Tamara van Donge

Chapter 1 18 drug-metabolizing enzymes and maturation of kidney function required for the disposition of drugs in newborns. 33 This information provides the basis for quantitative pharmacology and pediatric pharmacometrics (Figure 1). Pharmacometrics can be defined as the science that quantifies the interactions between drugs and patients, by the aid of mathematical models based on the features of pharmacology, (patho-) physiology and biology. 34 The use of quantitative pharmacology and pharmacometrics have been proven to be a useful tool to facilitate the optimization of pediatric pharmacotherapy. 33,35-37 These model-based approaches can deal with sparsely collected data, small sample size and irregularly collected data, which are common features when conducting clinical trials in the pediatric population. In addition, by applying modeling and simulation approaches, one can understand important age-related factors influencing drug disposition and the pharmacodynamic response in pediatric patients. 2,38-40 One of the main advantages of applying pharmacometrics in the pediatric (especially neonatal) population is that it allows the collection of sparse sampling and it empowers us to quantitatively assess the distinct effects of growth and development on drug exposure and response. 38 Aims and outline of this thesis A critical information gap still exists with regards to the PK of various drugs in the neonatal population and normative values for kidney biomarkers. Insight in the PK is the first step needed before moving to investigate whether dose adaptations are necessary in this vulnerable population. The studies described in this thesis aim to improve our knowledge on the PK of commonly used drugs in the neonatal population and enhance our awareness of age-dependent changes in kidney biomarkers in newborns, infants, children and adolescents. The aims of this thesis are as follows: • Review available literature and identify key factors for model-informed dose optimization in neonates and infants. • Understand the relationship between variability of amoxicillin dosing regimens and PK/PD target achievement. • Apply pharmacometrics to simplify dosing strategy of methadone in preterm neonates with neonatal abstinence syndrome. • Study PK behavior of ibuprofen in preterm neonates with patent ductus arteriosus. • Describe kidney maturation related dynamics of creatinine concentrations in extremely preterm neonates. • Review available literature and investigate eight kidney injury biomarkers in healthy infants, children and adolescents.