Northern Institute for Cancer Research and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Clin Cancer Res. 2013 Jan 15;19(2):469-79. doi: 10.1158/1078-0432.CCR-12-2225. Epub 2012 Oct 19.
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.
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 μmol/L, with dose increases of 25% to 50% implemented for patients with C(max) values less than 2 μmol/L. A population pharmacokinetic model was applied and polymorphisms in relevant cytochrome P450 genes analyzed.
13-cisRA C(max) values ranged from 0.42 to 11.2 μmol/L, with 34 of 103 (33%) patients failing to achieve a C(max) more than 2 μmol/L. Dose increases carried out in 20 patients in the dose adjustment study group led to concentrations more than 2 μmol/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 μmol/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 μmol/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 μmol/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.
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.
研究在高危神经母细胞瘤患儿中，药物剂量适应性调整的可行性，以及遗传变异对 13-顺式维甲酸（13-cisRA）处置的影响。
103 名年龄在 21 岁及以下的患者接受了 13-cisRA（160mg/m²或 5.33mg/kg/d）治疗，在第 14 天治疗时定量检测了 13-cisRA 和 4-氧-13-cisRA 的血浆浓度。71 名患者被纳入剂量调整组，目标是 13-cisRA 的 C（max）达到 2μmol/L，对于 C（max）值低于 2μmol/L 的患者，剂量增加 25%至 50%。应用群体药代动力学模型分析相关细胞色素 P450 基因的多态性。
13-cisRA 的 C（max）值范围为 0.42 至 11.2μmol/L，103 名患者中有 34 名（33%）未能达到 C（max）大于 2μmol/L。在剂量调整研究组的 20 名患者中进行的剂量增加，使 18 名患者（90%）的浓度超过 2μmol/L。接受 5.33mg/kg 剂量的 11 名体重小于 12kg 的患者中，有 8 名（73%）未能达到 2μmol/L 或更高的 C（max）。值得注意的是，接受 5.33mg/kg 治疗的患者的 C（max）值明显低于接受 160mg/m²治疗的患者（1.9±1.2 与 3.1±2.0μmol/L；均值±SD；P=0.023）。与从胶囊中提取的药物相比，吞服 13-cisRA 胶囊的患者的 C（max）更高（4.0±2.2 与 2.6±1.8μmol/L；P=0.0012）。这两组患者中，分别有 93%（25/27）和 55%（42/76）的患者达到了目标 C（max）。未发现遗传变异与 13-cisRA 药代动力学参数之间存在明确的关系。
给药方案和给药方式对 13-cisRA 血浆浓度有显著影响。对于体重小于 12kg 的儿童，不应采用基于体重的剂量方案，并且药物治疗数据支持对于不能吞服 13-cisRA 胶囊的儿童给予更高的剂量。
