Document Detail


Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience.
MedLine Citation:
PMID:  23276841     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cystic fibrosis (CF) is a life-shortening inherited disease caused by mutations in the CF transmembrane conductance regulator gene (CFTR), which encodes for the CF transmembrane conductance regulator (CFTR) ion channel that regulates chloride and water transport across the surface of epithelial cells. Ivacaftor, a drug recently approved by the US Food and Drug Administration, represents the first mutation-specific therapy for CF. It is a CFTR channel modulator and improves CFTR function in patients with CF who have a G551D mutation. A clinical trial performed to support ivacaftor dose selection demonstrated a dose-response relationship between improvement in FEV(1) and decrease in sweat chloride, a measure of CFTR function. Validation of such a relationship between FEV(1) and sweat chloride would facilitate development of new drugs that target the defective CFTR. Subsequently, in phase 3 studies, ivacaftor 150 mg bid resulted in significant improvements in FEV(1) (10%-12%) and reduction in sweat chloride (approximately 50 mmol/L). However, a decrease in sweat chloride did not correlate with improvement in FEV(1), nor did there appear to be a threshold level for change in sweat chloride above which an improvement in FEV(1) was apparent. The lack of correlation of sweat chloride with improvement in FEV(1) speaks to the multiplicity of factors, physiologic, environmental, and genetic, that likely modulate CF disease severity. Future clinical trials of drugs that are directed to the defective CFTR will need take into account the uncertainty of using even established measurements, such as sweat chloride, as clinical end points.
Authors:
Anthony G Durmowicz; Kimberly A Witzmann; Curtis J Rosebraugh; Badrul A Chowdhury
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Chest     Volume:  143     ISSN:  1931-3543     ISO Abbreviation:  Chest     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-01     Completed Date:  2013-04-02     Revised Date:  2013-12-24    
Medline Journal Info:
Nlm Unique ID:  0231335     Medline TA:  Chest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  14-8     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Aminophenols / therapeutic use*
Chlorides / analysis*
Clinical Trials as Topic
Cystic Fibrosis / drug therapy*,  genetics,  physiopathology
Cystic Fibrosis Transmembrane Conductance Regulator / genetics
Dose-Response Relationship, Drug
Forced Expiratory Volume / drug effects
Humans
Outcome Assessment (Health Care) / methods*
Quinolones / therapeutic use*
Sweat / chemistry*,  drug effects
Treatment Outcome
Chemical
Reg. No./Substance:
0/Aminophenols; 0/CFTR protein, human; 0/Chlorides; 0/N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide; 0/Quinolones; 126880-72-6/Cystic Fibrosis Transmembrane Conductance Regulator
Comments/Corrections
Comment In:
Chest. 2013 Oct;144(4):1418   [PMID:  24081360 ]
Chest. 2013 Oct;144(4):1418-9   [PMID:  24081359 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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