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

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.