Introduction: Elexacaftor/tezacaftor/ivacaftor (ETI) treatment is associated with significant improvement in lung function in people with cystic fibrosis (pwCF); however, some patients experience adverse effects (AEs) including hepatotoxicity. One potential strategy is dose reduction in ETI with the goal of maintaining therapeutic efficacy while resolving AEs. We report our experience of dose reduction in individuals who experienced AEs following ETI therapy. We provide mechanistic support for ETI dose reduction by exploring predicted lung exposures and underlying pharmacokinetics–pharmacodynamics (PK‐PD) relationships.Method: Adults prescribed ETI who underwent dose reduction due to the AEs were included in this case series, and their percent predicted forced expiratory volume in 1 s (ppFEV₁) and self‐reported respiratory symptoms were collected. The full physiologically based pharmacokinetic (PBPK) models of ETI were developed incorporating physiological information and drug‐dependent parameters. The models were validated against available pharmacokinetic and dose–response relationship data. The models were then used to predict lung concentrations of ETI at steady‐state.Results: Fifteen patients underwent dose reduction in ETI due to AEs. Clinical stability without significant changes in ppFEV₁ after dose reduction was observed in all patients. Resolution or improvement of AEs occurred in 13 of the 15 cases. The model‐predicted lung concentrations of reduced dose ETI exceeded the reported half maximal effective concentration (EC₅₀) from measurement of in vitro chloride transport, providing a hypothesis as to why therapeutic efficacy was maintained.Conclusion: Albeit in a small number of patients, this study provides evidence that reduced ETI doses in pwCF who have experienced AEs may be effective. The PBPK models enable exploration of a mechanistic basis for this finding by simulating target tissue concentrations of ETI that can be compared with drug efficacy in vitro.

Cystic 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. A 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. Dosing 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.

The use of elexacaftor/tezacaftor/ivacaftor (ETI) has been associated with increased fertility in women with cystic fibrosis (CF) and is increasingly used during pregnancy to support both maternal and fetal health. However, little is known about the pharmacokinetics (PK) of ETI during pregnancy, which is crucial for optimizing its efficacy and safety. This study aimed to predict the PK of ETI during pregnancy and to determine the maternal dose required to achieve therapeutic concentrations in both the maternal and fetus. The pregnancy physiological‐based pharmacokinetic (PBPK) model within the Simcyp Simulator was used to predict the maternal and feto‐placental exposure of ETI. Placental kinetics were parameterized using permeability parameters determined from the physicochemical properties of these compounds. The model closely predicted the observed data, with the observed ETI maternal plasma concentrations, cord concentrations, and infant plasma concentrations mostly falling within the range of predicted 5th to 95th percentiles. Steady‐state simulations up to gestational week 40 predicted a continuous decline in ETI concentrations, with the AUC declining to 32.4–37.5% of baseline levels by week 40. However, the 5th percentile of trough concentrations for ETI consistently remained above the efficacy thresholds, both in mother and fetus. Therefore, it appears reasonable to maintain standard dosing regimen during pregnancy, complemented by careful monitoring. A clinical trial, such as the ongoing Maternal and Fetal Outcomes in the Era of Modulators (MAYFLOWERS) study, is required to further confirm the efficacy and safety of ETI in this population.

Background/Objectives: The increasing use of statins in people with cystic fibrosis (CF) necessitates the investigation of potential drug–drug interactions (DDI) of statins with cystic fibrosis transmembrane conductance regulator (CFTR) modulators, including elexacaftor, tezacaftor, and ivacaftor (ETI). The interactions may involve the potential inhibition of cytochrome P450 isoenzymes (CYPs), organic anion-transporting polypeptides (OATPs), and Breast Cancer Resistance Protein (BCRP) by ETI. This presents a therapeutic challenge in CF due to the potential for elevated statin levels, consequently heightening the risk of myopathy. This study aimed to predict potential DDIs between statins and ETI using a physiologically based pharmacokinetic (PBPK) modeling approach. Methods: We performed in vitro assays to measure the inhibitory potency of ETI against OATPs and CYP2C9 and incorporated these data into our PBPK models alongside published inhibitory parameters for BCRP and CYP3A4. Results: The PBPK simulation showed that atorvastatin had the highest predicted AUC ratio (3.27), followed by pravastatin (2.27), pitavastatin (2.24), and rosuvastatin (1.83). Conclusions: Based on these findings, rosuvastatin appears to exhibit a weak interaction with ETI, whereas other statins exhibited a moderate interaction, potentially requiring appropriate dose reductions. These data indicate potential clinically significant DDIs between ETI and certain statins, which warrants a clinical study to validate these findings.