| Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience. | |
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MedLine Citation:
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PMID: 23276841 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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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 FEV1 and decrease in sweat chloride, a measure of CFTR function. Validation of such a relationship between FEV1 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 FEV1 (10%-12%) and reduction in sweat chloride (approximately 50 mmol/L). However, a decrease in sweat chloride did not correlate with improvement in FEV1, nor did there appear to be a threshold level for change in sweat chloride above which an improvement in FEV1 was apparent. The lack of correlation of sweat chloride with improvement in FEV1 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. |
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Authors:
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Anthony G Durmowicz; Kimberly A Witzmann; Curtis J Rosebraugh; Badrul A Chowdhury |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Chest Volume: 143 ISSN: 1931-3543 ISO Abbreviation: Chest Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-01-01 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0231335 Medline TA: Chest Country: United States |
Other Details:
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Languages: eng Pagination: 14-8 Citation Subset: AIM; IM |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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