在延长治疗期间，伊伐卡托在气道上皮中的积累和持续存在。
Accumulation and persistence of ivacaftor in airway epithelia with prolonged treatment.
机构信息
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.
Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, NC 27599, USA.
出版信息
J Cyst Fibros. 2020 Sep;19(5):746-751. doi: 10.1016/j.jcf.2020.04.010. Epub 2020 Jun 11.
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.
背景
目前 CFTR 调节剂的给药策略基于血清药代动力学，但气道上皮等靶组织中的药物浓度尚不清楚。先前的数据表明，CFTR 调节剂可能在气道上皮中蓄积，而血清药代动力学可能无法准确预测慢性治疗的效果。
方法
在气液界面培养的 CF（F508del 纯合子）原代人支气管上皮（HBE）细胞中，用伊伐卡托联合卢美卡托或伊伐卡托联合替扎卡托治疗 14 天，然后进行 14 天的洗脱期。在治疗和洗脱期的各个间隔时间，通过质谱法测量药物浓度，用电生理学Ussing 室评估功能，并通过 Western blot 定量成熟 CFTR 蛋白。
结果
在治疗期间，伊伐卡托在 CF-HBE 中的蓄积程度远高于卢美卡托或替扎卡托，即使在洗脱 14 天后仍持续升高。CFTR 活性在治疗的第 7 天达到峰值，但随着伊伐卡托的进一步蓄积而减少，尽管在洗脱后仍高于基线。
结论
CFTR 调节剂在慢性治疗期间和之后在气道上皮细胞内的蓄积和持续存在表明，靶组织中的药代动力学和药效动力学特性复杂，无法通过血清药代动力学预测。可能需要直接测量靶组织中的药物，以优化给药策略，并且治疗停止后 CFTR 调节剂的持续存在对个体化医学方法有影响。
Zotero 插件