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


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.
Formelli
Franca
F
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. franca.formelli@istitutotumori.m.it
Cavadini
Elena
E
Luksch
Roberto
R
Garaventa
Alberto
A
Appierto
Valentina
V
Persiani
Stefano
S
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D054316:Biomarkers, Pharmacological / Q000097:blood; D002648:Child; D002851:Chromatography, High Pressure Liquid; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D005260:Female; D017313:Fenretinide / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009447:Neuroblastoma / Q000097:blood / Q000188:drug therapy*; D009755:Night Blindness / Q000139:chemically induced; D014801:Vitamin A / Q000097:blood*
D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D014801:Vitamin A; D017313:Fenretinide