Physiologically Based Pharmacokinetic Modeling of Elexacaftor-Tezacaftor-Ivacaftor in Adults and Pediatric People with Cystic Fibrosis: Exploring Brain Exposure and Neuropsychiatric Adverse Events.

BACKGROUND AND

OBJECTIVE

Elexacaftor-Tezacaftor-Ivacaftor (ETI) has dramatically improved clinical outcomes in cystic fibrosis. However, neuropsychiatric adverse events (NAEs) have been increasingly reported, particularly in pediatric patients. It remains unknown whether these NAEs could be driven by ETI brain exposure. This study aimed to develop a physiologically based pharmacokinetic model of ETI to explore the variability in systemic and central nervous system exposure across age.

METHODS

We included all pediatric patients treated between 2022 and 2024, and for whom at least one ETI plasma concentration was available. Demographic, pharmacokinetic, biological, genetic, and NAE data were collected. The physiologically based pharmacokinetic model was developed based on published pharmacokinetic data for both adult and pediatric populations and validated in our population using standard goodness-of-fit diagnostics. The validated model was used to simulate age-related differences in systemic and central nervous system exposure and to compare predicted exposure between children with and without reported NAEs in our cohort.

RESULTS

Fifty children were included with a mean age of 6.6 ± 4.4 years, contributing 279 plasma concentrations. Dose-normalized area under the concentration-time curves were two times higher in younger children for all three drugs. Neuropsychiatric adverse events were documented in 38% of patients and were more frequent in children aged under 6 years. The physiologically based pharmacokinetic model adequately described both adult and pediatric populations, with over 95% of predicted area under the concentration-time curves and maximum concentration being within 1.3-fold of their observed values. Simulations revealed that ETI plasma exposure was two-fold to four-fold higher in those aged 2-6 years when compared with adults. Although central nervous system penetration was substantial for ivacaftor and elexacaftor, but minimal for tezacaftor, simulated central nervous system exposure did not differ between children with and without reported NAEs.

CONCLUSIONS

Younger children have higher dose-normalized exposure. While younger children experience more NAEs in our cohort, plasma and central nervous system exposures appeared similar between groups, suggesting that exposure may not be the only factor driving the NAEs. Further investigations are necessary.