Predictors of lung function response in adults with cystic fibrosis: the contribution of nasal elexacaftor, tezacaftor, and ivacaftor measurement

Background Highly effective CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor has transformed cystic fibrosis care, yet individuals receiving identical doses continue to show substantial variability in clinical response. Whether this variability reflects differences in systemic exposure alone or differences in airway drug levels remains unclear. This study examined whether ETI concentrations obtained from nasal airway swabs reflect clinical status more accurately than systemic measurements. Methods Forty clinically stable adults with CF receiving standard ETI therapy were enrolled. ETI concentrations were quantified in dried blood spots, plasma-equivalent values and nasal airway swab samples using a validated multimatrix LC–MS/MS approach. Spirometry and sweat chloride were measured at the same visit. Associations between ETI exposure and clinical parameters were assessed, and logistic regression was used to identify predictors of an improvement in FEV₁ >5%. Results Drug concentrations varied widely across all matrices. Nasal airway swabs showed the greatest inter-individual variability and were the only matrix in which higher elexacaftor and tezacaftor concentrations, with a similar trend for ivacaftor, were correlated with higher FEV₁ following ETI treatment. Systemic ETI concentrations showed no consistent relationships with lung function, sweat chloride or BMI. In logistic regression, nasal tezacaftor concentration independently classified good responder individuals who experienced an improvement in FEV₁ of more than 5%. Conclusions Despite uniform dosing, ETI exposure varies markedly between individuals. Nasal airway concentrations, but not systemic levels, reflect differences in lung function and may capture clinically meaningful variability in CFTR modulator exposure. Airway-based assessment can therefore complement systemic monitoring in efforts toward individualized treatment strategies.