Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-years with cystic fibrosis and a CFTR gating mutation (KIWI): An open-label, single-arm study

KIWI Study Group

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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-years. Methods: In the two-part KIWI study, we enrolled children aged 2-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. Findings: 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). Interpretation: Ivacaftor at doses of 50 mg and 75 mg seems to be safe in children aged 2-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. Funding: Vertex Pharmaceuticals Incorporated.

Original languageEnglish (US)
Pages (from-to)107-115
Number of pages9
JournalThe Lancet Respiratory Medicine
Volume4
Issue number2
DOIs
StatePublished - Feb 1 2016

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Cystic Fibrosis
Pharmacokinetics
Safety
Mutation
Sweat
Chlorides
Body Mass Index
ivacaftor
Pharmaceutical Preparations
Liver Function Tests
Therapeutics
Transaminases
Cough
Area Under Curve
Canada
Vomiting
Alleles
Weights and Measures

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

@article{bf23f019582c452c85bf137d1d507d0f,
title = "Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-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-years. Methods: In the two-part KIWI study, we enrolled children aged 2-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. Findings: 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). Interpretation: Ivacaftor at doses of 50 mg and 75 mg seems to be safe in children aged 2-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. Funding: Vertex Pharmaceuticals Incorporated.",
author = "{KIWI Study Group} and Davies, {Jane C.} and Steve Cunningham and Harris, {William T.} and Allen Lapey and Regelmann, {Warren E.} and Sawicki, {Gregory S.} and Southern, {Kevin W.} and Sarah Robertson and Yulia Green and Jon Cooke and Margaret Rosenfeld and Janine Bufi and {Sharon McNamara}, McNamara and Ginger Reeves and Heather Hathorne and Katie Brand and William Harris and Jonathan Spahr and Elizabeth Hartigan and Brooke Noren and Patricia Grover and Warren Regelmann and Eric Hunter and Seth Walker and Barbara Chatfield and Jane Vroom and April Williams and Candy Schmoll and Philip Black and Raquel Telfer and Colombo, {John Louis} and Lisa Bendy and Gregory Montgomery and Caitlin Doolittle and Thomas Symington and Cynthia Gile and Susan Millard and Jonathan Greenberg and Catherine Correia and Gregory Sawicki and Matthew Ward and Howard Schmidt and Frank Accurso and Sheryl Faut and Mark Chilvers and {Maggie McIlwaine}, McIlwaine and Melissa Richmond and Laura Hayers and Sandra Scott and Jane Davies",
year = "2016",
month = "2",
day = "1",
doi = "10.1016/S2213-2600(15)00545-7",
language = "English (US)",
volume = "4",
pages = "107--115",
journal = "The Lancet Respiratory Medicine",
issn = "2213-2600",
publisher = "Elsevier Limited",
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}

TY - JOUR

T1 - Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-years with cystic fibrosis and a CFTR gating mutation (KIWI)

T2 - An open-label, single-arm study

AU - KIWI Study Group

AU - Davies, Jane C.

AU - Cunningham, Steve

AU - Harris, William T.

AU - Lapey, Allen

AU - Regelmann, Warren E.

AU - Sawicki, Gregory S.

AU - Southern, Kevin W.

AU - Robertson, Sarah

AU - Green, Yulia

AU - Cooke, Jon

AU - Rosenfeld, Margaret

AU - Bufi, Janine

AU - Sharon McNamara, McNamara

AU - Reeves, Ginger

AU - Hathorne, Heather

AU - Brand, Katie

AU - Harris, William

AU - Spahr, Jonathan

AU - Hartigan, Elizabeth

AU - Noren, Brooke

AU - Grover, Patricia

AU - Regelmann, Warren

AU - Hunter, Eric

AU - Walker, Seth

AU - Chatfield, Barbara

AU - Vroom, Jane

AU - Williams, April

AU - Schmoll, Candy

AU - Black, Philip

AU - Telfer, Raquel

AU - Colombo, John Louis

AU - Bendy, Lisa

AU - Montgomery, Gregory

AU - Doolittle, Caitlin

AU - Symington, Thomas

AU - Gile, Cynthia

AU - Millard, Susan

AU - Greenberg, Jonathan

AU - Correia, Catherine

AU - Sawicki, Gregory

AU - Ward, Matthew

AU - Schmidt, Howard

AU - Accurso, Frank

AU - Faut, Sheryl

AU - Chilvers, Mark

AU - Maggie McIlwaine, McIlwaine

AU - Richmond, Melissa

AU - Hayers, Laura

AU - Scott, Sandra

AU - Davies, Jane

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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-years. Methods: In the two-part KIWI study, we enrolled children aged 2-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. Findings: 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). Interpretation: Ivacaftor at doses of 50 mg and 75 mg seems to be safe in children aged 2-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. Funding: Vertex Pharmaceuticals Incorporated.

AB - 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-years. Methods: In the two-part KIWI study, we enrolled children aged 2-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. Findings: 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). Interpretation: Ivacaftor at doses of 50 mg and 75 mg seems to be safe in children aged 2-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. Funding: Vertex Pharmaceuticals Incorporated.

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U2 - 10.1016/S2213-2600(15)00545-7

DO - 10.1016/S2213-2600(15)00545-7

M3 - Article

C2 - 26803277

AN - SCOPUS:84958107856

VL - 4

SP - 107

EP - 115

JO - The Lancet Respiratory Medicine

JF - The Lancet Respiratory Medicine

SN - 2213-2600

IS - 2

ER -