Tamara van Donge

Introduction 19 1 The outline of this thesis starts with a literature search ( Part I ). First, a general introduction into quantitative clinical pharmacology is provided ( Chapter 1 ) and a review of the literature on the physiological changes during pregnancy and early neonatal life is presented in Chapter 2 . Neonatal dosing optimization by applying pharmacometric modeling approaches are highlighted in Part II . Key components for antibiotic dose optimization in neonates with sepsis are discussed in Chapter 3, and Chapter 4 subsequently addresses amoxicillin dosing regimens for the treatment of neonatal sepsis. Modeling and simulation techniques are applied in Chapter 5 , where simplified dosing strategies for methadone in preterm neonates with neonatal abstinence syndrome are illustrated. A therapeutic drug monitoring approach to personalize the use of ibuprofen for the closure of patent ductus arteriosus in preterm neonates is highlighted in Chapter 6 . Part III comprises the description of pediatric kidney function by the characterization of various biomarkers. Chapter 7 focuses on serum creatinine and describes maturation related dynamics of this biomarker in extremely low birth weight newborns during their first six weeks of life. Chapter 8 demonstrates an extension, where the trends in creatinine after exposure to ibuprofen are clarified to detect ibuprofen-related maturational adverse events in neonatal life. Chapter 9 illustrates an overview of the current evidence on age- dependent changes of kidney injury biomarkers in the pediatric population, whereas Chapter 10 summarizes results of a pediatric clinical trial where eight kidney injury biomarkers in a healthy pediatric population were investigated. Finally, Part IV is concerned with a general discussion, where in Chapter 11 the results of the studies are put in a broader perspective and the main findings of this thesis are summarized in Chapter 12 .