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

Franca Formelli, Elena Cavadini, Roberto Luksch, Alberto Garaventa, Maria Grazia Villani, Valentina Appierto, Stefano Persiani

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: 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). Experimental design: 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. Results: 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/m 2; 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)655-665
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume62
Issue number4
DOIs
Publication statusPublished - Sep 2008

Keywords

  • Fenretinide
  • Metabolism
  • Neuroblastoma
  • Pediatric
  • Pharmacokinetics
  • Retinoids

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

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