Real-world pharmacokinetics of trametinib in pediatric low-grade glioma.

IF 2.3 4区医学 Q3 ONCOLOGY Cancer Chemotherapy and Pharmacology Pub Date : 2025-02-25 DOI:10.1007/s00280-025-04761-0

Laurie Pagnot, Isaline Granger, Jérôme Guitton, Bertrand Favier, Antony Ceraulo, Cécile Faure-Conter, Pierre Leblond, Michael Philippe

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Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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曲美替尼在小儿低级别胶质瘤中的实际药代动力学研究。

目的：曲美替尼是一种MEK1/2抑制剂，已成为治疗小儿低级别胶质瘤（LGG）的一种有希望的治疗方法。然而，曲美替尼表现出显著的个体间药代动力学（PK）变异性，在成人中的研究显示了暴露-功效关系。本研究旨在评估曲美替尼在儿科常规护理中的PK谱，并探讨潜在的暴露-结果关系。方法：我们分析了19例接受曲美替尼单药或与达非尼联用的儿童65份血液样本的PK数据。根据最大的儿科研究中报告的平均暴露量，谷浓度（Cmin）范围为8-15 ng/mL。结果：平均Cmin为8.82 ng/ml， 64.6%的样品在设定的目标范围内，35.4%的样品低于设定的目标范围。关于耐受性，84.2%的患者出现与治疗相关的毒性，主要是皮肤和皮下组织紊乱。疗效数据有限。结论：这些发现强调了在儿科患者中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，强调了曲美替尼在这一人群中个性化给药策略的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Chemotherapy and Pharmacology 医学-药学

CiteScore

6.10

自引率

3.30%

发文量

116

审稿时长

2.5 months

期刊介绍： Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.