학술논문
Lumacaftor/Ivacaftor Population Pharmacokinetics in Pediatric Patients with Cystic Fibrosis: A First Step Toward Personalized Therapy
Document Type
Original Paper
Author
Bouazza, Naïm; Urien, Saïk; Foissac, Frantz; Choupeaux, Laure; Lui, Gabrielle; Froelicher Bournaud, Léo; Rouillon, Steeve; Zheng, Yi; Bardin, Emmanuelle; Stremler, Nathalie; Bessaci, Katia; Bihouee, Tiphaine; Coirier-Duet, Emmanuelle; Marguet, Christophe; Deneuville, Eric; Laurans, Muriel; Reix, Philippe; Gerardin, Michèle; Mittaine, Marie; Epaud, Ralph; Thumerelle, Caroline; Weiss, Laurence; Berthaud, Romain; Semeraro, Michaela; Treluyer, Jean-Marc; Benaboud, Sihem; Sermet-Gaudelus, Isabelle
Source
Clinical Pharmacokinetics. 63(3):333-342
Subject
Language
English
ISSN
0312-5963
1179-1926
1179-1926
Abstract
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.