Pagnot Laurie, Granger Isaline, Guitton Jérôme, Favier Bertrand, Ceraulo Antony, Faure-Conter Cécile, Leblond Pierre, Philippe Michael
Department of Clinical Pharmacy and Oncology, Centre Leon Bérard, Lyon, France.
Biochemistry and Pharmacology-Toxicology Laboratory, Lyon Sud Hospital, Pierre Bénite, France.
Cancer Chemother Pharmacol. 2025 Feb 25;95(1):35. doi: 10.1007/s00280-025-04761-0.
Trametinib, a MEK1/2 inhibitor, has emerged as a promising treatment for pediatric patients with low-grade gliomas (LGG). However, trametinib exhibits significant inter-individual pharmacokinetic (PK) variability, and studies in adults demonstrated an exposure-efficacy relationship. This study aimed to evaluate the PK profile of trametinib in pediatric routine care and explore potential exposure-outcome relationships.
We analyzed PK data from 65 blood samples from 19 children receiving trametinib, either as single agent or in combination with dabrafenib. A trough concentration (Cmin) range of 8-15 ng/mL was considered, based on average exposure reported in the largest pediatric study.
The mean Cmin was 8.82 ng/ml, with 64.6% of samples falling within the predefined target range, while 35.4% were below it. Regarding tolerance, 84.2% of patients experienced treatment-related toxicities, predominantly skin and subcutaneous tissue disorders. Efficacy data were limited.
These findings underscore the necessity of therapeutic drug monitoring in pediatric patients to optimize treatment efficacy and minimize toxicity, highlighting trametinib's potential for personalized dosing strategies in this population.
曲美替尼，一种MEK1/2抑制剂，已成为治疗儿童低级别胶质瘤（LGG）的一种有前景的疗法。然而，曲美替尼表现出显著的个体间药代动力学（PK）变异性，并且在成人中的研究表明了暴露-疗效关系。本研究旨在评估曲美替尼在儿童常规护理中的PK概况，并探索潜在的暴露-结局关系。
我们分析了19名接受曲美替尼治疗的儿童的65份血样的PK数据，这些儿童接受曲美替尼单药治疗或与达拉非尼联合治疗。基于最大规模儿科研究报告的平均暴露量，将谷浓度（Cmin）范围设定为8 - 15 ng/mL。
平均Cmin为8.82 ng/ml，64.6%的样本落在预定义的目标范围内，而35.4%低于该范围。关于耐受性，84.2%的患者经历了与治疗相关的毒性，主要是皮肤和皮下组织疾病。疗效数据有限。
这些发现强调了对儿童患者进行治疗药物监测以优化治疗效果和最小化毒性的必要性，突出了曲美替尼在该人群中采用个性化给药策略的潜力。
