Physiologically based pharmacokinetic modelling of high- and low-dose etoposide: from adults to children

To evaluate the ability of a physiology-based pharmacokinetic (PBPK) model to predict the systemic drug exposure of high- and low-dose etoposide in children from a model developed with adult data. Simulations were performed with PK-Sim(A (R)) (Bayer Technology Services). Model development was done using data from adult patients receiving etoposide in a conventional and high-dose polychemotherapy regimen before stem cell transplantation. Michaelis-Menten parameters from in vitro experiments reported in the literature were applied to describe the metabolism and excretion processes by P450 enzymes and transporters. The model was scaled down to children and compared to etoposide plasma concentrations in this age group. Simulated plasma concentration-time courses of protein-bound and free etoposide in adults for high- and low-dose schedules agreed with the observed data. Mean simulated total clearance of high- and low-dose etoposide was 0.70 ml/min/kg (Cl-observed: 0.70 ml/min/kg) versus 0.50 ml/min/kg (Cl-observed: 0.60 ml/min/kg), respectively. Integrated Michaelis-Menten kinetics was adequately transformed to age-related pharmacokinetics in children. Predictions of the pharmacokinetics in different age groups were also in good agreement with observed data. Drug interactions triggered by P-glycoprotein inhibitors or nephrotoxic drugs can also be elucidated. The PBPK model matched the pharmacokinetics in different dosing regimens in adults. Furthermore, the scaling procedure from the adult model to children provides useful predictions for paediatric patients. Comedication with drugs influencing the metabolism and excretion has to be taken into account. This approach could be useful for planning pharmacokinetic studies in children.