Relationship among pharmacokinetics and pharmacodynamics of fenretinide and plasma retinol reduction in neuroblastoma patients.

Abstract

PURPOSE:

Fenretinide (4-HPR), a synthetic retinoid currently used in clinic for cancer therapy and prevention, markedly lowers plasma retinol levels, an effect associated with nyctalopia. Our aim was to investigate the relationship between 4-HPR pharmacokinetics, plasma retinol reduction and incidence of nyctalopia.

PATIENTS AND METHODS:

Children with neuroblastoma, participating in a phase I trial, were treated with oral 4-HPR, once a day for 28-day courses followed by a 7-day drug interruption, with escalating dose levels from 100 to 4,000 mg/m(2) per day. Blood samples were collected at baseline and up to 48 h after the 1st (50 patients) and 28th (41 patients) administration, and the plasma concentrations of 4-HPR and retinol were measured by HPLC.

RESULTS:

After the first administration, nadir retinol concentrations were reached at 16-20 h post-dosing; the extent of retinol reduction was related to 4-HPR dose and plasma concentrations as well as to pretreatment retinol concentrations. After repeated treatments, nadir retinol concentrations (10-20% of baseline values) were maintained during the 24 h dosing interval and were similar at all doses; the extent of retinol reduction was significantly (r = 0.97, P < 0.0001) related to pretreatment retinol concentrations. After a single dose, the relationship between 4-HPR pharmacokinetics and pharmacodynamics indicated a counterclockwise hysteresis suggesting the presence of an effect compartment. At steady state, the hysteresis collapsed suggesting that the 4-HPR concentrations in plasma and in the effect compartments were in equilibrium. Nyctalopia was not related to the administered dose, but was significantly associated (P = 0.05) with lower nadir retinol concentrations (0.11 +/- 0.012 vs. 0.17 +/- 0.015 microM).

CONCLUSIONS:

During 4-HPR chronic treatment, plasma retinol reduction is not proportional to the dose. Plasma retinol levels of 0.11 microM could be considered as a safety biomarker in children with neuroblastoma. Finally, since initial retinol levels strongly predict the extent of retinol reduction, retinol decrease could be used to monitor 4-HPR compliance.

• Authors: Franca Formelli, Elena Cavadini, Roberto Luksch, Alberto Garaventa, Valentina Appierto, Stefano Persiani
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 66 Issue 5 Pg. 993-8 (Oct 2010) ISSN: 1432-0843 [Electronic] Germany
• PMID: 20532509 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers, Pharmacological
• Vitamin A
• Fenretinide

Topics

• Antineoplastic Agents (administration & dosage, pharmacokinetics, pharmacology)
• Biomarkers, Pharmacological (blood)
• Child
• Chromatography, High Pressure Liquid
• Clinical Trials, Phase I as Topic
• Dose-Response Relationship, Drug
• Female
• Fenretinide (administration & dosage, pharmacokinetics, pharmacology)
• Humans
• Male
• Neuroblastoma (blood, drug therapy)
• Night Blindness (chemically induced)
• Vitamin A (blood)