Drug-drug interactions involving CFTR modulators: a review of the evidence and clinical implications

IntroductionCystic fibrosis (CF) is characterized by mucus accumulation impairing the lungs, gastrointestinal tract, and other organs. Cystic fibrosis transmembrane conductance regulator (CFTR) modulators (ivacaftor, tezacaftor, elexacaftor, and lumacaftor) significantly improve lung function and nutritional status; however, they are substrates, inhibitors, and/or inducers of certain CYP enzymes and transporters, raising the risk of drug-drug interactions (DDI) with common CF medications.Areas coveredA literature search was conducted for DDIs involving CFTR modulators by reviewing new drug applications, drug package inserts, clinical studies, and validated databases of substrates, inhibitors, and inducers. Clinically, CYP3A inducers and inhibitors significantly decrease and increase systemic concentrations of elexacaftor/tezacaftor/ivacaftor, respectively. Additionally, lumacaftor and ivacaftor alter concentrations of CYP3A and P-gp substrates. Potential DDIs without current clinical evidence include ivacaftor and elexacaftor's effect on CYP2C9 and OATP1B1/3 substrates, respectively, and OATP1B1/3 and P-gp inhibitors' effect on tezacaftor. A literature review was conducted using PubMed.Expert opinionDosing recommendations for CFTR modulators with DDIs are relatively comprehensive; however, recommendations on timing of dosing transition of CFTR modulators when CYP3A inhibitors are initiated or discontinued is incomplete. Certain drug interactions may be managed by choosing an alternative treatment to avoid/minimize DDIs. Next generation CFTR modulator therapies under development are expected to provide increased activity with reduced DDI risk.