Introduction/Aim: Orkambi (lumacaftor/ivacaftor) is approved for patients with cystic fibrosis ≥2 years, homozygous for Phe508del CFTR (F/F) in Australia. Limited studies showed increased medication exposure (AUC0-12hr by approximately 50% and maximum drug concentration [Cmax] by approximately 30%) in adults with moderately impaired hepatic function (Child-Pugh B). Patients with severe liver disease were excluded from these studies. The dosing and efficacy of Orkambi for pulmonary and nutritional optimization in F/F patients with severe liver disease is not known. The aim was to describe the pharmacokinetics of Orkambi in this patient group.

Methods: A prospective study was conducted at the Queensland Children's Hospital. Patients aged 6 to 18 years, meeting the inclusion and exclusion criteria were recruited. Baseline investigations were performed prior to commencement of twice daily Orkambi at half-dose, for 4 days. Patients aged 6 to 11 received lumacaftor 100 mg/ivacaftor 125 mg and patients ≥12 years received lumacaftor 200 mg/ivacaftor 125 mg. Pharmacokinetic studies of lumacaftor/ivacaftor were collected on day 1 at 0 hours (h), 2 h, 4 h, 6 h, 8 h, 24 h, on day 4 at 0 h, 2 h and 8 h post dose. Liver function was monitored for four weeks.

Results: Four patients completed the study. The expected mean AUC0-12 concentration for patients on lumacaftor 200 mg/ivacaftor 250 mg twice a day was lumacaftor 198 mg.h/L (65) and ivacaftor 250 mg was 3.66 mg.h/L (2.25). In comparison, our patient cohort had mean AUC0-12 for lumacaftor of 24.08 mg.h/L (5.26) and ivacaftor of 0.63 mg.h/L (0.32). Our patients had low drug exposure and achieved 12% of expected lumacaftor and 17% of target ivacaftor levels. Liver functions were stable.

Conclusion: Low lumacaftor and ivacaftor levels could be due to decreased drug availability secondary to protein losing enteropathy and lower protein binding in severe liver disease. Further studies are required to evaluate optimal Orkambi dosing in these patients.