title: Correlation of sweat chloride and percent predicted FEV1in cystic fibrosis patients treated with ivacaftor.
abstract: Ivacaftor, a CFTR potentiator that enhances chloride transport by acting directly on CFTR to increase its channel gating activity, has been evaluated in patients with different CFTR mutations. Several previous analyses have reported no statistical correlation between change from baseline in ppFEV1and reduction in sweat chloride levels for individuals treated with ivacaftor. The objective of the post hoc analysis described here was to expand upon previous analyses and evaluate the correlation between sweat chloride levels and absolute ppFEV1changes across multiple cohorts of patients with different CF-causing mutations who were treated with ivacaftor. The goal of the analysis was to help define the potential value of sweat chloride as a pharmacodynamic biomarker for use in CFTR modulator trials. For any given study, reductions in sweat chloride levels and improvements in absolute ppFEV1were not correlated for individual patients. However, when the data from all studies were combined, a statistically significant correlation between sweat chloride levels and ppFEV1changes was observed (p<0.0001). Thus, sweat chloride level changes in response to potentiation of the CFTR protein by ivacaftor appear to be a predictive pharmacodynamic biomarker of lung function changes on a population basis but are unsuitable for the prediction of treatment benefits for individuals.
authors: Vertex Pharmaceuticals LLC, 11010 Torreyanna Road, San Diego, CA 92121,USA. Electronic address: Meredith_fidler@vrtx.com.
authors: Meredith C
authors: MC
authors: Fidler
authors: Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston, MA 02210, USA.
authors: Jack
authors: J
authors: Beusmans
authors: Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston, MA 02210, USA.
authors: Paul
authors: P
authors: Panorchan
authors: Vertex Pharmaceuticals LLC, 11010 Torreyanna Road, San Diego, CA 92121,USA.
authors: Fredrick
authors: F
authors: Van Goor
mesh_terms: D000627:Aminophenols / Q000008:administration & dosage / Q000493:pharmacokinetics; D015415:Biomarkers / Q000032:analysis; D065101:Chloride Channel Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D002712:Chlorides / Q000032:analysis*; D002986:Clinical Trials as Topic; D003550:Cystic Fibrosis / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005541:Forced Expiratory Volume / Q000187:drug effects*; D006801:Humans; D009154:Mutation; D011237:Predictive Value of Tests; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics; D013542:Sweat / Q000737:chemistry*; D016896:Treatment Outcome
chemical_list: D000627:Aminophenols; D015415:Biomarkers; D065101:Chloride Channel Agonists; D002712:Chlorides; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor
keywords: Cystic fibrosis; FEV(1); Ivacaftor; Sweat chloride