Real-world population pharmacokinetics of tezacaftor-ivacaftor in children with cystic fibrosis: The SYM-CF study.

Abstract

Aims: The clinical effectiveness of tezacaftor-ivacaftor in children with cystic fibrosis (cwCF) varies; some patients respond while others do not or have adverse effects. The pharmacokinetics (PK) of tezacaftor-ivacaftor are inadequately published, especially in children. Knowledge of the PK in this cohort in relation to clinical outcomes may give further insight into the drug's exposure-response relationship and its associated interindividual variability. The aim of this study was to assess the real-world PK of tezacaftor-ivacaftor in cwCF.

Methods: A prospective, observational PK study was performed in cwCF using tezacaftor-ivacaftor. PK samples were obtained by dried blood spots at home and during routine outpatient hospital visits. Population PK (popPK) models were created using nonlinear mixed-effects modelling. Due to data scarcity, prior information from adolescent/adult PK models was required.

Results: The study involved 21 children (age 6-17 years, weight 24-70 kg). Novel popPK models were created for tezacaftor-ivacaftor and its main metabolites. Variability in PK was explained by variation in body weight. The area under the curve of tezacaftor-ivacaftor varied significantly within and across age groups, which corresponded to the reported area under the curve in the product information. Maximum concentration and elimination half-lives closely matched adult reported values.

Conclusions: This is the first study to investigate the popPK of tezacaftor-ivacaftor in cwCF. The established models can be used for more personalized dosing in children experiencing suboptimal efficacy, adverse effects, drug-drug interactions, or where adherence is a concern.