The Experts below are selected from a list of 3 Experts worldwide ranked by ideXlab platform
Esther C.r. - One of the best experts on this subject based on the ideXlab platform.
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Accumulation and persistence of Ivacaftor in airway epithelia with prolonged treatment
Elsevier B.V., 2020Co-Authors: Guhr Lee T.n., Cholon D.m., Quinney N.l., Gentzsch M., Esther C.r.Abstract:Background: Current dosing strategies of CFTR modulators are based on serum pharmacokinetics, but drug concentrations in target tissues such as airway epithelia are not known. Previous data suggest that CFTR modulators may accumulate in airway epithelia, and serum pharmacokinetics may not accurately predict effects of chronic treatment. Methods: CF (F508del homozygous) primary human bronchial epithelial (HBE) cells grown at air-liquid interface were treated for 14 days with Ivacaftor Plus Lumacaftor or Ivacaftor Plus tezacaftor, followed by a 14-day washout period. At various intervals during treatment and washout phases, drug concentrations were measured via mass spectrometry, electrophysiological function was assessed in Ussing chambers, and mature CFTR protein was quantified by Western blotting. Results: During treatment, Ivacaftor accumulated in CF-HBEs to a much greater extent than either Lumacaftor or tezacaftor and remained persistently elevated even after 14 days of washout. CFTR activity peaked at 7 days of treatment but diminished with further Ivacaftor accumulation, though remained above baseline even after washout. Conclusions: Intracellular accrual and persistence of CFTR modulators during and after chronic treatment suggest complex pharmacokinetic and pharmacodynamic properties within airway epithelia that are not predicted by serum pharmacokinetics. Direct measurement of drugs in target tissues may be needed to optimize dosing strategies, and the persistence of CFTR modulators after treatment cessation has implications for personalized medicine approaches
Guhr Lee T.n. - One of the best experts on this subject based on the ideXlab platform.
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Accumulation and persistence of Ivacaftor in airway epithelia with prolonged treatment
Elsevier B.V., 2020Co-Authors: Guhr Lee T.n., Cholon D.m., Quinney N.l., Gentzsch M., Esther C.r.Abstract:Background: Current dosing strategies of CFTR modulators are based on serum pharmacokinetics, but drug concentrations in target tissues such as airway epithelia are not known. Previous data suggest that CFTR modulators may accumulate in airway epithelia, and serum pharmacokinetics may not accurately predict effects of chronic treatment. Methods: CF (F508del homozygous) primary human bronchial epithelial (HBE) cells grown at air-liquid interface were treated for 14 days with Ivacaftor Plus Lumacaftor or Ivacaftor Plus tezacaftor, followed by a 14-day washout period. At various intervals during treatment and washout phases, drug concentrations were measured via mass spectrometry, electrophysiological function was assessed in Ussing chambers, and mature CFTR protein was quantified by Western blotting. Results: During treatment, Ivacaftor accumulated in CF-HBEs to a much greater extent than either Lumacaftor or tezacaftor and remained persistently elevated even after 14 days of washout. CFTR activity peaked at 7 days of treatment but diminished with further Ivacaftor accumulation, though remained above baseline even after washout. Conclusions: Intracellular accrual and persistence of CFTR modulators during and after chronic treatment suggest complex pharmacokinetic and pharmacodynamic properties within airway epithelia that are not predicted by serum pharmacokinetics. Direct measurement of drugs in target tissues may be needed to optimize dosing strategies, and the persistence of CFTR modulators after treatment cessation has implications for personalized medicine approaches
Cholon D.m. - One of the best experts on this subject based on the ideXlab platform.
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Accumulation and persistence of Ivacaftor in airway epithelia with prolonged treatment
Elsevier B.V., 2020Co-Authors: Guhr Lee T.n., Cholon D.m., Quinney N.l., Gentzsch M., Esther C.r.Abstract:Background: Current dosing strategies of CFTR modulators are based on serum pharmacokinetics, but drug concentrations in target tissues such as airway epithelia are not known. Previous data suggest that CFTR modulators may accumulate in airway epithelia, and serum pharmacokinetics may not accurately predict effects of chronic treatment. Methods: CF (F508del homozygous) primary human bronchial epithelial (HBE) cells grown at air-liquid interface were treated for 14 days with Ivacaftor Plus Lumacaftor or Ivacaftor Plus tezacaftor, followed by a 14-day washout period. At various intervals during treatment and washout phases, drug concentrations were measured via mass spectrometry, electrophysiological function was assessed in Ussing chambers, and mature CFTR protein was quantified by Western blotting. Results: During treatment, Ivacaftor accumulated in CF-HBEs to a much greater extent than either Lumacaftor or tezacaftor and remained persistently elevated even after 14 days of washout. CFTR activity peaked at 7 days of treatment but diminished with further Ivacaftor accumulation, though remained above baseline even after washout. Conclusions: Intracellular accrual and persistence of CFTR modulators during and after chronic treatment suggest complex pharmacokinetic and pharmacodynamic properties within airway epithelia that are not predicted by serum pharmacokinetics. Direct measurement of drugs in target tissues may be needed to optimize dosing strategies, and the persistence of CFTR modulators after treatment cessation has implications for personalized medicine approaches
Quinney N.l. - One of the best experts on this subject based on the ideXlab platform.
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Accumulation and persistence of Ivacaftor in airway epithelia with prolonged treatment
Elsevier B.V., 2020Co-Authors: Guhr Lee T.n., Cholon D.m., Quinney N.l., Gentzsch M., Esther C.r.Abstract:Background: Current dosing strategies of CFTR modulators are based on serum pharmacokinetics, but drug concentrations in target tissues such as airway epithelia are not known. Previous data suggest that CFTR modulators may accumulate in airway epithelia, and serum pharmacokinetics may not accurately predict effects of chronic treatment. Methods: CF (F508del homozygous) primary human bronchial epithelial (HBE) cells grown at air-liquid interface were treated for 14 days with Ivacaftor Plus Lumacaftor or Ivacaftor Plus tezacaftor, followed by a 14-day washout period. At various intervals during treatment and washout phases, drug concentrations were measured via mass spectrometry, electrophysiological function was assessed in Ussing chambers, and mature CFTR protein was quantified by Western blotting. Results: During treatment, Ivacaftor accumulated in CF-HBEs to a much greater extent than either Lumacaftor or tezacaftor and remained persistently elevated even after 14 days of washout. CFTR activity peaked at 7 days of treatment but diminished with further Ivacaftor accumulation, though remained above baseline even after washout. Conclusions: Intracellular accrual and persistence of CFTR modulators during and after chronic treatment suggest complex pharmacokinetic and pharmacodynamic properties within airway epithelia that are not predicted by serum pharmacokinetics. Direct measurement of drugs in target tissues may be needed to optimize dosing strategies, and the persistence of CFTR modulators after treatment cessation has implications for personalized medicine approaches
Gentzsch M. - One of the best experts on this subject based on the ideXlab platform.
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Accumulation and persistence of Ivacaftor in airway epithelia with prolonged treatment
Elsevier B.V., 2020Co-Authors: Guhr Lee T.n., Cholon D.m., Quinney N.l., Gentzsch M., Esther C.r.Abstract:Background: Current dosing strategies of CFTR modulators are based on serum pharmacokinetics, but drug concentrations in target tissues such as airway epithelia are not known. Previous data suggest that CFTR modulators may accumulate in airway epithelia, and serum pharmacokinetics may not accurately predict effects of chronic treatment. Methods: CF (F508del homozygous) primary human bronchial epithelial (HBE) cells grown at air-liquid interface were treated for 14 days with Ivacaftor Plus Lumacaftor or Ivacaftor Plus tezacaftor, followed by a 14-day washout period. At various intervals during treatment and washout phases, drug concentrations were measured via mass spectrometry, electrophysiological function was assessed in Ussing chambers, and mature CFTR protein was quantified by Western blotting. Results: During treatment, Ivacaftor accumulated in CF-HBEs to a much greater extent than either Lumacaftor or tezacaftor and remained persistently elevated even after 14 days of washout. CFTR activity peaked at 7 days of treatment but diminished with further Ivacaftor accumulation, though remained above baseline even after washout. Conclusions: Intracellular accrual and persistence of CFTR modulators during and after chronic treatment suggest complex pharmacokinetic and pharmacodynamic properties within airway epithelia that are not predicted by serum pharmacokinetics. Direct measurement of drugs in target tissues may be needed to optimize dosing strategies, and the persistence of CFTR modulators after treatment cessation has implications for personalized medicine approaches