Adaptive Dosing Approaches to the Individualization of 13-Cis-Retinoic Acid (Isotretinoin) Treatment for Children with High-Risk Neuroblastoma

Purpose: To investigate the feasibility of adaptive dosing and the impact of pharmacogenetic variation on 13-cis-retinoic acid (13-cisRA) disposition in high-risk patients with neuroblastoma. Experimental Design: 13-cisRA (160 mg/m(2) or 5.33 mg/kg/d) was administered to 103 patients ages 21 years or less and plasma concentrations of 13-cisRA and 4-oxo-13-cisRA quantitated on day 14 of treatment. Seventy-one patients were recruited to a dose adjustment group, targeting a 13-cisRA C-max of 2 mu mol/L, with dose increases of 25% to 50% implemented for patients with C-max values less than 2 mu mol/L. A population pharmacokinetic model was applied and polymorphisms in relevant cytochrome P450 genes analyzed. Results: 13-cisRA C-max values ranged from 0.42 to 11.2 mu mol/L, with 34 of 103 (33%) patients failing to achieve a Cmax more than 2 mu mol/L. Dose increases carried out in 20 patients in the dose adjustment study group led to concentrations more than 2 mu mol/L in 18 patients (90%). Eight of 11 (73%) patients less than 12 kg, receiving a dose of 5.33 mg/kg, failed to achieve a C-max of 2 mu mol/L or more. Significantly, lower C-max values were observed for patients treated with 5.33 mg/kg versus 160 mg/m(2) (1.9 +/- 1.2 vs. 3.1 +/- 2.0 mu mol/L; mean +/- SD; P = 0.023). C-max was higher in patients who swallowed 13-cisRA capsules as compared with receiving the drug extracted from capsules (4.0 +/- 2.2 vs. 2.6 +/- 1.8 mu mol/L; P = 0.0012). The target C-max was achieved by 93% (25/27) versus 55% (42/76) of patients in these 2 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-cisRA plasma concentrations. Body weight-based dosing should not be implemented for children less than 12 kg and pharmacologic data support higher doses for children unable to swallow 13-cisRA capsules. Clin Cancer Res; 19(2); 469-79. (C) 2012 AACR.