Plasma Etoposide Catechol Increases in Pediatric Patients Undergoing Multiple-Day Chemotherapy with Etoposide

Abstract

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/m2 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 (Cmax for total (0.262 ± 0.107 μg/ml) and free catechol (0.0186 ± 0.0082 μg/ml) on day 5 were higher than the mean C max for total (0.114 ± 0.028 μg/ml) and free catechol (0.0120 ± 0.0091 μg/ml) on day 1. The mean area under the plasma concentration-time curve (AUC)24h for total (105.4 ± 49.1 μg.min/ml) and free catechol (4.89 ± 2.23 μ.min/ml) on day 5 were much greater (P < 0.05) than those for total (55.9 ± 16.1 μg.min/ml) and free catechol (3.04 ± 1.04 μg.min/ml) on day 1. In contrast, the AUC24h for etoposide was slightly lower on day 5 than on day 1. Conclusions: The Cmax and AUC24h 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.