Lumacaftor-Ivacaftor in Pediatric Patients With Cystic Fibrosis and Advanced Liver Disease: A Pilot Study.

PURPOSE: Lumacaftor-ivacaftor (LI) is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator for patients with cystic fibrosis homozygous for the F508del-CFTR variant. All CFTR modulators, including LI, are metabolized in the liver, and their use in advanced cystic fibrosis-related liver disease (ACFRLD) is not recommended due to concerns of worsening liver impairment, despite potential benefits for nutrition and lung function.

METHODS

A pilot study was conducted at the Queensland Children's Hospital, Australia, to describe the pharmacokinetics of LI and its metabolites (ivacaftor-M1 and ivacaftor-M6) in pediatric patients with ACFRLD. Three patients aged 4, 10, and 18 years with ACFRLD received 2 weeks of half-dose LI followed by 2 weeks of full-dose LI with weekly liver function monitoring and pharmacokinetic sampling on week 2 and 4. Stool samples were also obtained. A single stool sample was obtained from 28 children taking LI without ACFRLD as a control group.

FINDINGS: Liver function remained stable for patients with ACFRLD, although one patient developed hyperammonemia at week 3 and ceased LI with resolution of hyperammonemia. In patients with ACFRLD, plasma concentrations of ivacaftor and lumacaftor were decreased, whereas M1 and M6 were elevated compared with reported values. Stool concentrations of ivacaftor were increased, lumacaftor and M1 decreased, and M6 variable compared with controls.

IMPLICATIONS: These findings suggest reduced ivacaftor absorption and impaired biliary excretion in ACFRLD, contributing to elevated M1, M6, and decreased lumacaftor concentrations. Pharmacokinetic variability in ACFRLD highlights the potential role of individualized profiling to support safe and effective CFTR modulator treatment in this population. Queensland Children's Hospital Human Research and Ethics Committee (HREC/19/QCHQ/53788); Australian New Zealand Clinical Trials Registry (ACTRN12619001347156).