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Pharmacokinetics and metabolism of 13-cis-retinoic acid (isotretinoin) in children with high-risk neuroblastoma - A study of the United Kingdom Children's Cancer Study Group

Lookup NU author(s): Professor Gareth Veal, Mike Cole, Julie Errington, Professor Alan Boddy

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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 (mean±s.d. 4.67±3.17 μM) higher than those of 13-cisRA (2.83±1.44 μM) 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. © 2007 Cancer Research.

Publication metadata

Author(s): Veal GJ, Cole M, Errington J, Pearson ADJ, Foot A, Whyman G, Boddy AV

Publication type: Article

Publication status: Published

Journal: British Journal of Cancer

Year: 2007

Volume: 96

Issue: 3

Pages: 424-431

Print publication date: 12/02/2007

ISSN (print): 0007-0920

ISSN (electronic): 1532-1827

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/sj.bjc.6603554

DOI: 10.1038/sj.bjc.6603554

PubMed id: 17224928

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