title: Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis.
abstract: BACKGROUND
  Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation.
  
  
  OBJECTIVE
  To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers.
  
  
  METHODS
  We conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, β-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P < 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m(2); P < 0.001). Sweat chloride decreased from baseline to 6 months (mean change, -53.8 mmol/L; 95% confidence interval, -57.7 to -49.9; P < 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P < 0.001) and Pseudomonas aeruginosa burden (P < 0.01). Significant improvements in mucociliary clearance (P < 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor.
  
  
  CONCLUSIONS
  Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology.
authors.affiliation: 1 Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rowe
authors.forename: Sonya L
authors.initials: SL
authors.lastname: Heltshe
authors.forename: Tanja
authors.initials: T
authors.lastname: Gonska
authors.forename: Scott H
authors.initials: SH
authors.lastname: Donaldson
authors.forename: Drucy
authors.initials: D
authors.lastname: Borowitz
authors.forename: Daniel
authors.initials: D
authors.lastname: Gelfond
authors.forename: Scott D
authors.initials: SD
authors.lastname: Sagel
authors.forename: Umer
authors.initials: U
authors.lastname: Khan
authors.forename: Nicole
authors.initials: N
authors.lastname: Mayer-Hamblett
authors.forename: Jill M
authors.initials: JM
authors.lastname: Van Dalfsen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Joseloff
authors.forename: Bonnie W
authors.initials: BW
authors.lastname: Ramsey
mesh_terms: D000293:Adolescent; D000328:Adult; D000627:Aminophenols / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D002648:Child; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005541:Forced Expiratory Volume / Q000187:drug effects; D005819:Genetic Markers; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology / Q000503:physiopathology; D008297:Male; D064307:Microbiota / Q000187:drug effects; D009079:Mucociliary Clearance / Q000187:drug effects; D009154:Mutation; D011552:Pseudomonas Infections / Q000150:complications / Q000175:diagnosis / Q000517:prevention & control; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification; D015363:Quinolones / Q000494:pharmacology* / Q000627:therapeutic use; D019141:Respiratory System Agents / Q000494:pharmacology* / Q000627:therapeutic use; D013183:Sputum / Q000378:metabolism / Q000382:microbiology; D013542:Sweat / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000627:Aminophenols; D015415:Biomarkers; D005819:Genetic Markers; D015363:Quinolones; D019141:Respiratory System Agents; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor
keywords: CFTR modulator; Pseudomonas aeruginosa; cystic fibrosis; ivacaftor; pH