Real-world pharmacokinetics of elexacaftor-tezacaftor-ivacaftor in children with cystic fibrosis: a prospective observational study.

Background: The clinical efficacy of elexacaftor-tezacaftor-ivacaftor (ETI) in children with cystic fibrosis (cwCF) is variable; some respond, while others do not or have side effects. The pharmacokinetics (PK) of ETI are poorly described in published research, particularly when it comes to children. Knowledge of the PK in this population may provide more insight into the exposure-response relationship of the drugs and its corresponding inter-patient variability (IIV). The aim of this study was to evaluate the PK of ETI in cwCF in a real-world setting.

Methods: A prospective, observational PK study was conducted in cwCF starting with ETI. PK samples were collected at home using dried blood spots (DBS), and during regular outpatient hospital visits. Clinical efficacy and safety data were gathered and evaluated. Population PK (popPK) models were developed using nonlinear mixed-effects modelling.

Results: A total of 29 children were included in this study. Novel popPK models were developed for ETI and its main metabolites. There was significant variability in AUC of ETI within and between age groups, aligning with the references in the product information. All children had concentrations within or above the range needed for a clinical response. An exploratory exposure-response analysis found no direct linear relationship between AUC and sweat chloride, or ppFEV1.

Conclusions: This study is the first analysis of ETI popPK in cwCF. The developed popPK models may be used to further study the exposure-response relationship and its variability within cwCF, as a basis for more personalized dosing.