Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis.

Academic Article


  • RATIONALE: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation. OBJECTIVES: 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


  • CFTR modulator, Pseudomonas aeruginosa, cystic fibrosis, ivacaftor, pH, Adolescent, Adult, Aminophenols, Biomarkers, Child, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Female, Follow-Up Studies, Forced Expiratory Volume, Genetic Markers, Hospitalization, Humans, Hydrogen-Ion Concentration, Intestine, Small, Lung, Male, Microbiota, Mucociliary Clearance, Mutation, Pseudomonas Infections, Pseudomonas aeruginosa, Quinolones, Respiratory System Agents, Sputum, Sweat, Treatment Outcome, Young Adult
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    Author List

  • Rowe SM; Heltshe SL; Gonska T; Donaldson SH; Borowitz D; Gelfond D; Sagel SD; Khan U; Mayer-Hamblett N; Van Dalfsen JM
  • Start Page

  • 175
  • End Page

  • 184
  • Volume

  • 190
  • Issue

  • 2