Structured abstract
Aim : 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 may give further insight into the
drug’s exposure-response relationship and its associated
inter-individual variability (IIV). 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 (DBS) at home and during routine outpatient hospital visits.
Population PK (popPK) models were created utilizing nonlinear
mixed-effects modeling. 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 active metabolites. Variability in PK was explained by variation in
body weight. The AUC of tezacaftor-ivacaftor varied significantly within
and across age groups, which corresponded to the reported AUC in the
product information. Cmax and elimination half-lives
closely matched adult reported values. There was a strong correlation
between Cmin and AUC for tezacaftor-ivacaftor.
Conclusions : This is the first study to investigate the popPK
of tezacaftor-ivacaftor in cwCF. The established models can be utilized
for more personalized dosing in children experiencing suboptimal
efficacy, adverse effects, drug-drug interactions, or where adherence is
a concern.