Ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, appears generally safe for young children with cystic fibrosis and a CFTR gating mutation, an open-label, single-arm study shows.

The study, published online Jan. 20, is the first to assess ivacaftor in children aged 2-5 years, suggests that the drug is well tolerated, somewhat improves sweat chloride and nutritional measures, and also might improve pancreatic function, reported Dr. Jane C. Davies of the National Heart & Lung Institute of Imperial College London, and her associates. “Reported side effects are similar to those in the general cystic fibrosis population, although children with previous cystic fibrosis liver disease might have transient rises in transaminase concentrations,” they added.

Ivacaftor is approved by the Food and Drug Administration for children aged 6 years and older with cystic fibrosis, and it should be even more beneficial if given before patients develop infections and inflammation as a result of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, the researchers noted.

The investigators enrolled children aged 2 to 5 years with cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the United States, the United Kingdom, and Canada. To establish short-term safety and pharmacokinetics of ivacaftor and its metabolites, nine patients received an oral dose of 50 mg (if they weighed less than 14 kg) or 75 mg (if they weighed 14 kg or more) every 12 hours for 4 days.

To assess longer-term safety, 34 patients received these doses for 24 weeks, followed by an open-label extension study that remains underway ( Lancet Respir Med. 2016 Jan 20. doi: 10.1016/S2213-2600[15]00545-7 ).

The pharmacokinetic analyses indicated that exposure was similar to that reported in adults, the researchers reported. The median Cmin was 536 ng per mL for the 50-mg dose and 580 ng per mL for the 75-mg dose, and median ivacaftor AUC values were 9,840 ng×h/mL and 10,200 ngxh/mL, respectively. The most common adverse events over 6 weeks of treatment included cough (56% of patients) and vomiting (29%). In addition five (15%) patients had liver function test results that were more than eight-fold higher than the upper limit of normal. As a result, four had the study drug interrupted and one discontinued. Hypertransaminasemia was the only serious adverse event considered related to ivacaftor, and the only adverse event leading to treatment discontinuation. By week 24, sweat chloride levels had dropped an average of 47 mmol per L from baseline (standard deviation, 26.2, P less than .0001), weight had dropped by a z score factor of 0.2 (P less than .0001), and BMI had fallen by a factor of 0.4 (P less than .0001).

“Unfortunately, this study could not generate meaningful data on pulmonary function, because only three patients produced research-quality measurements, and we did not provide specific training or quality control in preschool lung function testing,” the investigators said. The results “confirmed a safe and tolerable dose of an acceptable formulation of ivacaftor in children aged 2 to 5 years with a CFTR gating mutation, although liver function seems to require closer monitoring in this age range than in adults, particularly among those with a history of elevated [liver function tests].”

Vertex Pharmaceuticals funded the study. Dr. Davies reported serving on advisory boards for Proteostasis, Pharmaxis, Pulmocide, Novartis, and Vertex Pharmaceuticals, and participating in educational activities for which her institution received payment. Seven coinvestigators also reported financial relationships with Vertex, including three who reported employment with the company.

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