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

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/m(2)/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 microM and these concentrations roughly doubled at steady state (range 1.6-14.5 microM). 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/m(2). At steady state, pharmacologically relevant plasma concentrations (range 0.7-10 microM and 0.4-5 microM 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/m(2).

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.

• Authors: Franca Formelli, Elena Cavadini, Roberto Luksch, Alberto Garaventa, Maria Grazia Villani, Valentina Appierto, Stefano Persiani
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 62 Issue 4 Pg. 655-65 (Sep 2008) ISSN: 0344-5704 [Print] Germany
• PMID: 18066548 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-oxofenretinide
• Antineoplastic Agents
• Fenretinide

Topics

• Administration, Oral
• Adolescent
• Adult
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Child
• Child, Preschool
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug Screening Assays, Antitumor
• Female
• Fenretinide (administration & dosage, analogs & derivatives, blood, pharmacokinetics)
• Half-Life
• Humans
• Male
• Neuroblastoma (drug therapy, metabolism)