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.