Relation between unbound plasma concentrations and toxicity in a prolongedoral etoposide schedule

Objective: This study was undertaken in order to evaluate the impact of pha rmacokinetics on the toxicity of oral etoposide administered daily for 21 d ays. Methods: The daily dose was 50 mg/m(2). Thirty-two patients 24 males and ei ght females, 36-76 years old, treated for various tumour types), were evalu ated. Blood samples were obtained on day I for all patients, and on day 21 for 16 patients. Plasma etoposide concentrations were determined by high-pe rformance liquid chromatography, and etoposide plasma protein binding by eq uilibrium dialysis. Results: On day 1, the mean value (with coefficient of variation for interi ndividual variability) for the unbound fraction (f(u)), area under the conc entration versus time curve (AUC), and unbound AUC was 9.8% (59%), 34 mg.h/ l (39%), and 3.5 mg.h/l (92%), respectively. The ratio between AUC on day 1 and day 21 ranged between 0.5 and 1.8 (mean 0.9, with CV 33%). The plasma trough unbound concentrations and the unbound AUCs both corresponding to th e first administration were significantly higher in the 11 patients who had a severe neutropenia than in the 21 patients who had no or moderate toxici ty. However, total etoposide concentrations did not differ between these tw o groups. A limited sampling strategy using the NONMEM program and a databa se of 89 patients previously studied was performed. The optimal sampling sc hedule(i.e. 1, 4, and 24 h after oral etoposide administration) allowed to obtain the AUC accurately on day 1. Conclusion: Individual adjustment of oral etoposide based on unbound pharma cokinetics after the first administration appears relevant and feasible.