Evaluation of a Physiologically-Based Pharmacokinetic (PBPK) Model for the Application of Low Dose Etoposide in Children
M. Kallenbach (1), J. Hövener (2), G. Kersting (1,2), S. Willmann (3), J. Lippert (3), J. Boos (1), G. Hempel (1,2)
(1) Department of Pediatric Haematology and Oncology, University Children's Hospital Münster, (2) Department of Pharmaceutical and Medical Chemistry - Clinical Pharmacy, University of Münster, (3) Bayer Technology Services GmbH, Competence Centre Systems Biology and Computational Solutions, Leverkusen, Germany
Objectives: Etoposide is a widely-used anticancer drug in both pediatric and adult oncology. The pharmacokinetics is well characterized with high inter-patient and intra-patient variability in individual exposure possibly due to drug interactions during polychemotherapy regimens or enzyme polymorphism. The aim of the current project was to evaluate a physiology-based pharmacokinetic (PBPK) model - implemented in PK-Sim® - to predict the systemic drug exposure of low dose etoposide in children treated in the NB 97 regimen for neuroblastoma.
Methods: The simulations of etoposide were performed with the software PK-Sim®. Based on a previously established PBPK model for adults, individual simulations for every pediatric patient (n = 40, medium age = 3,78 a) were performed. To describe the main metabolism and excretion processes by P450 enzymes and drug transporters, Michaelis-Menten kinetics using parameters from in-vitro experiments reported in the literature were applied. Enzyme activities of CYP3A4 and UGT1A1 were scaled with age to account for growth and maturation processes in the pediatric patients.The concentration-time profiles from these patients receiving intravenous etoposide longtime infusion of 96h in the NB 97 regimen were compared to observed 24h and 95h plasma concentrations.
Results: The mean plasma concentration-time data of protein-bound and free etoposide observed in children treated in the NB 97 regimen were well predicted, but the inter-individual variability was underestimated by the model. The age-dependent scaling procedure for the Michaelis-Menten parameters was adequate to describe the metabolization and elimination of etoposide in children in different age groups.
Conclusions: This PBPK-model can be used to predict the etoposide pharmacokinetics in a low dose regimen in children after appropriate scaling of model parameters for metabolism and excretion from the adult model. In general, PBPK simulations in children can be a useful tool for pediatric clinical trial design.