Academic Journal
Lumacaftor-Ivacaftor in Pediatric Patients With Cystic Fibrosis and Advanced Liver Disease: A Pilot Study.
| Τίτλος: | Lumacaftor-Ivacaftor in Pediatric Patients With Cystic Fibrosis and Advanced Liver Disease: A Pilot Study. |
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| Συγγραφείς: | Lim AYL; Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, Brisbane, Queensland, Australia; University of Queensland Centre for Clinical Research, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland, Brisbane, Queensland, Australia. Electronic address: adeline.lim@health.qld.gov.au., Hernández-Mitre MP; University of Queensland Centre for Clinical Research, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland, Brisbane, Queensland, Australia., Lewindon PJ; Department of Gastroenterology, Queensland Children's Hospital, Brisbane, Queensland, Australia., Roberts JA; University of Queensland Centre for Clinical Research, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland, Brisbane, Queensland, Australia; Departments of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; Herston Infectious Diseases Institute (HeIDI), Metro North Health, Brisbane, Queensland, Australia; UR UM 103, University of Montpellier, Division of Anesthesia Critical Care and Emergency and Pain Medicine, Nimes University Hospital, Nimes, France., Schneider-Futschik EK; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia., Wainwright CE; Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, Brisbane, Queensland, Australia; University of Queensland Centre for Clinical Research, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland, Brisbane, Queensland, Australia. |
| Πηγή: | Clinical therapeutics [Clin Ther] 2026 Jun; Vol. 48 (6), pp. 534-538. Date of Electronic Publication: 2026 Apr 23. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Excerpta Medica Country of Publication: United States NLM ID: 7706726 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-114X (Electronic) Linking ISSN: 01492918 NLM ISO Abbreviation: Clin Ther Subsets: MEDLINE |
| Imprint Name(s): | Publication: 1998- : Belle Mead, NJ, : Excerpta Medica Original Publication: Princeton, N. J., Excerpta Medica. |
| Ιατρικοί όροι (MeSH): | Cystic Fibrosis*/drug therapy , Cystic Fibrosis*/complications , Aminophenols*/pharmacokinetics , Aminophenols*/therapeutic use , Aminophenols*/adverse effects , Aminophenols*/administration & dosage , Benzodioxoles*/pharmacokinetics , Benzodioxoles*/therapeutic use , Benzodioxoles*/adverse effects , Benzodioxoles*/administration & dosage , Quinolones*/pharmacokinetics , Quinolones*/therapeutic use , Quinolones*/adverse effects , Quinolones*/administration & dosage , Aminopyridines*/pharmacokinetics , Aminopyridines*/therapeutic use , Aminopyridines*/adverse effects , Aminopyridines*/administration & dosage , Liver Diseases*/drug therapy , Liver Diseases*/etiology, Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Humans ; Child ; Pilot Projects ; Adolescent ; Male ; Female ; Drug Combinations ; Child, Preschool ; Liver Function Tests |
| Περίληψη: | Purpose: Lumacaftor-ivacaftor (LI) is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator for patients with cystic fibrosis homozygous for the F508del-CFTR variant. All CFTR modulators, including LI, are metabolized in the liver, and their use in advanced cystic fibrosis-related liver disease (ACFRLD) is not recommended due to concerns of worsening liver impairment, despite potential benefits for nutrition and lung function. Methods: A pilot study was conducted at the Queensland Children's Hospital, Australia, to describe the pharmacokinetics of LI and its metabolites (ivacaftor-M1 and ivacaftor-M6) in pediatric patients with ACFRLD. Three patients aged 4, 10, and 18 years with ACFRLD received 2 weeks of half-dose LI followed by 2 weeks of full-dose LI with weekly liver function monitoring and pharmacokinetic sampling on week 2 and 4. Stool samples were also obtained. A single stool sample was obtained from 28 children taking LI without ACFRLD as a control group. Findings: Liver function remained stable for patients with ACFRLD, although one patient developed hyperammonemia at week 3 and ceased LI with resolution of hyperammonemia. In patients with ACFRLD, plasma concentrations of ivacaftor and lumacaftor were decreased, whereas M1 and M6 were elevated compared with reported values. Stool concentrations of ivacaftor were increased, lumacaftor and M1 decreased, and M6 variable compared with controls. Implications: These findings suggest reduced ivacaftor absorption and impaired biliary excretion in ACFRLD, contributing to elevated M1, M6, and decreased lumacaftor concentrations. Pharmacokinetic variability in ACFRLD highlights the potential role of individualized profiling to support safe and effective CFTR modulator treatment in this population. Queensland Children's Hospital Human Research and Ethics Committee (HREC/19/QCHQ/53788); Australian New Zealand Clinical Trials Registry (ACTRN12619001347156). (Copyright © 2026 Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of competing interest Claire E. Wainwright reports grants from the Cystic Fibrosis Foundation and the Medical Research Future Fund outside of the submitted work, is on the Advisory Board and is clinical trial investigator for Vertex Pharmaceuticals, and is clinical trial investigator and consultant for Spexis and Respirion Pharma. The authors have indicated that they have no other conflicts of interest regarding the content of this article. |
| Contributed Indexing: | Keywords: Advanced cystic fibrosis–related liver disease; Cystic fibrosis; Ivacaftor; Lumacaftor; Orkambi; Pharmacokinetics |
| Substance Nomenclature: | 0 (Aminophenols) 0 (Benzodioxoles) 0 (Quinolones) 0 (Aminopyridines) 0 (lumacaftor, ivacaftor drug combination) 0 (Drug Combinations) 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator) |
| Entry Date(s): | Date Created: 20260424 Date Completed: 20260715 Latest Revision: 20260715 |
| Update Code: | 20260716 |
| DOI: | 10.1016/j.clinthera.2026.03.022 |
| PMID: | 42031572 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1879-114X |
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| DOI: | 10.1016/j.clinthera.2026.03.022 |