Plasma etoposide catechol increases in pediatric patients undergoing multiple-day chemotherapy with etoposide.

PURPOSE The purpose of this research was to determine inter- and intrapatient differences in the pharmacokinetic profiles of etoposide and its genotoxic catechol metabolite during conventional multiple-day dosing of etoposide in pediatric patients. EXPERIMENTAL DESIGN Seven pediatric patients with various malignancies received etoposide at a dose of 100 mg/m(2) i.v. over 1 h daily for 5 days. Blood samples were taken at selected time points on days 1 and 5. Plasma and protein-free plasma concentrations of etoposide and etoposide catechol were determined using a validated liquid chromatography/tandem mass spectrometry assay. Pharmacokinetic parameters of both etoposide and etoposide catechol were calculated using the WinSAAM modeling program developed at NIH. RESULTS The mean maximum concentration (C(max)) for total (0.262 +/- 0.107 micro g/ml) and free catechol (0.0186 +/- 0.0082 micro g/ml) on day 5 were higher than the mean C(max) for total (0.114 +/- 0.028 micro g/ml) and free catechol (0.0120 +/- 0.0091 micro g/ml) on day 1. The mean area under the plasma concentration-time curve (AUC)(24h) for total (105.4 +/- 49.1 micro g.min/ml) and free catechol (4.89 +/- 2.23 micro g x min/ml) on day 5 were much greater (P < 0.05) than those for total (55.9 +/- 16.1 micro g x min/ml) and free catechol (3.04 +/- 1.04 micro g x min/ml) on day 1. In contrast, the AUC(24h) for etoposide was slightly lower on day 5 than on day 1. CONCLUSIONS The C(max) and AUC(24h) for etoposide catechol were significantly higher on day 5 than on day 1. This suggests that metabolism of etoposide to its catechol metabolite increases in pediatric patients receiving multiple-day bolus etoposide infusions. These findings may be relevant to future reduction of the risk of leukemia as a treatment complication, because etoposide and etoposide catechol are both genotoxins.