Clinical Mechanism of the Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Ivacaftor in G551D-mediated Cystic Fibrosis
Clinical Mechanism of the Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Ivacaftor in G551D-mediated Cystic Fibrosis
复制标题
DOI：
10.1164/rccm.201404-0703oc
复制
发表时间：
2014-07-15
影响因子：
24.7
通讯作者：
Ramsey, Bonnie W.
中科院分区：
文献类型：
--
作者：
Rowe, Steven M.;Heltshe, Sonya L.;Ramsey, Bonnie W.
基本原理：Ivacaftor是一种囊性纤维化跨膜传导调节因子（CFTR）增效剂，最近被批准用于6岁及6岁以上具有G551 D突变的CF患者。目的：评估批准后环境中的Ivacaftor，并确定临床相关标志物的作用机制和反应。我们在2012-2013年对6岁及以上既往未暴露于依伐卡托的G551 D CF患者进行了一项纵向队列研究。研究评估在基线、ivacaftor开始治疗后1、3和6个月进行。亚组研究评估了粘液纤毛清除率、β-肾上腺素能汗液分泌率、胃肠道pH值、痰液炎症和微生物学测量和主要结果：153例受试者中共有151例接受了依伐卡托处方，88%的受试者在6个月内完成了研究。FEV1%预测值从基线到6个月改善（平均绝对变化，6.7%; P < 0.001）。同样，体重指数从基线到6个月有所改善（平均变化，0.8 kg/m2; P < 0.001）。汗液氯化物从基线至6个月降低（平均变化，-53.8 mmol/L; 95%置信区间，-57.7至-49.9; P < 0.001），反映CFTR功能增强。住院率和铜绿假单胞菌负担明显改善（P <0.001）。还观察到粘膜纤毛清除率（P < 0.001）、胃肠道pH（P = 0.001）和微生物组的显著改善，提供了ivacaftor.Conclusions的治疗益处的临床机制：在广泛的患者群体中开始ivacaftor时观察到显著的临床和生理改善，包括减少铜绿假单胞菌的感染。生物标志物研究大大提高了对CFTR调节对肺和胃肠道生理学的机制后果的理解。
Rationale: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation.Objectives: To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers.Methods: We conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, beta-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiologyMeasurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P < 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m(2); P < 0.001). Sweat chloride decreased from baseline to 6 months (mean change, -53.8 mmol/L; 95% confidence interval, -57.7 to -49.9; P < 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P < 0.001) and Pseudomonas aeruginosa burden (P < 0.01). Significant improvements in mucociliary clearance (P < 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor.Conclusions: Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology.