Case Report: When access is limited: using CYP3A4 inhibition to maintain clinical benefit from elexacaftor/tezacaftor/ivacaftor
Introduction Cystic fibrosis transmembrane conductance regulator modulators (CFTRm), particularly elexacaftor/tezacaftor/ivacaftor (ETI), have transformed outcomes for people with cystic fibrosis (pwCF). However, access remains limited globally due to genotype-based eligibility and high medication cost. Pharmacokinetic manipulation using cytochrome P450 3A4 (CYP3A4) inhibitors has emerged as a potential strategy to extend ETI exposure in resource-constrained settings. Case We describe a 52-year-old female with CF (G542X/T1246I) whose genotype initially precluded subsidised ETI access in Australia. She experienced progressive clinical decline in 2024, with worsening bronchiectasis, recurrent Pseudomonas aeruginosa exacerbations, and a fall in ppFEV1 below 40%. Supported by in vitro evidence of T1246I responsiveness, she self-funded ETI, resulting in rapid symptomatic improvement, reduced sputum burden, and objective gains in lung function, sweat chloride, and weight. To improve affordability, azithromycin was replaced with clarithromycin, a potent CYP3A4 inhibitor, enabling a reduced ETI dosing schedule. Therapeutic drug monitoring demonstrated lower serum concentrations of all ETI components compared with full-dose therapy, yet clinical stability and improved quality of life were maintained, with no further exacerbations. Clarithromycin was selected due to its established safety profile and dual utility as macrolide therapy, avoiding the hepatotoxicity risk associated with azole antifungals. Conclusion This report supports the potential for CYP3A4 inhibition to aid with personalised ETI dosing strategies, particularly in low and middle-income countries where CFTRm access remains limited. Further research is needed to define optimal manipulation strategies, understand inter-individual variability in CFTRm metabolism, and evaluate the feasibility of therapeutic drug monitoring in diverse healthcare settings.