Pharmacokinetics of oral fenretinide in neuroblastoma patients: indications for optimal dose and dosing schedule also with respect to the active metabolite 4-oxo-fenretinide

Abstract

Pharmacokinetic data on fenretinide (4-HPR) are scant, thus limiting the rational use of the drug. We investigated the pharmacokinetics of 4-HPR and its active metabolite 4-oxo-fenretinide (4-oxo-4-HPR). Pharmacokinetics were assessed in 18 children (3 for each dose) with neuroblastoma who received oral 4-HPR once daily for 28 days at the doses of 100, 300, 400, 600, 1,700 and 4,000 mg/m²/day. 4-HPR and 4-oxo-4-HPR were determined by HPLC in plasma collected up to 48 h after the first and 28th administration. After single administration, 4-HPR mean C _max ranged from 0.9 to 6.6 μM and these concentrations roughly doubled at steady state (range 1.6–14.5 μM). 4-HPR mean t _1/2 was 22 h. 4-HPR pharmacokinetics were linear in the dose range 100–1,700 mg/m²; less than dose-proportional increase in exposure was found at 4,000 mg/m². At steady state, pharmacologically relevant plasma concentrations (range 0.7–10 μM and 0.4–5 μM for 4-HPR and 4-oxo-4-HPR, respectively) were maintained during the 24 h dosing interval in the dose range 300–4,000 mg/m². 4-HPR pharmacokinetics supports once-daily dosing. Steady state concentrations of 4-HPR and 4-oxo-4-HPR in children with neuroblastoma are in line with those found to have in vitro growth inhibitory effects in neuroblastoma cells.