Tara N Guhr Lee1, Deborah M Cholon2, Nancy L Quinney2, Martina Gentzsch3, Charles R Esther4. 1. Division of Pediatric Pulmonology, Department of Pediatrics, University of North Carolina School of Medicine, 450-D MacNider Hall, Campus Box 7217, Chapel Hill, NC 27599-7217, USA; Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: taraguhr@email.unc.edu. 2. Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, NC 27599, USA. 3. Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA. 4. Division of Pediatric Pulmonology, Department of Pediatrics, University of North Carolina School of Medicine, 450-D MacNider Hall, Campus Box 7217, Chapel Hill, NC 27599-7217, USA; Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, NC 27599, USA.
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.
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.
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