Tamara van Donge

General discussion and future perspectives 231 11 General discussion The impact of growth and development on the disposition of drugs that are cleared renally and/or hepatically is still not fully unraveled and this contributes to the uncertainty and risk of exposing neonates and infants to subtherapeutic or toxic drug concentrations. Obtaining knowledge about the pharmacokinetics (PK) of a drug is the first step before moving towards investigations to see if dose adaptations might be necessary. Clinical research on kidney biomarkers might help to reveal information on the maturation of various parts of the kidneys. Overall, conducting pediatric research is still considered burdensome because of the many practical and ethical challenges. Over recent years, a lot of progress has been made for dose selection in neonates and infants by the application of various methods such as population PK (Pop-PK) or physiological-based PK (PBPK) models including covariates beyond weight. 1-6 To leverage the limited data available, it is necessary to use these advanced modeling techniques to optimally investigate the drug disposition in neonates and infants. More than half of the work presented in this thesis has been carried out by using Pop-PK analyses as this approach is suited to understand the influence of physiological factors on the primary PK parameters such as clearance and volume of distribution. Therefore, this analysis method was extremely suitable to answer the research questions in Chapters 4 to 8 in which the potential dosing optimization of amoxicillin ( Chapter 4 ) and methadone ( Chapter 5 ) were investigated, a novel strategy to personalize the use of ibuprofen ( Chapter 6 ) was designed, and the development of kidney function in preterm neonates was described by the characterization of the dynamics of creatinine ( Chapters 7 and 8 ). The studies described in this thesis aim to improve our knowledge on the PK of commonly used drugs in the neonatal population ( Chapters 4 to 6 ) and enhance the current evidence of age-dependent changes in kidney biomarkers in newborns, infants, children and adolescents ( Chapters 7 to 10 ), with the ultimate goal to improve neonatal and pediatric pharmacotherapy. Pharmacometric modeling to optimize dosing in neonates Part II of this thesis deals with the investigation of potential optimization of pharmacotherapy in the neonatal population by using pharmacometric modeling and simulation. Most current dosing guidelines for antibiotic treatment across neonatal and pediatric intensive care units and international guidelines are highly variable and inconsistent ( Chapter 3 ). 7,8 Understanding the exposure profiles of antibiotics is needed but not sufficient for optimizing dosing strategies. Being aware of both PK behavior and microbiological characteristics (pharmacodynamics, PD) is necessary to understand