Academic Journal
Impact of CFTR modulator concentrations on clinical response in cystic fibrosis.
| Τίτλος: | Impact of CFTR modulator concentrations on clinical response in cystic fibrosis. |
|---|---|
| Συγγραφείς: | Chalamalla AR; Arkansas Children's Research Institute, Little Rock, AR, USA., Baker E; University of Alabama at Birmingham, Birmingham, AL, USA., Ryan KJ; University of Alabama at Birmingham, Birmingham, AL, USA., Dowell A; University of Alabama at Birmingham, Birmingham, AL, USA., Natt JR; University of Alabama at Birmingham, Birmingham, AL, USA., Zemanick ET; University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Konstan MW; Case Western Reserve University, Cleveland, OH, USA., Mayer-Hamblett N; Seattle Children's Hospital, Seattle, WA, USA.; University of Washington, Seattle, WA, USA., Acosta EP; University of Alabama at Birmingham, Birmingham, AL, USA., Guimbellot JS; Arkansas Children's Research Institute, Little Rock, AR, USA jguimbellot@uams.edu.; University of Arkansas Medical Center, Little Rock, AR, USA. |
| Συλλογικό Έργο: | CHEC-SC investigators |
| Πηγή: | The European respiratory journal [Eur Respir J] 2026 Jun 12; Vol. 67 (6). Date of Electronic Publication: 2026 Jun 12 (Print Publication: 2026). |
| Τύπος έκδοσης: | Journal Article; Multicenter Study; Observational Study |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: European Respiratory Society Country of Publication: England NLM ID: 8803460 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1399-3003 (Electronic) Linking ISSN: 09031936 NLM ISO Abbreviation: Eur Respir J Subsets: MEDLINE |
| Imprint Name(s): | Publication: Sheffield, United Kingdom : European Respiratory Society Original Publication: Copenhagen : Published jointly by the Society and Munksgaard, 1988- |
| Ιατρικοί όροι (MeSH): | Aminophenols*/therapeutic use , Aminophenols*/blood , Aminophenols*/administration & dosage , Benzodioxoles*/therapeutic use , Benzodioxoles*/blood , Benzodioxoles*/administration & dosage , Benzodioxoles*/pharmacokinetics , Cystic Fibrosis*/drug therapy , Cystic Fibrosis*/genetics , Cystic Fibrosis*/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator*/genetics , Cystic Fibrosis Transmembrane Conductance Regulator*/metabolism , Indoles*/therapeutic use , Indoles*/blood , Indoles*/administration & dosage , Indoles*/pharmacokinetics , Quinolones*/therapeutic use , Quinolones*/blood , Quinolones*/administration & dosage , Quinolones*/pharmacokinetics , Quinuclidines*/therapeutic use , Quinuclidines*/blood , Quinuclidines*/administration & dosage , Quinuclidines*/pharmacokinetics, Chlorides/metabolism ; Chlorides/analysis ; Cytochrome P-450 CYP3A/genetics ; Pyrazoles/therapeutic use ; Pyrazoles/blood ; Pyrazoles/administration & dosage ; Pyridines/therapeutic use ; Pyridines/blood ; Pyrrolidines/therapeutic use ; Pyrrolidines/blood ; Sweat/chemistry ; Adolescent ; Adult ; Child ; Female ; Humans ; Male ; Young Adult ; Genotype ; Treatment Outcome ; Drug Combinations ; Quinolines |
| Περίληψη: | Rationale: Cystic fibrosis (CF) is caused by variants in the CF transmembrane conductance regulator (CFTR), leading to defective chloride ion transport and multiorgan dysfunction. CFTR modulators substantially improve chloride ion transport and disease severity, but responses vary, which may in part be due to variation in drug concentrations. Objectives: This study aimed to evaluate modulator concentrations among people with CF and the potential impact of cytochrome P450 (CYP)3A5 genotypes on sweat chloride. Methods: This multicentre study enrolled 97 children and adult participants established on elexacaftor/tezacaftor/ivacaftor (ETI) therapy. ETI drug concentrations were quantified and CYP3A5 genotypes were determined. Relationship between drug concentrations, genotype, and sweat chloride response were investigated using correlation and multivariable regression models to examine associations between drug levels and sweat chloride. Measurements and Main Results: Plasma concentrations of elexacaftor, tezacaftor and ivacaftor were highly variable. Analyses revealed that CYP3A5 genotype status had no significant effect on drug concentrations. Association analysis demonstrated an association of sweat chloride with drug concentrations including after adjusting for pre-modulator sweat chloride, age, race, body mass index and sex, showing that lower drug concentrations are associated with worse outcomes in sweat chloride. Conclusion: This study provides evidence that lower drug concentration are associated with worse sweat chloride levels and may be a potential indicator of therapeutic effectiveness, especially for people with high sweat chloride despite treatment. The influence of drug variability underscores the need for personalised dosing strategies to improve CF treatment outcome, although well-known CYP3A5 genotypes are unlikely to be helpful. (Copyright ©The authors 2026. For reproduction rights and permissions contact permissions@ersnet.org.) |
| Competing Interests: | Conflict of interest: E. Baker reports grants from the Cystic Fibrosis Foundation and National Institutes of Health, and support for attending meetings from the Cystic Fibrosis Foundation. E.T. Zemanick reports support for the present study from the Cystic Fibrosis Foundation, grants from the NIH/NHLBI, Vertex Pharmaceuticals and the Cystic Fibrosis Foundation, consultancy fees from Vertex Pharmaceuticals, the Cystic Fibrosis Foundation and Boehringer Ingelheim, payment or honoraria for lectures, presentations, manuscript writing or educational events from the Cystic Fibrosis Foundation and the Association for Diagnostic and Laboratory Medicine, support for attending meetings from CF Therapeutics Development Network, European Cystic Fibrosis Society and the Cystic Fibrosis Foundation, and participation on a data safety monitoring board or advisory board with the Cystic Fibrosis Foundation, CFF Therapeutics Development Network and Vertex Pharmaceuticals. M.W. Konstan reports support for the present study from the Cystic Fibrosis Foundation, grants from the National Institutes of Health, consultancy fees from Vertex Pharmaceuticals and Sionna Therapeutics, participation on a data safety monitoring board or advisory board with Vertex Pharmaceuticals and Sionna Therapeutics, and a leadership role with the Cystic Fibrosis Foundation. N. Mayer-Hamblett reports support for the present study from the National Institutes of Health, grants from the Cystic Fibrosis Foundation and National Institutes of Health, consultancy fees from Vertex Pharmaceuticals and is Executive Director of the CF Therapeutics Development Network Coordinating Center. J.S. Guimbellot reports support for the present study from the Cystic Fibrosis Foundation, grants from the Cystic Fibrosis Foundation and National Institutes of Health, consultancy fees from Vertex Pharmaceuticals, and support for attending meetings from the Cystic Fibrosis Foundation and the American Thoracic Society. The remaining authors have no potential conflicts of interest to disclose. |
| Σχόλια: | Comment in: Eur Respir J. 2026 Jun 12;67(6):2600247. doi: 10.1183/13993003.00247-2026.. (PMID: 42285738) |
| Grant Information: | K23 HL143167 United States HL NHLBI NIH HHS; R01 HL171034 United States HL NHLBI NIH HHS |
| Substance Nomenclature: | 0 (Aminophenols) 0 (Benzodioxoles) 0 (CFTR protein, human) 0 (Chlorides) EC 1.14.14.1 (CYP3A5 protein, human) 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator) EC 1.14.14.1 (Cytochrome P-450 CYP3A) 0 (elexacaftor, ivacaftor, tezacaftor drug combination) 0 (Indoles) 1Y740ILL1Z (ivacaftor) 0 (Pyrazoles) 0 (Pyridines) 0 (Pyrrolidines) 0 (Quinolones) 0 (Quinuclidines) 8RW88Y506K (tezacaftor) 0 (tezacaftor, ivacaftor drug combination) 0 (Drug Combinations) 0 (Quinolines) |
| Entry Date(s): | Date Created: 20260219 Date Completed: 20260613 Latest Revision: 20260706 |
| Update Code: | 20260707 |
| PubMed Central ID: | PMC13086501 |
| DOI: | 10.1183/13993003.01594-2025 |
| PMID: | 41713946 |
| Βάση Δεδομένων: | MEDLINE |
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