Tamara van Donge

Introduction 15 1 Many anatomical and physiological differences can be found between the pediatric and adult population. 5 Understanding these differences and the impact they have on the ADME processes is essential to ensure effective and safe therapy in the pediatric population. 10,11 For instance, the gastric pH in newborns directly after delivery approximates neutral pH values and declines to acidic pH values early after birth. 10,12 The distribution of drugs is dependent on the body composition and on the properties of the drug of interest. Hydrophilic drugs have a larger distribution volume in newborns due to their higher percentage of extracellular water (around 70-80%) and therefore might require a higher dose per kilogram of bodyweight to ensure effective plasma and tissue concentrations. 5 The ontogeny of drug-metabolizing enzymes plays an important role in the possibility of extrapolation of adult PK data into pediatric populations as it affects the PK profile. Generally, the maturation of drug-metabolizing enzymes are characterized by iso-enzyme specific maturation and does not follow a uniform pattern. 7,13 For instance, the expression of CYP3A7 is high during fetal life and its activity decreases within two years after birth, whereas CYP3A5 becomes more active later in pediatric life, after a moderate increase after birth. 13,14 The glomerular filtration rate (GFR) is mainly responsible for the filtration and elimination of drugs and their metabolites and reaches adult values by the end of the first year. Pediatric biomarkers To understand these physiological changes during pediatric development, biomarkers have an enormous potential to improve the patient care by establishing assessments of diagnosis, prognosis, treatment effects, and adverse drug reactions. 15 The successful translation of a biomarker to clinical application, tailored to the pediatric population is essential (Figure 1). 16 There are various challenges that make biomarker research more demanding in pediatrics than in adults. The prevalence of diseases in children is usually lower in pediatrics than in adults and therefore the sample size is often smaller and the population more heterogeneous because of their age-dependent physiological characteristics. 15 The establishment of pediatric normal value ranges for existing (adult) and developing biomarkers is a step forward in the field of pediatric biomarker research. 15,17 For example, validated adequate kidney injury biomarkers to early and easily detect kidney injury are still lacking in clinical practice. The ideal pediatric biomarker for kidney injury should be noninvasive, highly specific and sensitive, monitor kidney function independent of age and should have no interference with administered drugs or nutrition. Today, serum creatinine is the most widely used biomarker for monitoring the kidney function and serves as a marker of glomerular filtration. Throughout the neonatal period (i.e. first 4 weeks of life), serum creatinine