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
{"title":"Lumacaftor/Ivacaftor Population Pharmacokinetics in Pediatric Patients with Cystic Fibrosis: A First Step Toward Personalized Therapy.","authors":"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","doi":"10.1007/s40262-023-01342-3","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objectives and methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"333-342"},"PeriodicalIF":4.6000,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Pharmacokinetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s40262-023-01342-3","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/2/4 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
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.