Tamara van Donge

Chapter 11 234 between ibuprofen concentrations and exposure at 72 hours post first dose (area under the concentration-time curve, AUC 0-72h ) was observed, indicating that at 8 hours after the first dose, an ibuprofen concentration >20.5 mg/L was associated with a 90% probability of reaching target exposure. This newly acquired knowledge can support the individualization of ibuprofen dosing and therefore improve the efficacy of treatment with ibuprofen for the closure of a patent ductus arteriosus ( Chapter 6 ). Pediatric kidney function and injury biomarkers Recognizing a change in serum creatinine concentration is commonly used to monitor kidney function and to detect an adverse drug reaction. Assessing these potential nephrotoxic side effects in extremely low birth weight neonates (≤1000 grams birth weight) is challenging because of the high degree of variability in creatinine concentrations. 23,24 This variability can be caused by rapid changes in maturation or due to pathological factors such as neonatal sepsis or therapeutic interventions. Reference ranges are provided in Chapter 7 based on real world data on serum creatinine concentrations and its associated creatinine clearance for extremely low birth weight neonates during their first six weeks of life by means of a mathematical model. We have applied the similar population approach as addressed in Chapters 4 , 5 and 6 , but rather than describing PK data, we have quantified the dynamics of serum creatinine, a marker of glomerular filtration, by mathematical equations. Two physiological factors were identified as factors contributing positively to the clearance capacity of creatinine, being both GA and postnatal age ( Chapter 7 ). GA was quantified as the major determinant for the initial creatinine concentration after birth (increasing 6% per week of GA) suggesting gestational-dependent maternal creatinine transfer to the maternal compartment until birth. 25 The therapeutic intervention with ibuprofen illustrated a negative effect on the clearance capacity of creatinine and was considered to be a contributor of potential renal impairment ( Chapters 7 and 8 ). 25,26 The extent of increase in serum creatinine due to ibuprofen treatment is most profound during the first week of life and the difference in serum creatinine values between ibuprofen-exposed versus non-exposed neonates decreases with increasing postnatal age, independent of GA ( Chapter 8 ). These model- derived GA adjusted reference ranges for neonates with an extremely low birth weight (≤1000 grams) provide a rationale for normative serum creatinine concentrations and as such may assist clinicians to further optimize monitoring and treatment decisions in this vulnerable patient population, or to assess adverse drug reactions. The availability of reference ranges for any specific laboratory test or biomarker to support clinical decision making and tailor pharmacotherapy to the individual patient greatly supports neonatal andpediatric care ( Chapter9 ). 27,28 The literature review in Chapter9 highlights thatmore pediatric studies are needed to better characterize references ranges for kidney biomarkers in healthy pediatric populations. This will accelerate the evaluation of these kidney biomarkers in