囊性纤维化儿科患者的 Lumacaftor/Ivacaftor 群体药代动力学:迈向个性化治疗的第一步。

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Clinical Pharmacokinetics Pub Date : 2024-03-01 Epub Date: 2024-02-04 DOI:10.1007/s40262-023-01342-3
Naïm Bouazza, Saïk Urien, Frantz Foissac, Laure Choupeaux, Gabrielle Lui, Léo Froelicher Bournaud, Steeve Rouillon, Yi Zheng, Emmanuelle Bardin, Nathalie Stremler, Katia Bessaci, Tiphaine Bihouee, Emmanuelle Coirier-Duet, Christophe Marguet, Eric Deneuville, Muriel Laurans, Philippe Reix, Michèle Gerardin, Marie Mittaine, Ralph Epaud, Caroline Thumerelle, Laurence Weiss, Romain Berthaud, Michaela Semeraro, Jean-Marc Treluyer, Sihem Benaboud, Isabelle Sermet-Gaudelus
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引用次数: 0

摘要

背景:CFTR调节剂在囊性纤维化(CF)治疗方面取得了重大突破AQ1。Lumacaftor/ivacaftor组合适用于治疗6岁以上儿童患者的CF。在这些脆弱的儿科人群中对 lumacaftor/ivacaftor 进行药代动力学(PK)研究对于优化治疗方案至关重要:本研究的目的是描述 CF 儿童中鲁马卡夫托和伊伐卡夫托的群体 PK (PPK),并确定与个体间变异相关的因素。研究还探讨了药物暴露与临床反应之间的关联:共有75名儿童参与了这项PPK研究,每种化合物和已知代谢物(仑马卡夫托、伊伐卡夫托、伊伐卡夫托-M1和伊伐卡夫托-M6)的浓度为191。PPK 分析使用 Monolix 软件进行。观察到个体间差异较大。患者体重和肝功能(天门冬氨酸氨基转移酶)是患者间变异性的主要来源。治疗48周后,第一秒用力呼气容积(FEV1)与伊伐卡夫托的暴露水平存在统计学关联:本研究是首次分析lumacaftor/ivacaftor PPK在CF患儿中的应用。这些数据表明,在确定变异因素后需要调整剂量,以优化疗效。使用治疗药物监测作为 CF 儿童剂量调整的依据可能会有所帮助。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Lumacaftor/Ivacaftor Population Pharmacokinetics in Pediatric Patients with Cystic Fibrosis: A First Step Toward Personalized Therapy.

Lumacaftor/Ivacaftor Population Pharmacokinetics in Pediatric Patients with Cystic Fibrosis: A First Step Toward Personalized Therapy.

Background: A major breakthrough in cystic fibrosis (CF) therapy was achievedAQ1 with CFTR modulators. The lumacaftor/ivacaftor combination is indicated for the treatment of CF in pediatric patients above 6 years old. Pharmacokinetic (PK) studies of lumacaftor/ivacaftor in these vulnerable pediatric populations are AQ2crucial to optimize treatment protocols.

Objectives and methods: The objectives of this study were to describe the population PK (PPK) of lumacaftor and ivacaftor in children with CF, and to identify factors associated with interindividual variability. The association between drug exposure and clinical response was also investigated.

Results: A total of 75 children were included in this PPK study, with 191 concentrations available for each compound and known metabolites (lumacaftor, ivacaftor, ivacaftor-M1, and ivacaftor-M6). PPK analysis was performed using Monolix software. A large interindividual variability was observed. The main sources of interpatient variability identified were patient bodyweight and hepatic function (aspartate aminotransferase). Forced expiratory volume in the first second (FEV1) was statistically associated with the level of exposure to ivacaftor after 48 weeks of treatment.

Conclusions: This study is the first analysis of lumacaftor/ivacaftor PPK in children with CF. These data suggest that dose adjustment is required after identifying variability factors to optimize efficacy. The use of therapeutic drug monitoring as a basis for dose adjustment in children with CF may be useful.

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来源期刊
CiteScore
8.80
自引率
4.40%
发文量
86
审稿时长
6-12 weeks
期刊介绍: Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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