Robin Michelet

The use of PBPK modeling across the pediatric age range using propofol as a case

The project SAFEPEDRUG aims to provide guidelines for drug research in children, based on bottom-up and top-down approaches. Propofol, one of the studied model compounds, was selected because it is extensively metabolized in liver and kidney, with an important role for the glucuronidation pathway. Besides, being a lipophilic molecule, it is distributed into fat tissues, from where it redistributes into the systemic circulation. In the past, both bottom-up (Physiologically based pharmacokinetic, PBPK) and top-down approaches (population pharmacokinetic, popPK) were applied to describe its pharmacokinetics (PK). In this work, a combination of the two was used to check their performance to describe PK in children and neonates (both term and preterm) using propofol as a case compound. First, in vitro data was generated in human liver microsomes and recombinant enzymes and used to develop an adult PBPK model in Simcyp®. Activity adjustment factors (AAFs) were calculated to account for differences between in vitro and in vivo enzyme activity. Clinical data were analyzed using a 3-compartment model in NONMEM. These data were used to construct a retrograde PBPK model and for qualification of the PBPK models. Once an accurate in vivo clearance was obtained accounting for the contribution of the different metabolic pathways, the resulting PBPK models were challenged with new data for qualification. After that, the constructed adult PPBK model for propofol was extrapolated to the pediatric population. Both the default built-in and in vivo derived ontogeny functions were used to do so. The models were qualified by comparing their predicted PK parameters to published values, and by comparison of predicted concentration–time profiles to available clinical data. Clearance values were predicted well, especially when compared with values obtained from trials where long-term sampling was applied, whereas volume of distribution was lower compared to the most common popPK model predictions. Concentration–time profiles were predicted well up until and including the preterm neonatal population. In this work, it was thus shown that PBPK can be used to predict the PK up to and including the preterm neonatal population without the use of pediatric in vivo data. This work adds weight to the need for further development of PBPK models, especially regarding distribution modeling and the use of in vivo derived ontogeny functions.

O-9 Paediatric pbpk modelling of propofol using the middle out approach

Introduction 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.