A limited-sampling strategy for estimation of etoposide pharmacokinetics in cancer patients

Etoposide (VP16), a widely used anticancer drug, is a topoisomerase II inhi bitor. A number of studies have highlighted a correlation between hematolog ic toxicity and pharmacokinetic or physiological parameters, Other studies have also suggested that the anti-tumor response could be related to the pl asma etoposide concentration. Therefore, it would seem of interest to indiv idualize VP16 dose regimens on the basis of pharmacokinetic parameters. The aim of this study was to develop and validate a limited-sampling strategy allowing VP16 pharmacokinetic evaluation with minimal disturbance to the pa tient. A total of 34 patients (54 kinetics) received VP16 at various dose r egimens, with doses ranging between 30 and 200 mg and infusion times varyin g between 0.5 and 2 h. The statistical characteristics of the pharmacokinet ic parameters were assessed from the first courses of treatment performed i n 23/34 patients; then the following three-sample protocol was designed: th e end of the infusion and 5 and 24 h after the start of the infusion. For v alidation of the model the main pharmacokinetic parameters (clearance, half -lives, volume of distribution) were estimated in the 11 remaining patients by maximum-likelihood estimation (ML) and by Bayesian estimation (BE) usin g the three sampling times designed. Statistical comparison showed a good c oncordance between ML and BE estimates (the bias for clearance was -1.72%). The limited-sampling strategy presented herein can thus be used for accura te estimation of VP16 pharmacokinetic parameters.