Association between biomarkers of tobacco smoke exposure and clinical efficacy of ivacaftor in the G551D observational trial (GOAL).
J Cyst Fibros
; 23(5): 959-966, 2024 Sep.
Article
in En
| MEDLINE
| ID: mdl-39033068
ABSTRACT
BACKGROUND:
Acrolein, an aldehyde in smoke from tobacco products, inhibits CFTR function in vitro. Ivacaftor is an FDA-approved potentiator that improves mutant CFTR function. This human clinical study investigated the relationship between two urinary markers of tobacco smoke exposure - the acrolein metabolite 3-HPMA and the nicotine metabolite NNAL - and sweat chloride response to ivacaftor in the G551D Observational Trial (GOAL).METHODS:
3-HPMA (low <50th centile; moderate 50-75th centile; high >75th centile) and NNAL (detectable/undetectable) in GOAL samples was quantified with LC-MS/MS. Self-report of tobacco smoke exposure (Y/N) served as a subjective measure. Change in sweat chloride from pre- to 6 months post-ivacaftor treatment (ΔSC) was the primary CFTR-dependent readout.RESULTS:
The sample included 151 individuals, mean age 20.7 (SD 11.4) years, range 6-59 years. Smoke exposure prevalence was 15 % per self-reports but 27 % based on detectable NNAL. 3-HPMA was increased in those reporting tobacco smoke exposure (607 vs 354 ng/ml, p = 0.008), with a higher proportion of smoke-exposed in the high- vs low-acrolein group (31 % vs 9 %, p=0.040). Compared to low-acrolein counterparts, high-acrolein participants experienced less decrease in sweat chloride (-35.2 vs -48.2 mmol/L; p = 0.020) and had higher sweat chloride values (50.6 vs 37.6 mmol/L; p = 0.020) 6 months post-ivacaftor. The odds of ivacaftor-mediated potentiation to near normative CFTR function (defined as SC6mo <40 mmol/L) was more than twice as high in the low-acrolein cohort (OR 2.51, p = 0.026).CONCLUSIONS:
Increased urinary 3-HPMA, an acrolein metabolite of tobacco smoke, is associated with a diminished sweat chloride response to ivacaftor potentiation of CFTR function.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Sweat
/
Biomarkers
/
Quinolones
/
Cystic Fibrosis Transmembrane Conductance Regulator
/
Cystic Fibrosis
/
Chloride Channel Agonists
/
Aminophenols
Limits:
Adolescent
/
Adult
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Child
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
J Cyst Fibros
/
J. cyst. fibros
/
Journal of cystic fibrosis
Year:
2024
Type:
Article