Tamara van Donge

Chapter 6 108 described elsewhere. 16 This allowed us to characterize the enantiomer specific population PK of orally administered ibuprofen in (preterm) neonates with a relatively low sample size and therefore a limited burden for participants. Engbers et al. studied a population of 67 preterm neonates and identified several factors influencing the clearance of S-ibuprofen, namely, being SGA, GA and PNA. 17 We estimated clearance for S-ibuprofen at 0.0057 L/h for a typical individual, which is around the same values as previous published (0.00398 L/h and 0.0035 L/h/kg). 17,19 Similar to these studies, we found that the elimination of R-ibuprofen is much higher than S-ibuprofen. Moreover, in our study we found that clearance of both S- and R-ibuprofen increases with PNA, with an additional effect of GA on S-ibuprofen clearance. This is consistent with previous studies reporting increases of clearance of S-ibuprofen with PNA with exponents of 2.25 or 1.49, for Engbers et al . and Hirt et al . respectively. 11,17 Given available data, we could not identify the effect of SGA as reported by Engbers et al ., and additional studies with adequate sample size are required to further investigate this reported difference. Some limitations of our study should be addressed. We based our target ibuprofen concentrations on the exposure target as proposed by Hirt et al. (AUC 0-72h >900 mg·h/L). 11 To date, this target level is the only exposure metric that has been linked to successful closure of PDA and is based on studies that used IV ibuprofen. Such studies are not available for oral ibuprofen and thus this exposure-response relationship should be confirmed for orally administered ibuprofen. However, this does not influence our primary conclusions with regard to the optimal sampling time windows using a TDM strategy. Secondly, our analysis would benefit even further from the enantiomer specific PK analysis if specific exposure targets for the biologically active S-ibuprofen are available. Future clinical trials should focus on filling in these knowledge gaps. We designed a novel and clinically acceptable single sampling strategy where we have demonstrated that the total ibuprofen exposure during the first three days of treatment can be robustly predicted with a single sample collection on the first day of treatment at least 8 hours after the first dose. By applying this monitoring strategy, patients at risk for not reaching their target exposure can be already identified on the first day of treatment. This knowledge can be applied to personalize ibuprofen dosing regimens and improve successful closure of a PDA, with the ultimate goal to further enhance treatment success in this vulnerable population.