Physiologically-Based Pharmacokinetic (PBPK) Model for High- and Low Dose Etoposide: From Adults to Children
G. Kersting (1,2), S. Willmann (3), G. Würthwein (2), J. Lippert (3) , J. Boos (2), G. Hempel (1,2)
(1) Department of Pharmaceutical and Medical Chemistry – Clinical Pharmacy, University of Münster (2) Department of Paediatric Haematology and Oncology, University Children’s Hospital Münster (3) Bayer Technology Services GmbH, Competence Centre Systems Biology, Leverkusen, Germany
Objectives: Etoposide is a widely-used anticancer drug in both paediatric and adult oncology. The pharmacokinetics is well- characterized with high interpatient variability in individual exposure partly due to drug interactions during polychemotherapy regimens. The aim of the current project was to evaluate a generic 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..
Methods: The simulations of etoposide were performed with the software PK-SIM® (Bayer Technology Services). The model was developed and evaluated using concentration-time profiles from adult patients receiving intravenous etoposide in a conventional and high dose polychemotherapy regimen before stem cell transplantation (Busse et al. 2002). 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. The validated model was scaled down to children and finally compared to observed etoposide plasma concentrations in this age group (Würthwein et al. 1999; Würthwein et al. 2002). In addition, drug interactions triggered by eg. P-glycoprotein inhibitors or nephrotoxic drugs such as cyclosporine A and carboplatin were elucidated.
Results: 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 were 0.74 ml/min/kg (CLpred: 0.7 ml/min/kg) vs. 0.52 ml/min/kg (CLpred: 0.6 ml/min/kg), respectively. Integrated Michaelis-Menten kinetics was adequately transformed to age-related pharmacokinetics in children. The predictions of the pharmacokinetics in different age groups by the PBPK model were also in good agreement with observed data. .
Conclusions: The PBPK-model simulations matched the etoposide pharmacokinetics in different dosing regimens in adults. Furthermore, the scaling procedure from the adult model to children by adjusting model parameters for metabolism and excretion procedures to the physiological processes in children provides useful predictions of the pharmacokinetics in paediatric patients. This approach can be useful for planning pharmacokinetic studies in children. However, comedication with drugs influencing the metabolism and excretion has to be taken into account.
References:
[1] Busse D et al. Naunyn Schmiedebergs Archives of Pharmacology 366: 218-225, 2002
[2] Würthwein G et al. Anticancer Drugs. 1999 10:807-14, 1999. 2, etc etc
[3] Würthwein G et al.Anticancer Drugs 13:101-10, 2002
