Pharmacokinetics and pharmacodynamics of 21-day continuous oral etoposide in pediatric patients with solid tumors

The objectives of this study were to determine etoposide pharmacokinetics during continuous low-dose oral administration to children with solid tumors and to evaluate the relationships between parameters of etoposide systemic exposure and toxicity.

In this phase I study, children were administered oral etoposide (25 to 75 mg/m2/day) for 21 days as a diluted solution of the intravenous preparation, divided into three equal daily doses. Plasma pharmacokinetics were studied on day 1 of therapy in 18 children and again on day 21 in 14 of these children. Etoposide plasma concentration-time data were fitted to a first-order absorption, two-compartment model with use of bayesian estimation. Pharmacokinetic parameter estimates from day 1 were used to estimate steady-state etoposide systemic exposure in all children. Stepwise multivariate regression was used in an exploratory manner to determine patient, laboratory, or pharmacokinetic predictors of toxicity.

Although there was substantial intrapatient variability, there was no difference in the area under the concentration-time curve [AUC(0-8hr)] measured at day 21 compared with the steady-state AUC(0-8hr) estimated from day 1 pharmacokinetic parameters (p = 0.64). Degree of neutropenia was best predicted by the estimated duration that steady-state plasma etoposide concentrations were maintained above 1 microgram/ml (t > 1 microgram/ml) rather than peak plasma concentrations, AUC(0-8hr), dosage, or other patient characteristics. Assuming a bioavailability of the oral solution of approximately 50%, the median etoposide systemic clearance was 21.4 ml/min/m2, a value similar to clearance estimates after intravenous etoposide in pediatric populations.

We conclude that a parameter reflective of etoposide systemic exposure (t > 1 microgram/ml) correlates more strongly with neutropenia than does dosage or other patient characteristics.