The development of CFTR modulators has transformed the care of patients with cystic fibrosis (CF). Although the clinical efficacy of modulators depends on their concentrations in target tissues, the pharmacokinetic properties of these drugs in epithelia are not utilized to guide patient care. We developed assays to quantitate ivacaftor in cells and plasma from patients on modulator therapy, and our analyses revealed that cellular ivacaftor concentrations differ from plasma concentrations measured concurrently, with evidence of in vivo accumulation of ivacaftor in the cells of patients. While the nature of this study is exploratory and limited by a small number of patients, these findings suggest that techniques to measure modulator concentrations in vivo will be essential to interpreting their clinical impact, particularly given the evidence that ivacaftor concentrations influence the activity and stability of restored CFTR protein.

中文翻译：

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囊性纤维化患者接受调节剂治疗时细胞内依伐卡托浓度变化

CFTR 调节剂的开发改变了囊性纤维化 (CF) 患者的护理。尽管调节剂的临床疗效取决于它们在靶组织中的浓度，但这些药物在上皮细胞中的药代动力学特性并未用于指导患者护理。我们开发了对接受调节剂治疗的患者的细胞和血浆中ivacaftor进行定量的测定法，我们的分析显示细胞ivacaftor浓度与同时测量的血浆浓度不同，有证据表明ivacaftor在患者细胞中体内积累。虽然这项研究的性质是探索性的并且受到少数患者的限制，但这些发现表明测量体内调节剂浓度的技术对于解释其临床影响至关重要，特别是考虑到 ivacaftor 浓度影响活性和稳定性的证据。恢复CFTR蛋白。