Valemetostat is an oral, selective inhibitor of enhancer of zeste homolog-2 (EZH2) and EZH1. In a first-in-human phase-1 trial, valemetostat capsules were well tolerated and clinically active in patients with relapsed/refractory non-Hodgkin lymphoma. Subsequently, a film-coated tablet formulation was developed for future clinical trials and commercialization. We report outcomes from 2 phase 1 trials in healthy Japanese participants, assessing the safety, tolerability, and pharmacokinetics (PK) of valemetostat tablets at single ascending doses (50, 100, and 200-mg), the relative bioavailability between capsules and tablets, and the effect of food (high-fat or low-fat meals) on the PK of valemetostat tablets. In the ascending-dose study, valemetostat maximum plasma concentration (C_max) and area under the concentration–time curve (AUC) increased dose-proportionally. Valemetostat plasma PK parameters were similar between the capsule and tablet formulations following a single 200-mg dose. Administration of valemetostat, 200 mg after a meal, was associated with 50%-60% lower C_max, 30%-50% lower AUC, and a median T_max delay of 2.5-3 hours relative to fasted administration. Valemetostat was well tolerated in healthy subjects; treatment-emergent adverse events were mild (grade 1) in severity. Based on these trials, the tablet formulation of valemetostat is suitable for use in subsequent clinical trials and should be administered under fasted conditions to avoid a negative food effect.

中文翻译：

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Valemetostat 片剂的安全性、耐受性和药代动力学以及食物对健康受试者中 Valemetostat 药代动力学的影响：两项 1 期研究


Valemetostat 是一种口服、选择性的 zeste 同源物-2 (EZH2) 和 EZH1 增强子抑制剂。在一项首次人体 1 期试验中，valemetostat 胶囊在复发/难治性非霍奇金淋巴瘤患者中具有良好的耐受性和临床活性。随后，开发了薄膜包衣片剂配方，用于未来的临床试验和商业化。我们报告了在日本健康受试者中进行的 2 项 1 期试验的结果，评估了单剂量递增剂量（50、100 和 200 毫克）valemetostat 片剂的安全性、耐受性和药代动力学 (PK)，胶囊和片剂之间的相对生物利用度，以及食物（高脂或低脂膳食）对 valemetostat 片 PK 的影响。在剂量递增研究中，valemetostat 最大血浆浓度 (C _max ) 和浓度-时间曲线下面积 (AUC) 随剂量成比例增加。单次 200 mg 剂量后，胶囊和片剂制剂的 Valemetostat 血浆 PK 参数相似。相对于空腹给药，饭后服用 200 mg valemetostat，C _max降低 50%-60%，AUC 降低 30%-50%，中位 T _max延迟 2.5-3 小时。 Valemetostat 在健康受试者中具有良好的耐受性；治疗中出现的不良事件的严重程度为轻度（1 级）。基于这些试验，valemetostat的片剂配方适合在后续临床试验中使用，并且应在禁食条件下给药，以避免食物的负面影响。