Size does matter : drug glucuronidation in children

Leiden Repository

Size does matter : drug glucuronidation in children

Title: Size does matter : drug glucuronidation in children
Author: Krekels, Elke Henriëtte Josephina
Publisher: Division of Pharmacology, Leiden/Amsterdam Center for Drug Research (LACDR), Faculty of Science, Leiden University
Issue Date: 2012-10-10
Keywords: Glucuronidation
Morphine
Ontogeny
Paediatrics
Pharmacokinetics
Population modeling
UGT2B7
Zidovudine
Abstract: The maturation of UGT2B7-mediated drug glucuronidation was studied in preterm and term neonates up to infants of three years of age using a population approach. A pharmacokinetic model was developed for morphine, which was used as a paradigm compound. In this model, the maturation of morphine glucuronidation is described by a bodyweight-based exponential relationship with an exponent of 1.44. The model-derived dosing algorithm was evaluated prospectively in a clinical trial and it was shown that this dosing algorithm may reduce overdosing of neonates and exposure to ineffective doses in older infants. Additionally, it was found that the bodyweight-based exponential relationship that describes the maturation of morphine glucuronidation can be directly applied to the maturation of zidovudine, which is also a UGT2B7 substrate. This expedites the development of paediatric pharmacokinetic models and evidence-based paediatric drug dosing algorithms. Based on a study using physiologically-based pharmacokinetic modeling it was concluded that the equation for maturation of morphine glucuronidation could be applicable to all small molecular drugs and to paediatric patient populations with normal hepatic function. Finally, a framework was developed to properly validate paediatric pharmacokinetic population models and the validation of paediatric pharmacokinetic models for morphine in literature were investigated.
Description: Promotores: C.A.J. Knibbe, D. Tibboel
With Summary in Dutch
Faculty: Faculteit der Wiskunde en Natuurwetenschappen
Citation: Krekels, E.H.J., 2012, Doctoral Thesis, Leiden University
ISBN: 9789461083524
Sponsor: TI Pharma
Handle: http://hdl.handle.net/1887/19947
 

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