Tamara van Donge

Chapter 11 236 Creatinine is still considered to be the gold standard to monitor glomerular filtration rate and kidney function. Figure 2 illustrates the creatinine values studied in this thesis collected from extreme preterm neonates, preterm neonates and healthy infants, children and adolescents. An increase early after birth is observed for extremely low birth weight neonates, due to the potential reabsorption of creatinine as a result of immature renal tubules ( Chapter 7 ). Treatment with ibuprofen has negative impact on the clearance capacity of creatinine and consequently, higher creatinine values are observed when being exposed to the nephrotoxic drug ibuprofen ( Chapter 8 ). As the effect of ibuprofen on creatinine clearance is relatively minor, it is of most relevance directly after birth when the clearance capacity is at its lowest. Later in life, creatinine concentrations are characterized by an increase until approximately 0.5-1.2 mg/dL and reach adult levels ( Chapter 10 ). Future perspectives Pediatric clinical (pharmacology) studies are often conducted as post-marketing studies of already approved agents with the aim of investigating the PK (and PD) properties of the drug in a population which was not described in the package leaflet. The main hurdles of pediatric clinical studies are to determine an adequate sample size and design a feasible enrollment strategy because the number of infants and children who require drug therapy is almost always lower than the number of eligible adults. 30 Pharmacometric approaches can enhance pediatric and neonatal clinical pharmacology as it is able to analyze sparsely collected and unbalanced data. We believe that applying pharmacometric approaches together with the use of routinely collected or scavenged samples, lowers the burden of the patient as additional (venous stick or heel prick) blood draws can be avoided. The use of scavenged blood sampling is especially useful in (extremely) preterm neonates, who have a limited blood volume. 31 Applying modeling and simulation techniques has been shown to be a suitable analysis method to quantify the PK and to investigate new and not yet clinically investigated dosing scenarios. The studies described in this thesis ( Chapters 5 and 6 ) focused on PK properties and assumptions on the target exposure (PD) were obtained from literature. Leveraging these PK models to predict which doses will result in a target concentration is only valid if we do know which drug concentrations to target. The studies described in this thesis focused on developmental pharmaco kinetics , yet increased focus must be devoted to developmental pharmaco dynamics as well. The characterization of pharmacodynamics is challenging because this can often not be extrapolated from the adult population since many diseases observed in the neonatal population are inherent to the population itself (neonatal sepsis, neonatal abstinence syndrome, patent ductus arteriosus). Well defined PD endpoints in clinical studies should be considered equally important as the investigation of the PK. If the target