title: Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study.
abstract: BACKGROUND
  Ivacaftor has been shown to be a safe, effective treatment for cystic fibrosis in patients aged 6 years or older with a CFTR gating mutation. We aimed to assess the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in children aged 2-5 years.
  
  
  METHODS
  In the two-part KIWI study, we enrolled children aged 2-5 years weighing 8 kg or more with a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the USA, UK, and Canada. Participants received oral ivacaftor 50 mg (if bodyweight <14 kg) or 75 mg (if bodyweight ≥14 kg) every 12 h for 4 days in part A (to establish the short-term safety of doses for subsequent assessment in part B), and then for 24 weeks in part B (to assess safety and longer-term pharmacodynamics). Children could participate in both or just one part of the study. Primary outcomes were pharmacokinetics and safety, analysed in all patients who received at least one dose of ivacaftor. Secondary outcomes were absolute change from baseline in sweat chloride concentrations and bodyweight, body-mass index (BMI), and height Z scores, and pharmacokinetic parameter estimation of ivacaftor. This study is registered with ClinicalTrials.gov, number NCT01705145.
  
  
  RESULTS
  Between Jan 8, 2013, and March 1, 2013, nine patients were enrolled onto part A of the study, all of whom completed the 4 day treatment period, and eight of whom took part in part B. Between June 28, 2013, and Sept 26, 2013, 34 patients were enrolled in part B, 33 of whom completed the 24 week treatment period. All patients received at least one dose of ivacaftor. Results of ivacaftor pharmacokinetics suggested that exposure was similar to that reported in adults (median Cmin were 536 ng/mL for the 50 mg dose; 580 ng/mL for the 75 mg dose; median ivacaftor AUC values were 9840 ng × h/mL and 10 200 ng × h/mL, respectively). Common adverse events in part B included cough (in 19 [56%] of 34 patients) and vomiting (in ten [29%]). Five (15%) patients had liver function test (LFT) results that were more than eight times higher than the upper limit of normal, four of whom had study drug interrupted, and one of whom had study drug discontinued. Six (18%) of 34 patients had seven serious adverse events; a raised concentration of transaminases was the only serious adverse event regarded as related to ivacaftor and the only adverse event that resulted in study treatment discontinuation. At week 24, in patients for whom we had data, sweat chloride had changed from baseline by a mean of -46·9 mmol/L (SD 26·2, p<0·0001), weight Z score by 0·2 (0·3; p<0·0001), BMI Z score by 0·4 (0·4, p<0·0001), and height Z score by -0·01 (0·3; p=0·84).
  
  
  CONCLUSIONS
  Ivacaftor at doses of 50 mg and 75 mg seems to be safe in children aged 2-5 years with cystic fibrosis with a gating mutation followed up for 24 weeks, although the frequency of elevated LFTs suggests that monitoring should be frequent in young children, particularly those with a history of elevated LFTs. Results of an ongoing extension study assessing durability of these effects and longer-term safety are warranted.
  
  
  BACKGROUND
  Vertex Pharmaceuticals Incorporated.
authors.affiliation: Imperial College London, London, UK; Royal Brompton and Harefield NHS Foundation Trust, London, UK. Electronic address: j.c.davies@imperial.ac.uk.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Davies
authors.affiliation: Royal Hospital for Sick Children, NHS Lothian, Edinburgh, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Cunningham
authors.affiliation: University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Harris
authors.affiliation: Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Lapey
authors.affiliation: University of Minnesota, Minneapolis, MN, USA.
authors.forename: Warren E
authors.initials: WE
authors.lastname: Regelmann
authors.affiliation: Harvard Medical School, Boston, MA, USA.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Sawicki
authors.affiliation: University of Liverpool, Liverpool, UK.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Southern
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, MA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Robertson
authors.affiliation: Vertex Pharmaceuticals Incorporated, Milton Park, UK.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Green
authors.affiliation: Vertex Pharmaceuticals Incorporated, Milton Park, UK.
authors.forename: Jon
authors.initials: J
authors.lastname: Cooke
authors.affiliation: Seattle Children's Hospital, Seattle, WA, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Rosenfeld
mesh_terms: D000627:Aminophenols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002675:Child, Preschool; D065101:Chloride Channel Agonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002712:Chlorides / Q000378:metabolism*; D003371:Cough / Q000139:chemically induced; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005260:Female; D005541:Forced Expiratory Volume; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D015363:Quinolones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013542:Sweat / Q000737:chemistry*
chemical_list: D000627:Aminophenols; C505032:CFTR protein, human; D065101:Chloride Channel Agonists; D002712:Chlorides; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor