Tamara van Donge

General discussion and future perspectives 233 11 be effective enough in those situations ( Chapter 4 ). This analysis highlights the paradox of identifying optimal amoxicillin dosing regimens in neonates (Figure 1); the acceptability of regimens will differ according to selected PKPD targets (for efficacy and toxicity) and MICs, the selection of which in turn is challenging and highly influenced by microbiological epidemiology of neonatal sepsis (dominant pathogens and their resistance patterns). Although anti-infectives are one of the most frequently administered drugs in neonatal intensive care units, neonatal pharmacotherapy with opioids is on the rise partially due to the current prescription opioid epidemic. 14-17 These patients, who are often born prematurely, show withdrawal symptoms (neonatal abstinence syndrome, NAS) after birth that are caused by the abrupt discontinuation of prolonged in utero drug exposure ( Chapter 5 ). In order to treat these withdrawal symptoms, methadone, a racemic stereoselective opioid metabolized by the drug metabolizing enzyme cytochrome P450 2B6, is frequently used. 18,19 Current dosing recommendations for methadone are often quite complex and require a taper or weaning period. 20,21 The study described in Chapter 5 focuses on quantifying the single dose PK of both methadone enantiomers administered to preterm neonates. The impact of in utero maturation was illustrated as the clearance of methadone increases with advancing GA and differs between (R)- and (S)-methadone, being slightly higher for the former. The impact of GA on the clearance of (S)-methadone was substantial as a five-fold increase was observed between a neonate of 26 weeks or 36 weeks of gestation (0.0692 L/h vs 0.3708 L/h). 22 Model- based simulations illustrated that a dosing strategy with a simplified tapering period, ensures target exposure of methadone in preterm neonates (Table 1). Such dosing strategy will not only reduce the risk of measurement errors related to complex dosing schedules, but also lowers the number of interventions in these preterm patients. Table 1 Methadone dosing strategy for preterm neonates with neonatal abstinence syndrome as suggested in Chapter 5. Tapering Dose (mg/kg) Frequency Day 1 0.1 mg/kg Every 6 hours Day 2 0.1 mg/kg Every 12 hours Day 3 0.05 mg/kg Every 12 hours Day 4 0.01 mg/kg Every 12 hours Individualizing the dose based on therapeutic drug monitoring (TDM) is another potential approach towards personalized pharmacotherapy while minimizing the collection of samples in (preterm) neonates, who have a limited blood volume and high risk of anemia. The feasibility of a novel TDM strategy where a single sample drawn on the first day of treatment with ibuprofen was explored in Chapter 6 . A strong correlation