Pharmacometric approaches to guide neonatal and pediatric pharmacotherapy

The studies presented in this thesis have increased our understanding of the impact of growth and development on how to optimally use commonly prescribed drugs in the neonatal population and also have provided insights in the maturation of the kidney, illustrated by different kidney function and injury biomarkers over the entire pediatric age range (extreme preterm to adolescents).
Throughout this thesis we have developed multiple population pharmacokinetic models allowing to assess the impact of maturation on the drug disposition of commonly used drugs in the neonatal population such as amoxicillin (Chapter 4), methadone (Chapter 5) and ibuprofen (Chapter 6). We have shown that characterizing developmental pharmacokinetics is a crucial first step to gain insights in drug exposure in neonates and infants, although further research on developmental pharmacodynamics is warranted to unravel the exposure-response relationship in these vulnerable pediatric populations. Moreover, we have provided age-dependent reference ranges for kidney function and injury biomarkers in extreme preterm neonates (Chapter 7) and healthy infants, children and adolescents (Chapters 9 and 10), which will support earlier detection of kidney injury in neonatal and pediatric patients who are exposed to nephrotoxic drugs. The results of the developed population pharmacokinetic models and the implementation of their outcome, together with the established age-dependent reference ranges for kidney biomarkers will hopefully contribute to current clinical practice and ultimately will help guide neonatal and pediatric pharmacotherapy.