Elexacaftor/Tezacaftor/Ivacaftor Population Pharmacokinetics in Pediatric Patients With Cystic Fibrosis

Abstract

Elexacaftor/tezacaftor/ivacaftor (ETI) significantly improves treatment outcomes for people with cystic fibrosis (pwCF) with at least one F508del allele. In 2023, the Food and Drug Administration approved ETI for children with CF aged 2-5 years. However, real-world pharmacokinetic-pharmacodynamic data for ETI in pediatric and adult populations are still limited. This study aimed to characterize the population PK of ETI in children with CF (chCF) and evaluate current dosing recommendations. Population PK modeling was conducted using Monolix software on 150 ETI concentrations obtained from therapeutic drug (TDM) monitoring in 96 children with CF aged 2-18 years, as part of the MODUL-CF study. Area under the curve was derived from individual Bayesian pharmacokinetic estimates. A one-compartment model with a lag time, first-order absorption, and elimination best described the PK of elexacaftor/ivacaftor, while the PK of tezacaftor followed a one-compartment model with first-order absorption and elimination. A large between-subject variability was observed. The effect of body weight was significant on apparent clearance and volume of distribution parameters using allometric scaling. Children weighing 30-40 kg who received the adult-recommended dose showed higher drug exposure compared to adults with cystic fibrosis. This is the first study to describe the population pharmacokinetics of ETI in chCF aged 2-18 years, revealing high between-subject variability for all three drugs. In this context, TDM is likely essential for managing ETI exposure levels and guiding dosing adjustments. The appropriateness of current dosing recommendations for children under 12 years old weighing 30-40 kg remains to be clarified.

Keywords: CFTR modulators; cystic fibrosis; pediatrics; pharmacokinetics; therapeutic drug monitoring.

FIGURE 1

Prediction‐corrected visual predictive check (pcVPC) plots for ETI. The lines show the 10th, 50th, and 90th percentiles of observed data. The areas represent the 95% confidence interval around the simulated percentiles.

FIGURE 2

Boxplots of the ETI exposures (AUC_0‐τ) obtained from 2000 simulations of the final PK models using the current dosing recommendations. AUC boxplots were presented as a function of different weight bands. For each graph, the dashed horizontal line represent the median of the adult AUC values, and the gray horizontal lines indicates the 5th (bottom line) and 95th percentiles (top line) of the adult AUC values.