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

¹ Center for Cancer Pharmacology, Department of Pharmacology, University of Pennsylvania, Philadelphia; ² Division of Oncology, The Children’s Hospital of Philadelphia, Philadelphia; ³ Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia; and ⁴ Biomathematics Unit, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pennsylvania

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 (C_max) 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 µg.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 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.

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