Prediction of pediatric pharmacokinetics to optimize dose regimens using bottom-up, top-down and middle-out approaches

Robin Michelet
Faculteit Farmaceutische Wetenschappen
Vakgroep Bioanalyse
MSc. in Bioscience engineering, major in Chemistry and Bioprocess Technology, Ghent University, graduated magna cum laude, 2012 – 2014 Erasmus to Lunds Tekniska Högskola, Lund, Sweden, 2012-2013 BSc. in Bioscience engineering, major in Chemistry and Nutrition, Ghent University, 2009-2012
Academische graad
Doctor in de farmaceutische wetenschappen
Taal proefschrift
Vertaling titel
Voorspelling van farmacokinetiek in kinderen voor optimale dosering gebruikmakende van ‘bottom-up’, ‘top-down’ en ‘middle-out’ methodologieën
Prof. dr., An Vermeulen, UGent-Bioanalyse - Prof. dr., Jan Van Bocxlaer, UGent-Bioanalyse
Prof. dr., Koen Boussery, UGent-Bioanalyse - Prof. dr., Dieter Deforce, UGent-Geneesmiddelenleer - Dr. ir., Loeckie de Zwart, Johnson & Johnson - Prof. dr., Karel Allegaert, KULeuven - Prof. dr., Søren Rittig, Aarthus Univerity - Prof. dr. Catherijne Knibbe, Leiden Academic Centre for Drug

Korte beschrijving

During drug development testing and/or evaluation, knowledge about the pharmacokinetics and pharmacodynamics (PK/PD) of the compound under study are of pivotal importance. These data are classically obtained using clinical trials on healthy adult volunteers or adult patients. It is known that the physiology of children is vastly different compared to adults and is not constant over time: children undergo growth and maturation. This phenomenon requires paediatric research in order to map the distinct PK and/or PD behaviour in paediatrics vs. adult. Since children are not small adults, adult data cannot be readily extrapolated to paediatric populations. To cope with this, paediatric clinical trials are perfomed. However, due to the ethical and logistical constraints, these trials are hard, rare and yield less informative data. Other approaches are thus necessary. A number of scaling techniques have surfaced in recent years in an attempt to predict the PK/PD in children, mainly divided in 2 categories: top-down scaling and mechanism-based bottom-up scaling. Top-down methods such as Population PK/PD modelling and simulation use adult PK data in combination with observable covariates to account for the growth and development differences. Structural models are combined with stochastic models to obtain a mixed effects model, describing the PK/PD of a certain drug in a certain population. Bottom-up methods such as Physiologically-based pharmacokinetic (PBPK) modelling and simulation use a full knowledge of physiological, anatomical and biochemical ontogeny. In this PhD thesis, a combination of modelling tools, in vitro and in vivo generated data was used to explore the PK/PD of the model compounds Propofol, Desmopressine and in paediatric populations. Bottom-up, top-down and combined middle-out modelling approaches were applied to available and generated data and scrutinized for their applicability in paediatric drug research.


Woensdag 29 augustus 2018, 17:00
Auditorium 2, Ottergemsesteenweg 460, 9000 Gent