Optimizing nasal potential difference analysis for CFTR modulator development: assessment of ivacaftor in CF subjects with the G551D-CFTR mutation.
Nasal potential difference (NPD) is used as a biomarker of the cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC) activity. We evaluated methods to detect changes in chloride and sodium transport by NPD based on a secondary analysis of a Phase II CFTR-modulator study. Thirty-nine subjects with CF who also had the G551D-CFTR mutation were randomized to receive ivacaftor (Kalydeco™; also known as VX-770) in four doses or placebo twice daily for at least 14 days. All data were analyzed by a single investigator who was blinded to treatment assignment. We compared three analysis methods to determine the best approach to quantify changes in chloride and sodium transport: (1) the average of both nostrils; (2) the most-polarized nostril at each visit; and (3) the most-polarized nostril at screening carried forward. Parameters of ion transport included the PD change with zero chloride plus isoproterenol (CFTR activity), the basal PD, Ringer's PD, and change in PD with amiloride (measurements of ENaC activity), and the delta NPD (measuring CFTR and ENaC activity). The average and most-polarized nostril at each visit were most sensitive to changes in chloride and sodium transport, whereas the most-polarized nostril at screening carried forward was less discriminatory. Based on our findings, NPD studies should assess both nostrils rather than a single nostril. We also found that changes in CFTR activity were more readily detected than changes in ENaC activity, and that rigorous standardization was associated with relatively good within-subject reproducibility in placebo-treated subjects (± 2.8 mV). Therefore, we have confirmed an assay of reasonable reproducibility for detecting chloride-transport improvements in response to CFTR modulation.
University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Steven M
SM
Rowe
Bo
B
Liu
Aubrey
A
Hill
Heather
H
Hathorne
Morty
M
Cohen
John R
JR
Beamer
Frank J
FJ
Accurso
Qunming
Q
Dong
Claudia L
CL
Ordoñez
Anne J
AJ
Stone
Eric R
ER
Olson
John P
JP
Clancy
D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D000627:Aminophenols / Q000009:adverse effects / Q000627:therapeutic use*; D001692:Biological Transport / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D003710:Demography; D053503:Epithelial Sodium Channels / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009666:Nose / Q000187:drug effects / Q000503:physiopathology*; D010919:Placebos; D015363:Quinolones / Q000009:adverse effects / Q000627:therapeutic use*; D018401:Sample Size; D012964:Sodium / Q000378:metabolism; D012996:Solutions; D055815:Young Adult
D000627:Aminophenols; D002712:Chlorides; D053503:Epithelial Sodium Channels; D010919:Placebos; D015363:Quinolones; D012996:Solutions; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor; D012964:Sodium