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

Am J Respir Crit Care Med. 2014 Jul 15;190(2):175-84. doi: 10.1164/rccm.201404-0703OC.

Abstract

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.

Keywords: CFTR modulator; Pseudomonas aeruginosa; cystic fibrosis; ivacaftor; pH.

Publication types

  • Multicenter Study
  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aminophenols / pharmacology*
  • Aminophenols / therapeutic use
  • Biomarkers / metabolism
  • Child
  • Cystic Fibrosis / drug therapy*
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis / microbiology
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Female
  • Follow-Up Studies
  • Forced Expiratory Volume / drug effects
  • Genetic Markers
  • Hospitalization / statistics & numerical data
  • Humans
  • Hydrogen-Ion Concentration / drug effects
  • Intestine, Small / drug effects*
  • Intestine, Small / metabolism
  • Lung / drug effects*
  • Lung / metabolism
  • Lung / microbiology
  • Lung / physiopathology
  • Male
  • Microbiota / drug effects
  • Mucociliary Clearance / drug effects
  • Mutation
  • Pseudomonas Infections / complications
  • Pseudomonas Infections / diagnosis
  • Pseudomonas Infections / prevention & control
  • Pseudomonas aeruginosa / isolation & purification
  • Quinolones / pharmacology*
  • Quinolones / therapeutic use
  • Respiratory System Agents / pharmacology*
  • Respiratory System Agents / therapeutic use
  • Sputum / metabolism
  • Sputum / microbiology
  • Sweat / drug effects
  • Sweat / metabolism
  • Treatment Outcome
  • Young Adult

Substances

  • Aminophenols
  • Biomarkers
  • Genetic Markers
  • Quinolones
  • Respiratory System Agents
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • ivacaftor