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

期刊论文
发表日期：

2024年2月4日

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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

摘要

Background

A major breakthrough in cystic fibrosis (CF) therapy was achievedAQ1 with CFTR modulators. Thelumacaftor/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 tooptimize treatment protocols.

Objectives and Methods

The objectives of this study were to describe the population PK (PPK) of lumacaftor andivacaftor in children with CF, and to identify factors associated with interindividual variability. The associationbetween 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 eachcompound and known metabolites (lumacaftor, ivacaftor, ivacaftor-M1, and ivacaftor-M6). PPK analysis wasperformed using Monolix software. A large interindividual variability was observed. The main sources of interpatientvariability identified were patient bodyweight and hepatic function (aspartate aminotransferase). Forced expiratoryvolume in the first second (FEV1) was statistically associated with the level of exposure to ivacaftor after 48 weeksof treatment.

Conclusions

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