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Adaptive dosing approaches to the individualization of 13-cis-retinoic acid (isotretinoin) treatment for children with high-risk neuroblastoma

Lookup NU author(s): Professor Gareth Veal, Julie Errington, Sophie Rowbotham, Nicola Illingworth, Dr Ghada Malik, Mike Cole, Professor Ann Daly, Professor Andrew Pearson, Professor Alan Boddy

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Abstract

Purpose: To investigate the feasibility of adaptive dosing and the impact of pharmacogenetic variation on 13-cisRA disposition in high-risk neuroblastoma patients. Experimental Design: 13cisRA (160mg/m2 or 5.33mg/kg/day) was administered to 103 patients ≤21 years and plasma concentrations of 13-cisRA and 4-oxo 13-cisRA quantitated on day 14 of treatment. 71 patients were recruited to a dose adjustment group, targeting a 13-cisRA Cmax of 2μM, with dose increases of 25-50% implemented for patients with Cmax values <2μM. A population pharmacokinetic model was applied and polymorphisms in relevant cytochrome P450 genes analyzed. Results: 13-cisRA Cmax values ranged from 0.42–11.2μM, with 34/103 (33%) patients failing to achieve a Cmax >2μM. Dose increases carried out in 20 patients in the dose adjustment study group led to concentrations >2μM in 18 patients (90%). 8/11 (73%) patients <12kg, receiving a dose of 5.33mg/kg, failed to achieve a Cmax ≥2μM. Significantly lower Cmax values were observed for patients treated with 5.33mg/kg versus 160mg/m2 (1.9±1.2 versus 3.1±2.0μM; mean±SD; P=0.023). Cmax was higher in patients who swallowed 13-cisRA capsules as compared to receiving the drug extracted from capsules (4.0±2.2 versus 2.6±1.8μM; P=0.0012). The target Cmax was achieved by 93% (25/27) versus 55% (42/76) of patients in these two groups respectively. No clear relationships were found between genetic variants and 13-cisRA pharmacokinetic parameters. Conclusions: Dosing regimen and method of administration have a marked influence on 13-cisRAplasma concentrations. Body weight-based dosing should not be implemented for children <12kg and pharmacological data support higher doses for children unable to swallow 13-cisRA capsules.


Publication metadata

Author(s): Veal GJ, Errington J, Rowbotham SE, Illingworth NA, Malik G, Cole M, Daly AK, Pearson ADJ, Boddy AV

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2013

Volume: 19

Issue: 2

Pages: 469-479

Print publication date: 19/10/2012

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

Publisher: American Association for Cancer Research

URL: http://dx.doi.org/10.1158/1078-0432.CCR-12-2225

DOI: 10.1158/1078-0432.CCR-12-2225


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