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

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

Research output: Contribution to journalArticlepeer-review

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/m2 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 μM). Conclusions: During 4-HPR chronic treatment, plasma retinol reduction is not proportional to the dose. Plasma retinol levels of 0.11 μM 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.

Original languageEnglish
Pages (from-to)993-998
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume66
Issue number5
DOIs
Publication statusPublished - Oct 2010

Keywords

  • Fenretinide
  • Neuroblastoma
  • Pharmacodynamics
  • Retinoids
  • Retinol
  • Safety biomarker

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

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