Therapeutic Drug Monitoring of Elexacaftor, Tezacaftor, and Ivacaftor: An Overview of Bioanalytical Methods

Over the past decade, cystic fibrosis transmembrane conductance regulator (CFTR) modulators have revolutionized the treatment of cystic fibrosis. Currently, 4 modulators are approved for clinical use: ivacaftor, lumacaftor, tezacaftor, and elexacaftor. Despite their clinical benefits, these drugs show significant pharmacokinetic variability and interindividual differences in therapeutic response. This review aimed to evaluate the available evidence supporting therapeutic drug monitoring of CFTR modulators and to highlight knowledge gaps that may limit its clinical implementation.

A comprehensive literature review was conducted, focusing on elexacaftor, tezacaftor, and ivacaftor. Bioanalytical methods developed for quantifying these compounds in biological fluids were systematically analyzed, and reported drug concentration ranges were summarized.

Multiple analytical methods have been described for the quantification of CFTR modulators, showing varying degrees of sensitivity and suitability for clinical application. Reported plasma concentration ranges confirm a high degree of interindividual pharmacokinetic variability. However, the relationship between drug exposure, therapeutic efficacy, and safety outcomes remains only partially defined.

Although CFTR modulators meet many of the established criteria for therapeutic drug monitoring, critical gaps persist, particularly regarding exposure-response relationships and optimal sampling strategies. Addressing these issues will be essential to establish therapeutic drug monitoring as a reliable tool for personalizing CFTR modulator therapy in patients with cystic fibrosis.