Developmental pharmacokinetics of etoposide in 67 children: lack of dexamethasone effect

Abstract

A randomized clinical trial examined whether dexamethasone administration prior to ondansetron followed by etoposide and carboplatin infusions, and single-nucleotide polymorphisms (SNPs) of CYP3A4, CYP3A5 and MDR1 genes could modify etoposide pharmacokinetics in pediatric patients. Patients, 67 children, aged 14 weeks to 16.7 years, were treated for various malignancies and received either 3- or 5-day courses of etoposide and carboplatin: these two drugs were always administered after ondansetron infusion but combined or not with dexamethasone 5 mg/m²/day 30 min prior to etoposide infusion. Population pharmacokinetics was modeled using a non-linear mixed effect model program (Monolix version 31 s). Etoposide pharmacokinetics was ascribed to a 2-compartment model. The most significant covariate effect was bodyweight (BW), so the parameters were standardized to a 70-kg BW using the allometric ¾ or 1 power model for clearance (CL, Q) or volume terms (V), respectively. The population means for clearance and central volume of distribution were 2.05 l/h/70 kg and 9.21 l/70 kg with the corresponding between-subject variabilities, 0.26 and 0.28. Dexamethasone treatment had no effect on CL, either at the first or at the last administration occasion. CYP3A and MDR1 examined SNPs had no significant effect. Pharmacokinetics of etoposide was influenced by BW on an allometric basis in this pediatric population. Dexamethasone did not influence etoposide pharmacokinetics during these 3-5 days courses. These results should allow a better individualization of etoposide dosing in children.