The project SAFEPEDRUG aims to pro-vide guidelines for drug research in children, based on bottom-up and top-down approaches. Propofol, one of their model compounds, is extensively metabolised in liver and kidney.1 and, being a lipophilic molecule, dis-tributed into fat tissues, from where it redistributes into the circulation.2 In the past, both bottom-up (PBPK)3 and top-down approaches (popPK)4 were applied to describe the PK of this compound. In this work, a combi-nation of the two (middle-out approach) was applied to describe propofol PK in children.Methods
Data from different trials were analysed using a 3-compartment-model in NONMEM. In vitro metabolism data was generated using the methodology from Gill et al.5 All data was then described using a full PBPK model in SimcypV16. In vivo clearances were either obtained starting from in vitro clearance or scaled back from the in vivo clearance values estimated using NONMEM. Once an accurate in vivo clearance was obtained, the adult mod-el was scaled to paediatrics and the resulting model was challenged with paediatric data.Results
A CL of 1.07 L/h/kg and Vd of 822L were esti-mated using the population approach. In vitro CLint val-ues were consistent with literature, and an IVIVE would thus result in the same underprediction of total CL as described before. Therefore, the published model3 was examined to see which parameters could increase the predicted CLiv. It was found that estimating the B:P and fu resulted in a predicted average CLiv of 1.01 L/h/kg compared to 0.39 L/h/kg before. Using the retrograde approach based on literature data, a match between pre-dicted CLiv and NONMEM-derived CL was obtained. The model performed better than previous models and was able to describe PK for both long-and short-term infu-sions in adults. Extrapolation to children gave better re-sults compared to bottom-up or top-down models.Conclusion
In the past, PBPK and PopPK have mostly been used side by side to describe PK. However, a better result is achieved if both are combined. When studying a complex ADME compound such as propofol, a PBPK approach is often recommended. However, current in vitro systems and IVIVE are not yet optimised for these complexities. Therefore, the best strategy is to integrate in vivo data with in vitro studies. Once an adult PBPK model is built, it can be scaled to children using knowledge of the ontogeny and maturation, which implies a correctly predicted contribution of each subsystem to the systemic clearance.