Tamara van Donge

Personalized use of ibuprofen in preterm neonates 103 6 age (SGA) as reported by Engbers et al ., and therefore did not include this effect in the model. 18 Given available data, comedications such as fluconazole (potential interaction because of being an inhibitor of CYP2C19) or gentamicin (potentially of interest because of nephrotoxicity) did not explain the inter-individual variability of ibuprofen’s clearance or volume of distribution. Lastly, we were not able to characterize a conversion from R-ibuprofen to S-ibuprofen. Goodness-of-fit plots show negligible bias around the line of unity, indicating that the PK model accurately describes the observations (Supporting Information 3 - Figure S1). Visual predictive check illustrates that the simulations of the PK model are able to reproduce the central trend and the variability in the observed data (Supporting Information 3 - Figure S2). 0 20 40 60 0 4 8 12 16 20 24 28 32 36 40 44 48 Time after last dose (h) (R/S)−ibuprofen plasma PK concentration (mg/L) Figure 1: Observed (R/S)-ibuprofen plasma PK concentrations versus time after last dose. Smoothed conditioned means for (S)-ibuprofen and (R)-ibuprofen are presented by green and blue solid lines, respectively. Exploration of feasible TDM strategies Monte Carlo simulations using the 20-10-10 mg/kg (PNA >3 days) or 10-5-5 mg/kg (PNA ≤3 days) dosing strategies showed that 87.2% of the neonates reach the target total ibuprofen AUC 0-72h of 900 mg·h/L (Figure 2).