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 min 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

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

Fingerprint

Cystic Fibrosis
Pharmacokinetics
Safety
Mutation
Sweat
Liver Function Tests
Transaminases
Cough
Pharmaceutical Preparations
Area Under Curve
Canada
Vomiting
Chlorides
Alleles
ivacaftor
Therapeutics

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

@article{b1b8eafdf470455780773e5bd46bcd6b,
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 min 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",
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 John Colombo 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

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 min 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

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 min 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

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

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

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AN - SCOPUS:84958107856

VL - 4

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EP - 115

JO - The Lancet Respiratory Medicine

JF - The Lancet Respiratory Medicine

SN - 2213-2600

IS - 2

ER -