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Isotope dilution LC-MS/MS quantification of the cystic fibrosis transmembrane conductance regulator (CFTR) modulators ivacaftor, lumacaftor, tezacaftor, elexacaftor, and their major metabolites in human serum

Authors
  • Habler, Katharina1
  • Kalla, Anne-Sophie1, 2
  • Rychlik, Michael2
  • Bruegel, Mathias1
  • Teupser, Daniel1
  • Nährig, Susanne3
  • Vogeser, Michael1
  • Paal, Michael1
  • 1 Institute of Laboratory Medicine, University Hospital, LMU Munich, Germany , (Germany)
  • 2 Chair of Analytical Food Chemistry, Technical University of Munich, Germany , (Germany)
  • 3 Cystic Fibrosis Center for Adults, University Hospital, LMU Munich, Germany , (Germany)
Type
Published Article
Journal
Clinical Chemistry and Laboratory Medicine (CCLM)
Publisher
Walter de Gruyter GmbH
Publication Date
Oct 20, 2021
Volume
60
Issue
1
Pages
82–91
Identifiers
DOI: 10.1515/cclm-2021-0724
Source
De Gruyter
Keywords
License
Yellow

Abstract

Objectives Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators have revolutionized the therapeutic landscape in CF treatment. These vital drugs are extensively metabolized via CYP3A, so caution must be exercised in multimodal CF therapy because of the risk of adverse drug interactions. Our goal was to develop a highly sensitive assay for the purpose of therapeutic drug monitoring (TDM) in diagnostic laboratories. Methods After protein precipitation, the CFTR modulators ivacaftor, lumacaftor, tezacaftor, elexacaftor, and their metabolites ivacaftor-M1, ivacaftor-M6, and tezacaftor-M1 were separated with a two-dimensional chromatography setup within 5 min, and quantified with stable isotope-labeled internal standards. The method was validated according to the European Medicines Agency (EMA) guideline on bioanalytical method validation and applied to CF patient samples. Results Inaccuracy was ≤7.0% and the imprecision coefficient of variation (CV) was ≤8.3% for all quality controls (QCs). The method consistently compensated for matrix effects, recovery, and process efficiency were 105–115 and 96.5–103%, respectively. Analysis of CF serum samples provided concentrations comparable to the pharmacokinetic profile data reported in the EMA assessment report for the triple combination therapy Kaftrio. Conclusions We hereby present a robust and highly selective isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) assay for the simultaneous quantification of the so far approved CFTR modulators and their metabolites in human serum. The assay is suitable for state-of-the-art pharmacovigilance of CFTR modulator therapy in CF patients, in order to maximize safety and efficacy, and also to establish dose-response relationships in clinical trials.

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