2 - 5岁儿童elexaftor /tezacaftor/ivacaftor的药代动力学和行为障碍的发生

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis Pub Date : 2025-06-01 DOI:10.1016/j.jcf.2025.03.503

N.H. Truong , S. Benaboud , L. Chouchana , A.-S. Bonnel , M. Barboura , N. Bouazza , S. Gautier , S. Rouillon , L. Froelicher-Bournaud , T. Bihouee , S. Bui , J.-M. Treluyer , I. Sermet- Gaudelus , F. Foissac , Modul-CF research group

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引用次数: 0

摘要

目的：eleexacaftor /tezacaftor/ivacaftor （ETI）可改善至少有一个F508del等位基因的囊性纤维化（CF）患者的CFTR功能和临床症状。2023年，FDA和EMA批准了2至5岁CF （chCF）儿童的ETI，这些儿童至少有一个F508del突变拷贝或其他突变在体外研究中显示出对ETI的反应性。根据我们的经验，我们观察到治疗开始后出现了大量的行为问题，包括这些chCF中的多动、情绪障碍和睡眠障碍。本研究旨在确定这些行为问题是否可能与ETI药代动力学（PK）参数有关。方法：本研究是module - cf队列（NCT04301856）的一部分，纳入了2-5岁的chCF患者，他们遵守目前的给药建议，有治疗药物监测和记录的行为数据。利用Monolix软件建立ETI种群PK模型，并根据个体贝叶斯PK估计得到曲线下面积（AUC）、最大浓度（Cmax）和谷浓度（Ctrough）。结果共纳入63例儿童，其中男孩占70%，体重14 kg 20例（32%），中位年龄2.9±0.7岁，体重14 kg 43例（68%），中位年龄4.6±0.9岁。35名儿童（55.6%）出现异常行为，常见问题包括睡眠障碍、多动、易怒和情绪障碍。各组之间的年龄、体重或性别分布没有显著差异。同样，ETI auc、Cmax和cough在表现出异常行为的儿童和没有表现出异常行为的儿童之间没有统计学差异。结论：据我们所知，这是第一个评估ETI血浆暴露与2-5岁chCF行为问题之间关系的研究。总的来说，我们的研究结果并不表明这些副作用与暴露的增加有关。

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WS02.06Elexacaftor/tezacaftor/ivacaftor pharmacokinetics and occurrence of behavioural disorders in children aged 2 to 5 years old

Objectives

Elexacaftor/tezacaftor/ivacaftor (ETI) was shown to improve CFTR function and clinical symptoms in people with cystic fibrosis (CF) with at least one F508del allele. In 2023, the FDA and the EMA approved ETI for children with CF (chCF) aged 2 to 5 who have at least one copy of the F508del mutation or other mutations that have demonstrated responsiveness to ETI in in vitro studies. In our experience, we observed a significant number of behavioral issues emerging after treatment initiation, including hyperactivity, mood disorders and sleep disturbances among these chCF. This study aimed to determine whether these behavioral issues may be associated with ETI pharmacokinetic (PK) parameters.

Methods

This study, part of the MODUL-CF cohort (NCT04301856), included chCF aged 2–5 years who adhered to current dosing recommendations, with therapeutic drug monitoring and documented behavioral data. Population PK models of ETI were performed using the Monolix software with area under the curve (AUC), maximal concentration (Cmax) and trough concentration (Ctrough) derived from individual Bayesian PK estimates.

Results

Sixty-three children (70% boys) were included: 20 (32%) weighed <14 kg (median age 2.9±0.7 years), and 43 (68%) weighed >14 kg (median age 4.6±0.9 years). Abnormal behavior was observed in 35 children (55.6%), with common issues including sleep disturbances, hyperactivity, irritability and mood disorders. No significant differences were observed in age, weight or sex distributions between the groups. Similarly, ETI AUCs, Cmax and Ctrough showed no statistical differences between children exhibiting abnormal behavior and those who did not.

Conclusion

To our knowledge, this is the first study assessing ETI plasma exposure in relation to behavioral issues in chCF aged 2–5 years. Overall, our findings do not indicate that these side effects are associated with increased exposure.

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来源期刊

Journal of Cystic Fibrosis 医学-呼吸系统

CiteScore

10.10

自引率

13.50%

发文量

1361

审稿时长

50 days

期刊介绍： The Journal of Cystic Fibrosis is the official journal of the European Cystic Fibrosis Society. The journal is devoted to promoting the research and treatment of cystic fibrosis. To this end the journal publishes original scientific articles, editorials, case reports, short communications and other information relevant to cystic fibrosis. The journal also publishes news and articles concerning the activities and policies of the ECFS as well as those of other societies related the ECFS.