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,