MEI Pharma, Inc., San Diego, CA, United States.
MEI Pharma, Inc., San Diego, CA, United States.
Clin Ther. 2018 Nov;40(11):1855-1867. doi: 10.1016/j.clinthera.2018.09.006. Epub 2018 Oct 26.
ME-401 is a novel selective inhibitor of phosphatidylinositol 3 kinase p110δ, an enzyme often found overexpressed and overactive in B-cell malignancies. The current study was performed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending oral doses of ME-401 in healthy volunteers.
This analysis was an open-label, nonrandomized study in healthy male volunteers. Three sequential groups were dosed. Each group received single doses of ME-401 on two occasions; the doses tested ranged from 10 to 150 mg. Blood was drawn at various time points to analyze plasma concentrations of ME-401 and inhibition of basophil activation, a marker of phosphatidylinositol 3 kinase p110δ inhibition.
Fifteen subjects received a single dose of ME-401 on two occasions. Three adverse events that were considered possibly related to the study drug were reported: one event of pain, one event of headache, and one event of upper abdominal pain. ME-401 exhibited dose proportionality up to 60 mg, and supra-proportional increases in exposure were observed above doses of 60 mg. In addition, there was a dose-proportional increase in the inhibition of basophil activation up to 60 mg. Mean t ranged from 9.36 to 29.23 hours across the dose range. A 60 mg dose of ME-401 approached 90% inhibition of basophil activation, and thereafter no further increase to the percent inhibition of basophil activation was observed for higher doses. Once-daily dosing of 60 mg ME-401 was forecasted to result in trough plasma levels exceeding the concentration needed for 90% inhibition of basophil activation.
This first-in-human study showed that ME-401 was well tolerated after single doses up to 150 mg. Pharmacologic activity was confirmed after administration of single ascending oral doses of 10 to 150 mg. ME-401 60 mg, administered once daily, was selected as the starting dose for patient studies. ClinicalTrials.gov identifier: NCT02521389.
ME-401 是一种新型的磷酸肌醇 3 激酶 p110δ选择性抑制剂，该酶在 B 细胞恶性肿瘤中经常过度表达和过度活跃。本研究旨在评估健康志愿者单次口服 ME-401 的安全性、耐受性、药代动力学和药效学。
这是一项在健康男性志愿者中进行的开放标签、非随机研究。三个连续的组进行了剂量给药。每个组在两次接受 ME-401 的单剂量；测试的剂量范围为 10 至 150 毫克。在不同时间点抽取血液以分析 ME-401 的血浆浓度和嗜碱性粒细胞活化的抑制作用，这是磷酸肌醇 3 激酶 p110δ 抑制的标志物。
15 名受试者两次接受了 ME-401 的单次剂量。报告了三起被认为与研究药物可能相关的不良事件：一起疼痛事件，一起头痛事件和一起上腹痛事件。ME-401 在 60 毫克以下呈剂量比例，在 60 毫克以上呈超比例增加。此外，在 60 毫克以下，嗜碱性粒细胞活化的抑制作用呈剂量比例增加。在整个剂量范围内，平均 t 范围为 9.36 至 29.23 小时。ME-401 60 毫克剂量接近 90%抑制嗜碱性粒细胞活化，此后，较高剂量的嗜碱性粒细胞活化抑制率不再增加。预测每日一次给予 60 毫克 ME-401 将导致谷浓度超过抑制嗜碱性粒细胞活化所需的浓度。
这项首次人体研究表明，单次剂量高达 150 毫克的 ME-401 耐受性良好。在给予 10 至 150 毫克的单次递增口服剂量后，确认了药理活性。ME-401 60 毫克，每日一次给药，被选为患者研究的起始剂量。临床试验.gov 标识符：NCT02521389。
