Change in Sweat Chloride as a Clinical End Point in Cystic Fibrosis Clinical Trials The Ivacaftor Experience
Change in Sweat Chloride as a Clinical End Point in Cystic Fibrosis Clinical Trials The Ivacaftor Experience
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DOI：
10.1378/chest.12-1430
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发表时间：
2013-01-01
期刊：
影响因子：
9.6
通讯作者：
Chowdhury, Badrul A.
中科院分区：
文献类型：
--
作者：
Durmowicz, Anthony G.;Witzmann, Kimberly A.;Chowdhury, Badrul A.
囊性纤维化（CF）是一种由CF跨膜电导调节基因（CFTR）突变引起的缩短寿命的遗传性疾病，CFTR编码CF跨膜电导调节基因（CFTR）离子通道，该通道调节氯离子和水在上皮细胞表面的运输。Ivacaftor是美国食品和药物管理局最近批准的一种药物，代表了CF的第一个突变特异性治疗药物。它是一种CFTR通道调节剂，可改善具有G551D突变的CF患者的CFTR功能。一项支持活化剂剂量选择的临床试验表明，FEV1的改善与汗液氯化物（CFTR功能的衡量指标）的降低之间存在剂量-反应关系。验证FEV1和汗液氯化物之间的这种关系将有助于开发针对有缺陷的CFTR的新药。随后，在3期研究中，ivacaftor 150 mg hid显著改善了FEV1(10% - 42%)，降低了汗液氯化物（约50 mmol/L）。然而，汗液氯化物的减少与FEV1的改善并不相关，汗液氯化物的变化似乎也没有一个阈值水平，超过这个阈值，FEV1的改善就会很明显。汗液氯化物与FEV1的改善缺乏相关性说明了多种因素，包括生理、环境和遗传因素，这些因素可能起调节作用。CF疾病严重程度。针对有缺陷CFTR的药物的未来临床试验将需要考虑使用均匀的、既定的测量方法（如汗液氯化物）作为临床终点的不确定性。胸部2013;143 (1): 14 - 18
Cystic fibrosis (CF) is a life-shortening inherited disease caused by mutations in the CF transmembrane conductance regulator gene (CFTR), which encodes for the CF transmenibrane conductance regulator (CFTR) ion channel that regulates chloride and water transport across the surface of epithelial cells. Ivacaftor, a drug recently approved by the US Food and Drug Administration, represents the first mutation-specific therapy for CF. It is a CFTR channel modulator and improves CFTR function in patients with CF who have a G551D mutation. A clinical trial performed to support ivacaftor dose selection demonstrated a dose-response relationship between improvement in FEV1 and decrease in sweat chloride, a measure of CFTR function. Validation of such a relationship between FEV1 and sweat chloride would facilitate development of new drugs that target the defective CFTR. Subsequently, in phase 3 studies, ivacaftor 150 mg hid resulted in significant improvements in FEV1 (10%42%) and reduction in sweat chloride (approximately 50 mmol/L). However, a decrease in sweat chloride did not correlate with improvement in FEV1, nor did there appear to be a threshold level for change in sweat chloride above which an improvement in FEV1 was apparent. The lack of correlation of sweat chloride with improvement in FEV1 speaks to the multiplicity of factors, physiologic, environmental, and genetic, that likely modulate. CF disease severity. Future clinical trials of drugs that are directed to the defective CFTR will need take into account the uncertainty of using even,established measurements, such as sweat chloride, as clinical end points. CHEST 2013; 143(1):14-18