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/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.
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.
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Acknowledgment
Grant support: Associazione Italiana per la Ricerca sul Cancro, Milan, Italy and Gateway for Cancer Research (formerly Cancer Treatment Research Foundation) Grant G-96-131.
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Formelli, F., Cavadini, E., Luksch, R. et al. Pharmacokinetics of oral fenretinide in neuroblastoma patients: indications for optimal dose and dosing schedule also with respect to the active metabolite 4-oxo-fenretinide. Cancer Chemother Pharmacol 62, 655–665 (2008). https://doi.org/10.1007/s00280-007-0649-7
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DOI: https://doi.org/10.1007/s00280-007-0649-7