, maar ook een fijne vriendschap met Ann! Zelfs tijdens het wroeten in kippendarmen bleven we gezellig verder babbelen Bedankt, Ann, voor de gezellige, maar ook leerrijke, momenten in het labo. Veel succes verder, zowel professioneel als met je gezin! Gedurende die 5,5 jaar op het LMBKA begeleidde ik ook 4 thesisstudenten. Bedankt Els, Sylvie, Michiel en Tine: jullie werk leverde een grote bijdrage aan mijn finale resultaat. Als je eens rekent, dan ontdek je dat je eigenlijk meer tijd doorbrengt met je collega’s dan met je gezin.. Gelukkig maar dus dat ik een pak fijne collega’s had, daar op het LMBKA! Prof Vermeulen, Nadine, Wim, Marianne en Sofie: merci voor de gezellige babbelkes. En Sofie: bedankt voor je hulp en tips bij al wat bioanalyse was! De MS heeft gelukkig minder geheimen voor u dan voor mij! Blijf zorg dragen van ons Bomma en doe af en toe de groeten aan Roxanne van mij. Julie en Ruben, de assistenten die voor mij weg waren: bedankt om mij bij de start van mijn periode hier op het LMBKA wegwijs te maken in alles. Mijn huidige collega-doctoraatsstudenten: Pieter en Huybrecht, aka statistics dude en plotman, aka de modelling and simulating tandem.. Ik kan jullie totaal niet meer volgen als jullie over jullie onderzoek discussiëren, maar we zaten wel op dezelfde lijn op alle andere gespreksonderwerpen! Merci voor de discussies over wetenschap die mij verder hielpen met mijn onderzoek, maar ook voor de niet- wetenschappelijke – al dan niet vreselijk sarcastische – gesprekken die mij vaak deden lachen. Ik wens jullie super veel succes met het verder onderzoek, maar blijf vooral onthouden “’t Kan ni al meezitten…”! Ook wens ik jullie alle geluk toe op privé vlak met huis, tuin en kinderen. Ook de collega’s van de Farmaceutische Zorg (Bart, Inge, Els, Leen, Leen, Elke en Elien) wil ik bedanken voor de aangename momenten! Elke en Elien: jullie zijn ook nog volop aan het ‘onderzoeken’: nog veel succes daarmee!! Ik heb het onderwerp en resultaten van mijn onderzoek waarschijnlijk al zo’n 1000 x beschreven, in 7 verschillende niveaus op basis van achtergrondkennis aan ontelbaar veel mensen.. Bedankt, vriendjes en vriendinnetjes, van mijn klasje, van de Pagadders, van in de sneeuw en van de farma, om toch telkens geïnteresseerd te kijken, of tenminste te doen alsof! Gelukkig vond ik ook altijd – en snel – één of meerdere slachtoffers om mijn onderzoeksfrustraties te uiten! Een extra woordje van dank voor Karen en Stijn voor hun hulp bij het maken van mijn cover. Bedanken van familie moet sinds kort uitgebreider dan vroeger (hoewel trouwen niet nodig was om jullie als familie te beschouwen!). Dank jullie wel, Ann en Edwin, Elien en VI ACKNOWLEDGEMENTS - DANKWOORD Alex, Jeroen en Leonie, meter en meme dat ik ook bij jullie zoveel steun kon krijgen de voorbije jaren!! Broerie, merci voor de (soms meer verwarrende dan verhelderende) MS talks die we vaak hadden aan het begin van mijn doctoraat! Maar ook voor onze vriendschap.. Uw wetenschappelijke carrière krijgt terwijl ik dit schrijf ook een serieuze boost daar in Grenoble! Gelukkig past de cliché – weliswaar aangepast – ook voor u: “naast elke man staat een sterke vrouw” (niet waar, Julie?) ... Lieve mamie, ik ben zo blij dat ik dit met jou kan delen!! Je bent altijd al een super- mamie geweest voor ons vieren, en nu zijn Ruube, Lobke en Warre ook aan het genieten van jou! "You do not really understand something unless you can explain it to your grandmother", zei Einstein. Wat hij natuurlijk niet kon weten was dat mijn grootmoeder zo veel nieuwe dingen ging willen leren na haar 2 keer 40 jaar (+ 1) Mama en papa.. Het is erg moeilijk in woorden uit te drukken hoe dankbaar ik jullie ben! Jullie steun tijdens mijn doctoraat was onbetaalbaar, maar verdwijnt als een emmer water in de grote zee van steun en liefde die jullie mij (ons!) al heel mijn leven geven! Ik ben trots op wie ik ben en dat heb ik zo hard aan jullie te danken! Last but not least, bedankt aan mijn man Tim. Marie Curie zei ooit: “I have frequently been questioned, especially by women, of how I could reconcile family life with a scientific career. Well, it has not been easy.” Jouw onvoorwaardelijke steun hielp mij echter door de moeilijke momenten die elke doctoraatsstudent kent! Elke avond thuiskomen in een liefdevol huis geeft mij de mogelijkheid mijn batterijtjes op te laden om de dag erna weer te gaan werken. Bedankt ook dat je zo’n superpapa bent voor Ruube!! Ik kijk uit naar wat onze toekomst ons nog allemaal zal brengen.. VII TABLE OF CONTENTS TABLE OF CONTENTS Copyright I Acknowledgements / Dankwoord V Table of contents IX List of abbreviations XV INTRODUCTION 1 1. Children are not small adults: better medicines for children. 3 2. Development of drug disposition and action in children 4 2.1 Developmental pharmacodynamics 4 2.2 Developmental pharmacokinetics 6 2.3 The cytochrome P450 enzyme system 8 3. Liver disease 12 3.1 Liver disease in adults 12 3.2 Liver disease in infants and children 13 3.3 Treatment of liver disease in children 15 4. Pharmacokinetics in liver disease 17 4.1 PK in adults with liver disease 17 4.2 Dose alterations in adults with liver disease 21 5. Safer drug use in children with liver disease: the (potential) role of PBPK 26 modelling 5.1 Modelling and simulation: tools to meet the current needs? 26 5.2 Properties of a PBPK model 27 5.3 Applications of PBPK models 28 5.4 PBPK models: tools to meet the current needs in paediatric drug use? 30 6. Conclusion 30 OUTLINE AND AIMS OF THIS THESIS 39 CHAPTER 1: QUANTIFICATION OF SIX PROBE METABOLITES AFTER DERIVATIZATION WITH 43 PYRIDINE-3-SULFONYL CHLORIDE (PS) IN AN AQUEOUS ENVIRONMENT 1. Introduction 45 2.
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