Phase I trial of pirfenidone in children with neurofibromatosis 1 and plexiform neurofibromas
Phase I trial of pirfenidone in children with neurofibromatosis 1 and plexiform neurofibromas
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DOI：
10.1016/j.pediatrneurol.2007.01.009
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发表时间：
2007-05-01
影响因子：
3.8
通讯作者：
Packer, Roger J.
中科院分区：
文献类型：
--
作者：
Babovic-Vuksanovic, Dusica;Widemann, Brigitte C.;Packer, Roger J.
我们的目的是确定吡非尼酮在儿童和青少年神经纤维瘤病1型和丛状神经纤维瘤患者中的剂量，该剂量在药代动力学上与成人活性剂量相当。吡非尼酮按连续给药方案口服给药。起始剂量水平为250 mg/m2/剂。第二个剂量水平（500 mg/m2/剂）对应于先前在硬化条件下显示活性的成人剂量。如果儿童中的药物暴露量比接受800 mg每日3次治疗的成人中的药物暴露量低< 1个标准差，则认为该剂量具有药代动力学可比性。首次给药后24小时进行药代动力学采样。使用自动容积磁共振成像分析评价治疗反应;使用儿科疾病影响量表评价生活质量。16例患者入组并评价毒性。在12例接受500 mg/m2每日3次的患者中，有2例观察到剂量限制性毒性。吡非尼酮的血浆药代动力学具有高度变异性，但不具有年龄依赖性。第二个剂量水平是药代动力学相当的剂量，目前正在进行的吡非尼酮治疗I型神经纤维瘤病和进行性丛状神经纤维瘤儿童的II期试验中使用。(C)2007年，Elsevier Inc. All rights reserved.
We aimed to define the dose of pirfenidone in children and adolescents with neurofibromatosis 1 and plexiform neurofibromas that is pharmacokinetically comparable to the active adult dose. Pirfenidone was administered orally on a continuous dosing schedule. The starting dose level was 250 mg/m(2)/dose. The second dose level (500 mg/m2/dose) corresponded to the adult dose that previously showed activity in sclerosing conditions. A dose was considered pharmacokinetically comparable if the drug exposure in children was < 1 standard deviation below the drug exposure in adults treated with 800 mg three times a day. Pharmacokinetic sampling was performed for 24 hours after the first dose. Response to treatment was evaluated using automated volumetric magnetic resonance imaging analysis; quality of life was evaluated using the Impact of Pediatric Illness Scale. Sixteen patients were entered and evaluated for toxicity. Dose-limiting toxicities were observed in 2 of 12 patients receiving 500 mg/m(2) three times a day. The plasma pharmacokinetics of pirfenidone were highly variable, but not age dependent. The second dose level was the pharmacokinetically comparable dose and is being used in an ongoing phase II trial of pirfenidone for children with neurofibromatosis I and progressive plexiform neurofibroma. (C) 2007 by Elsevier Inc. All rights reserved.