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

• Published in: British journal of cancer Vol. 96; no. 3; pp. 424 - 431
• Main Authors: VEAL, G. J, COLE, M, ERRINGTON, J, PEARSON, A. D. J, FOOT, A. B. M, WHYMAN, G, BODDY, A. V
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 12.02.2007
• Subjects: Absorption; Acids; Adolescent; Biological and medical sciences; Cancer research; Cancer therapies; Child; Child, Preschool; Clinical Study; Drug dosages; Female; Humans; Infant; Isotretinoin - adverse effects; Isotretinoin - pharmacokinetics; Isotretinoin - therapeutic use; Male; Medical research; Medical sciences; Metabolism; Metabolites; Neuroblastoma; Neuroblastoma - drug therapy; Neurology; Oxidation-Reduction; Patients; Pharmacokinetics; Plasma; Toxicity; Tumors; Tumors of the nervous system. Phacomatoses; United Kingdom; Europe; United Kingdom > UK; Human; Antineoplastic agent; Drug; High risk; Nervous system diseases; 13-cis-retinoic acid; Retinoid; Neuroblastoma; Malignant tumor; Metabolism; dosing; Posology; Cancerology; drug metabolism; Clinical pharmacology; Isotretinoin; Autonomic neuropathy; Pharmacokinetics; Child; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6603554

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 microM) higher than those of 13-cisRA (2.83+/-1.44 microM) 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.