Impact of CFTR Modulator Concentrations on Clinical Response in Cystic Fibrosis

Rationale Cystic fibrosis is caused by variants in the CF transmembrane conductance regulator ( CFTR ), leading to defective chloride ion transport and multi-organ dysfunction. CFTR modulators substantially improve chloride ion transport and disease severity, but responses vary, which may in part be due to variation in drug concentrations. Objectives This study aimed to evaluate modulator concentrations among people with CF and the potential impact of cytochrome P450 (CYP) 3A5 genotypes on sweat chloride. Methods This multicenter study enrolled 97 children and adult participants established on elexacaftor/tezacaftor/ivacaftor (ETI) therapy. ETI drug concentrations were quantified and CYP3A5 genotypes were determined. Relationship between drug concentrations, genotype, and sweat chloride response were investigated using correlation and multivariable regression models to examine associations between drug levels and sweat chloride. Measurements and Main Results Plasma concentrations of elexacaftor, tezacaftor and ivacaftor were highly variable. Analyses revealed that CYP3A5 genotype status had no significant effect on drug concentrations. Association analysis demonstrated an association of sweat chloride with drug concentrations including after adjusting for pre-modulator sweat chloride, age, race, BMI, and sex, showing that lower drug concentrations are associated with worse outcomes in sweat chloride. Conclusion This study provides evidence that lower drug concentration are associated with worse sweat chloride levels and may be a potential indicator of therapeutic effectiveness, especially for people with high sweat chloride despite treatment. The influence of drug variability underscores the need for personalised dosing strategies to improve CF treatment outcome, although well-known CYP3A5 genotypes are unlikely to be helpful.