Background
Cystic fibrosis (CF) is an autosomal genetic disease, characterized by a
mutation in the cystic fibrosis transmembrane conductance regulator
(CFTR) gene. A mutation in this gene results in thick and sticky mucus,
which impairs various organ functions including the lungs and pancreas.
Until the early 2010s, therapy concentrated on airway clearance to
remove mucus, pancreatic enzyme supplementation to aid digestion, and
antibiotics to treat lung infections. The therapeutic management of
people with CF (pwCF) is rapidly changing due to the emergence of highly
effective modulator therapy. CFTR modulators are the first treatments
for CF to address the fundamental cause of the disease. (1)
Tezacaftor-ivacaftor was the second available combination of a CFTR
corrector and a potentiator, respectively. In the Netherlands,
tezacaftor-ivacaftor was approved in 2020 for children and adults from
12 years. In 2021 the approval was extended to children from 6-11 years.
Tezacaftor-ivacaftor is registered for pwCF with a homozygousF508del-mutation or a heterozygous F508del-mutation , in
combination with one of the 14 residual function mutations (P67L, R117C,
L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H,
2789+5G→A, 3272-26A→G, and 3849+10kbC→T) which accounts for
Eligible children with CF (cwCF) start modulator treatment as soon as it
becomes available for their age, and treatment is required indefinitely.
At the moment of tezacaftor-ivacaftor introduction, children weighing
30kg or more receive the adult dose, while those weighing less than 30kg
receive half the dose. (3) In real-life therapy response varies greatly,
with some cwCF responding and some experiencing side effects. The
pharmacokinetics (PK) appear to exert significant inter-individual
variability (IIV), raising the possibility that specific patient groups
are receiving dosages that are either too high or too low. Aside from
that, tezacaftor-ivacaftor is susceptible to drug-drug interactions,
since both components are substantially metabolized by cytochrome P450
3A4. This can lead to drug-drug interactions with for example –azole
antifungals or rifampicin, which are commonly used by pwCF to treat
infections. (3)
A limited number of PK studies has been performed in children. The only
population PK (popPK) results available are those published in the
registration documents, where data from adolescents (>12y)
and adults are presented together. (4) In a phase 3 study conducted by
the registration holder area under the curve (AUC) of
tezacaftor-ivacaftor has been evaluated in children aged 6-11 years, but
data are not presented in the publication. (5) Furthermore, there is
currently a lack of independent studies evaluating the PK of
tezacaftor-ivacaftor in children. Therefore, it is crucial to
investigate the PK of tezacaftor-ivacaftor in children aged 6-17 years
in real-world clinical settings. Even though most children have since
switched to the newest triple therapy elexacaftor-tezacaftor-ivacaftor
(ETI), this is still relevant since tezacaftor-ivacaftor are two of the
three components in ETI. Gaining a deeper understanding of PK could
improve knowledge of the exposure-response relationship and its
associated IIV. This information may lead to better insights into drug
efficacy and side effects and support the development of personalized
dosing regimens.
Pediatric trials are often limited by the number of PK samples that can
be collected, and traditional methods for PK analysis are not suitable.
PopPK modelling methods can offer a solution in this case. However,
because of the limited amount of data available, it is often not
possible to precisely estimate all PK parameters of the model. Combining
popPK methods with prior information from previous or adult models can
improve the precision of the estimated PK parameters (6). The objective
of this study is to describe the popPK of tezacaftor-ivacaftor and its
active metabolites (tezacaftor-M1, ivacaftor-M1 and ivacaftor-M6) in
cwCF using prior information. Secondary goals are to assess AUC,