Drug–drug plasma protein binding interactions of ivacaftor

Schneider, Elena K., Huang, Johnny X., Carbone, Vincenzo, Baker, Mark, Azad, Mohammad A., Cooper, Matthew A., Li, Jian and Velkov, Tony (2015) Drug–drug plasma protein binding interactions of ivacaftor. Journal of Molecular Recognition, 28 6: 339-348. doi:10.1002/jmr.2447


Author Schneider, Elena K.
Huang, Johnny X.
Carbone, Vincenzo
Baker, Mark
Azad, Mohammad A.
Cooper, Matthew A.
Li, Jian
Velkov, Tony
Title Drug–drug plasma protein binding interactions of ivacaftor
Journal name Journal of Molecular Recognition   Check publisher's open access policy
ISSN 0952-3499
1099-1352
Publication date 2015-02-24
Year available 2015
Sub-type Article (original research)
DOI 10.1002/jmr.2447
Open Access Status
Volume 28
Issue 6
Start page 339
End page 348
Total pages 10
Place of publication Oxford, United Kingdom
Publisher John Wiley and Sons
Collection year 2016
Language eng
Formatted abstract
Ivacaftor is a novel cystic fibrosis (CF) transmembrane conductance regulator (CFTR) potentiator that improves the pulmonary function for patients with CF bearing a G551D CFTR-protein mutation. Because ivacaftor is highly bound (>97%) to plasma proteins, there is the strong possibility that co-administered CF drugs may compete for the same plasma protein binding sites and impact the free drug concentration. This, in turn, could lead to drastic changes in the in vivo efficacy of ivacaftor and therapeutic outcomes. This biochemical study compares the binding affinity of ivacaftor and co-administered CF drugs for human serum albumin (HSA) and α1-acid glycoprotein (AGP) using surface plasmon resonance and fluorimetric binding assays that measure the displacement of site-selective probes. Because of their ability to strongly compete for the ivacaftor binding sites on HSA and AGP, drug–drug interactions between ivacaftor are to be expected with ducosate, montelukast, ibuprofen, dicloxacillin, omeprazole, and loratadine. The significance of these plasma protein drug–drug interactions is also interpreted in terms of molecular docking simulations. This in vitro study provides valuable insights into the plasma protein drug–drug interactions of ivacaftor with co-administered CF drugs. The data may prove useful in future clinical trials for a staggered treatment that aims to maximize the effective free drug concentration and clinical efficacy of ivacaftor.
Keyword human α 1 acid glycoprotein
Binding affinity
Human serum albumin
Ivacaftor
Cystic Fibrosis
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Tue, 14 Apr 2015, 10:14:25 EST by Susan Allen on behalf of Institute for Molecular Bioscience