1. ¹Northern Institute for Cancer Research, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK
2. ²Royal Marsden Hospital, Surrey SM2 5PT, UK
3. ³Bristol Royal Hospital for Children, Bristol BS2 8BJ, UK
4. ⁴UKCCSG, University of Leicester, Leicester LE1 6TH, UK

Correspondence: Dr AV Boddy, E-mail: Alan.Boddy@ncl.ac.uk

Received 31 July 2006; Revised 19 September 2006; Accepted 27 November 2006; Published online 16 January 2007.

Abstract

The administration of 13-cis-retinoic acid (13-cisRA), following myeloablative therapy improves 3-year event-free survival rates in children with high-risk neuroblastoma. This study aimed to determine the degree of inter-patient pharmacokinetic variation and extent of metabolism in children treated with 13-cisRA. 13-cis-retinoic acid (80 mg m^-2 b.d.) was administered orally and plasma concentrations of parent drug and metabolites determined on days 1 and 14 of courses 2, 4 and 6 of treatment. Twenty-eight children were studied. The pharmacokinetics of 13-cisRA were best described by a modified one-compartment, zero-order absorption model combined with lag time. Mean population pharmacokinetic parameters included an apparent clearance of 15.9 l h^-1, apparent volume of distribution of 85 l and absorption lag time of 40 min with a large inter-individual variability associated with all parameters (coefficients of variation greater than 50%). Day 1 peak 13-cisRA levels and exposure (AUC) were correlated with method of administration (P<0.02), with 2.44- and 1.95-fold higher parameter values respectively, when 13-cisRA capsules were swallowed as opposed to being opened and the contents mixed with food before administration. Extensive accumulation of 4-oxo-13-cisRA occurred during each course of treatment with plasma concentrations (means.d. 4.673.17 M) higher than those of 13-cisRA (2.831.44 M) in 16 out of 23 patients on day 14 of course 2. Extensive metabolism to 4-oxo-13-cisRA may influence pharmacological activity of 13-cisRA.