Abstract 4348: Pharmacokinetic dose individualisation of 13-cis-retinoic acid in high-risk neuroblastoma patients
Authors: Veal Gareth J. , Errington Julie , Malik Ghada , Boddy Alan V. 
Published: June 2012

Abstract
13-cis-retinoic acid (13cisRA) is now an established part of the clinical treatment of high-risk neuroblastoma. However, the efficacy observed with the current regimen contrasts with a lack of clinical benefit reported with low dose 13cisRA, suggesting that drug exposure may be a key factor determining response. We have previously published data showing significant interpatient variation in 13cisRA pharmacokinetics and extensive drug metabolism, with many patients achieving potentially sub-therapeutic plasma concentrations. The current study was carried out to investigate the feasibility of 13cisRA pharmacokinetic dose individualisation to achieve peak plasma concentrations &gt;2µM in all patients. 13cisRA (80 mg/m2 b.d. or 5.33 mg/kg/day for children &lt;12kg) was administered orally to 30 children and plasma concentrations of parent drug and metabolites determined by HPLC analysis at 0,1,2,4 and 6h on day 14 of course 1 of treatment. Dose increases of 25% and 50% were implemented on course 2 for patients who achieved peak plasma concentrations of &lt;2 µM and &lt;1µM, respectively. Where dose increases were implemented, plasma concentrations were again analysed on day 14 of course 2 at the increased dose level. 13cisRA was extracted from capsules and administered with food in 15 patients and by nasogastric tube in 9 patients. The remaining 6 patients were able to swallow the capsules. Peak plasma concentrations determined on course 1 ranged from 0.6 – 11.2 µM, with a total of 10 patients (33%) achieving peak plasma concentrations below the target level of 2µM. Dose increases were carried out in 9 of these 10 patients, with peak plasma concentrations &gt;2µM achieved on course 2 in 7 patients (78%) and following a further dose increase on course 3 in an additional patient. The remaining patient did not achieve plasma concentrations &gt;2 µM despite several dose increases. The patient cohort included a total of 8 infant patients, with 7 (88%) of these patients failing to achieve peak plasma concentrations &gt;2µM at a reduced dose level of 5.33mg/kg. Dose increases implemented in all 7 of these patients led to plasma concentrations &gt;2µM on course 2 of treatment, with increased doses well tolerated in all cases. All 6 patients who swallowed 13cisRA capsules achieved plasma concentrations &gt;2µM, as compared to 8/15 (53%) and 6/9 patients (67%) when the drug was extracted and mixed with food or administered via nasogastric tube, respectively. These data indicate the feasibility of 13cisRA pharmacokinetic dose individualisation and suggest that reduced dosing should not be implemented for children &lt;12kg. Individualisation of dosing may be particularly beneficial for children unable to swallow capsules, who require the drug to be extracted and mixed with food prior to administration. This study will continue to recruit patients to investigate the potential long-term clinical benefit of 13cisRA pharmacokinetic dose individualisation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4348. doi:10.1158/1538-7445.AM2011-4348