Tamara van Donge

Personalized use of ibuprofen in preterm neonates 107 6 in a prospective clinical trial. Such a study will enhance knowledge about the possible maximum concentration and target exposure that provides an optimal efficacy and safety profile for gastro-enteral ibuprofen therapy in preterm neonates with a PDA. In exploring different sampling time points for prediction of the total (R/S)-ibuprofen exposure during the treatment, we found that, as expected, the correlation between the ibuprofen concentrations and AUC 0-72h increased with time after the first dose. Although the C min (i.e. 23.5 h after dosage) showed the highest correlation and predictive performance, this time point does not allow a timely dose adjustment before the second drug administration due to the lag time in return of test results. To account for laboratory turn-around times, we investigated earlier time points for their feasibility in predicting the total exposure. We have shown that it is possible to measure the ibuprofen concentration as early as 8 hours after the first dose, since this ibuprofen measurement shows a high correlation (R 2 = 0.73) and predictive performance (AUC-ROC = 0.84) for attainment of the target exposure. When the concentration is at least 20.5 mg/L, in 90% of the cases the target exposure (AUC 0-72h of 900 mg·h/L) will be reached. However, since in daily clinical practice it can be challenging to sample the ibuprofen concentration at a fixed time point, we have provided a nomogram that shows the target total ibuprofen concentration for any given time-point upward of 8 hours after the first ibuprofen dose (Figure 3). In this study, we have employed a pharmacometric approach using population PK modelling and simulation to explore TDM strategies. A strong aspect of our approach was that we analyzed the PK of oral ibuprofen for both enantiomers separately in order to study the impact of individual characteristics on the independent kinetics of the two enantiomers. By performing an enantiomer specific analysis, we can more precisely predict the total (R/S)-ibuprofen concentrations over time, which is the basis for the established exposure target from Hirt et al. . We included variability in patient characteristics such as PNA or GA as well as unexplained or random variability in assessing the relationship between different ibuprofen concentrations at different sampling time points with the expected exposure during the treatment. As our included patient population had a broad distribution in patient characteristics, typical for neonates with PDA, we were able to draw valid conclusions, using the model-informed simulations, that are expected to be applicable to the whole clinical populations of neonates with PDA. As a first step in this approach, we have, for the first time, characterized the enantiomer specific population PK for orally administered ibuprofen in preterm neonates. To be able to estimate all model parameters with adequate precision, we included prior information from a PK study by Engbers et al. , conducted with IV administered ibuprofen in a similar population, using a structured methodology as