脂蛋白相关磷脂酶A（Lp-PLA）抑制剂[F]GSK2647544在健康男性受试者中的脑生物分布研究。
Investigation of the Brain Biodistribution of the Lipoprotein-Associated Phospholipase A (Lp-PLA) Inhibitor [F]GSK2647544 in Healthy Male Subjects.
作者信息
Huiban Mickael, Coello Christopher, Wu Kai, Xu Yanmei, Lewis Yvonne, Brown Andrew P, Buraglio Mauro, Guan Chenbing, Shabbir Shaila, Fong Regan, Passchier Jan, Rabiner Eugenii A, Lockhart Andrew
机构信息
Imanova Limited, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
WuXi Clinical Development Service, 19th Floor, Building A, FuXing Plaza, 388 Ma Dang Road, Shanghai, 200025, China.
出版信息
Mol Imaging Biol. 2017 Feb;19(1):153-161. doi: 10.1007/s11307-016-0982-5.
PURPOSE
GSK2647544 is a potent and specific inhibitor of lipoprotein-associated phospholipase A (Lp-PLA), which was in development as a potential treatment for Alzheimer's disease (AD). In order to refine therapeutic dose predictions and confirm brain penetration, a radiolabelled form of the inhibitor, [F]GSK2647544, was manufactured for use in a positron emission tomography (PET) biodistribution study.
PROCEDURES
[F]GSK2647544 was produced using a novel, copper iodide (Cu(I)) mediated, [F]trifluoromethylation methodology. Healthy male subjects (n = 4, age range 34-42) received an oral dose of unlabelled GSK2647544 (100 mg) and after 2 h an intravenous (iv) injection of [F]GSK2647544 (average injected activity and mass were 106 ± 47 MBq and 179 ± 55 μg, respectively) followed by dynamic PET scans for 120 min. Defined regions of interest (ROI) throughout the brain were used to obtain regional time-activity curves (TACs) and compartmental modelling analysis used to estimate the primary outcome measure, whole brain volume of distribution (V). Secondary PK and safety endpoints were also recorded.
RESULTS
PET dynamic data were successfully obtained from all four subjects and there were no clinically significant variations of the safety endpoints. Inspection of the TACs indicated a relatively homogenous uptake of [F]GSK2647544 across all the ROIs examined. The mean whole brain V was 0.56 (95 % CI, 0.41-0.72). Secondary PK parameters, C (geometric mean) and T (median), were 354 ng/ml and 1.4 h, respectively. Metabolism of GSK2647544 was relatively consistent across subjects, with 20-40 % of the parent compound [F]GSK2647544 present after 120 min.
CONCLUSIONS
The study provides evidence that GSK2647544 is able to cross the blood brain barrier in healthy male subjects leading to a measurable brain exposure. The administered doses of GSK2647544 were well tolerated. Exploratory modelling suggested that a twice-daily dose of 102 mg, at steady state, would provide ~80 % trough inhibition of brain Lp-PLA activity.
TRIAL REGISTRATION
Clintrials.gov: NCT01924858.
目的
GSK2647544是一种强效且特异性的脂蛋白相关磷脂酶A（Lp-PLA）抑制剂，正作为阿尔茨海默病（AD）的潜在治疗药物进行研发。为了优化治疗剂量预测并确认脑渗透性，制备了该抑制剂的放射性标记形式[¹⁸F]GSK2647544，用于正电子发射断层扫描（PET）生物分布研究。
程序
[¹⁸F]GSK2647544采用一种新型的碘化铜（Cu(I)）介导的[¹⁸F]三氟甲基化方法制备。健康男性受试者（n = 4，年龄范围34 - 42岁）口服未标记的GSK2647544（100 mg），2小时后静脉注射[¹⁸F]GSK2647544（平均注射活度和质量分别为106 ± 47 MBq和179 ± 55 μg），随后进行120分钟的动态PET扫描。使用全脑特定的感兴趣区域（ROI）获取区域时间 - 活度曲线（TAC），并通过房室模型分析估计主要结局指标，即全脑分布容积（V）。还记录了次要的药代动力学和安全性终点。
结果
成功从所有四名受试者获得PET动态数据，安全性终点无临床显著差异。对TAC的检查表明，在所有检查的ROI中，[¹⁸F]GSK2647544的摄取相对均匀。全脑平均V为0.56（95%CI，0.41 - 0.72）。次要药代动力学参数C（几何均值）和T（中位数）分别为354 ng/ml和1.4小时。GSK2647544在受试者之间的代谢相对一致，120分钟后母体化合物[¹⁸F]GSK2647544的含量为20% - 40%。
结论
该研究提供了证据表明GSK2647544能够在健康男性受试者中穿过血脑屏障，导致可测量的脑暴露。GSK2647544的给药剂量耐受性良好。探索性建模表明，稳态下每日两次102 mg的剂量将提供约80%的脑Lp-PLA活性谷值抑制。
试验注册
Clintrials.gov：NCT01924858。
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