PDF(Pubmed)
Abstract：
This study aimed to assess the safety, pharmacokinetics, and food impact on sudapyridine (WX-081), a novel drug designed to inhibit mycobacterium ATP synthase, with clinical applications for drug-resistant tuberculosis (TB) treatment. The research comprised two arms: a single ascending dose (SAD) arm (30 to 600 mg, N = 52) and a multiple ascending dose (MAD) arm (200 to 400 mg, N = 30). The influence of food was evaluated using a 400 mg dose within an SAD cohort. Plasma concentrations of WX-081 and M3 (main metabolite of WX-081) were analyzed using a validated liquid-chromatography tandem mass spectrometry method. In the SAD arm, mean residence time (MRT0-t), terminal half-life, and clearance of WX-081 ranged from 18.87 to 52.8 h, 31.39 to 236.57 h, and 6.4 to 80.34 L/h, respectively. The area under the curve from time zero to the last measurable timepoint (AUC0-t) of WX-081 showed dose-proportional increases in the SAD arm. The disparity between fasted and fed states of WX-081 was significant (p < 0.05), with fed dosing resulting in a 984.07% higher AUC0-t and 961.55% higher maximum plasma concentration. In both the SAD and MAD arms, one case each exhibited a 1 degree atrioventricular block. No QTc elongation was observed, and adverse events were not dose-dependent. Favorable exposure, tolerability, safety, and an extended MRT0-t suggest that WX-081 holds promise as a phase II development candidate for drug-resistant TB treatment.
摘要：
本研究旨在评估安全性，药代动力学，和食物对苏丹吡啶的影响（WX-081），一种抑制分枝杆菌ATP合成酶的新药，临床应用于耐药结核病（TB）治疗。该研究包括两个臂：单个递增剂量（SAD）臂（30至600mg，N=52）和多次递增剂量（MAD）臂（200至400mg，N=30)。在SAD队列中使用400mg剂量评价食物的影响。使用经验证的液相色谱串联质谱法分析WX-081和M3(WX-081的主要代谢物)的血浆浓度。在SAD手臂中，平均停留时间(MRT0-t)，终末半衰期，WX-081的间隙范围为18.87至52.8小时，31.39至236.57h,和6.4至80.34L/h，分别。从时间零到WX-081的最后可测量时间点(AUC0-t)的曲线下面积显示SAD臂中的剂量成比例的增加。WX-081的禁食状态和进食状态之间的差异显着（p<0.05），进食给药导致AUC0-t升高984.07%和最大血浆浓度升高961.55%。在SAD和MAD武器中，各1例出现1度房室传导阻滞.没有观察到QTc伸长率，和不良事件不是剂量依赖性的.有利的曝光，耐受性,安全,和扩展的MRT0-t表明WX-081有望成为耐药结核病治疗的II期开发候选药物。
