Model-informed dose reduction of elexacaftor/tezacaftor/ivacaftor therapy in adult people with cystic fibrosis: A simulation study.

BACKGROUND

Most people with cystic fibrosis (pwCF) use elexacaftor/tezacaftor/ivacaftor (ETI) therapy. While generally efficacious, some pwCF experience adverse events. This is typically managed by empirical dose reduction, but the optimal regimen remains unknown. We performed a population pharmacokinetic (PK) study incorporating a simplified exposure effect approximation to evaluate ETI dose reduction strategies.

METHODS

ETI exposure under five dose reduction strategies was simulated using available population PK models. Standard dose ETI PK was simulated, from which individuals were selected for dose reduction based on elexacaftor predicted minimum concentrations (Cmin). ETI exposure was translated to predicted relative effect using simplified PD models constructed from previously reported exposure-effect data.

RESULTS

Demographic data of 885 adults pwCF were available as virtual population. Dose reduction for pwCF showing simulated elexacaftor Cmin >75th percentile (8687 µg/L) yielded seemingly limited PK-PD impact compared to the standard dose. Reduction to a 100/50/75 mg ETI morning dose with a 75-150 mg ivacaftor evening dose (regimen A-B) resulted in limited median predicted effect shifts of 93.7%→92.7% and 89.9%→88.7% for elexacaftor and tezacaftor, and 96.2%→95.8 and 96.2%→95.5 for ivacaftor. This was accompanied by limited predicted EC70-90 attainment reductions of ≤13.5% for elexacaftor, ≤30.1% for tezacaftor, and ≤4.6% and ≤7.8% for ivacaftor.

CONCLUSIONS

In this simulation study, dose reduction to one morning ETI tablet (100/50/75 mg) with an evening 75-150 mg ivacaftor dose showed a seemingly limited simulated PK and predicted exposure-effect impact in pwCF displaying high elexacaftor exposure. This hypothetical regimen shows promise for clinical evaluation in a formal dose reduction study.