Simulation tool for schedule-dependent etoposide exposure based on pharmacokinetic findings published in the...

It is the aim of this study to establish a simulation tool for etoposide (Eto) which can be used to interpret drug monitoring data in clinical practice and to design new schedules for future protocols. As schedule dependency was observed for Eto, knowledge of concentration-time profiles is important. Pharmacokinetic data from children after low-dose i.v. administration of Eto together with data reported in the literature were used to construct the simulation tool. Validation was performed by independently reproducing various published data. Dose linearity of AUC was shown over the whole dose range of 20-2000 mg/m2 reported in the literature and fits the predictions by the simulation tool. There was no difference in clearance between children and adults. Close agreement was found between predicted and reported concentration-time profiles after various administration schedules. However, subgroups with significantly altered pharmacokinetics of Eto, such as patients with renal impairment or concurrent cisplatin chemotherapy, were excluded from the comparisons. In these patients values predicted for a 'regular' patient might be used as a base for possible dose modifications. In summary, a pharmacokinetic model of high predictive value is presented which allows simulations of Eto concentration-time profiles for low- as well as high-dose conditions and various infusion times.