Valemetostat是一种口服、选择性抑制剂，作用于增强子同源物2 (EZH2)和EZH1。在一项首次人体试验中，valemetostat胶囊在复发/难治性非霍奇金淋巴瘤患者中获得了良好的耐受性和临床活性。随后，我们开发了一种薄膜包衣片剂的配方，以供未来的临床试验和商业化使用。我们报道了2项对健康的日本参与者进行的一期试验结果，评估了单剂量(50、100和200毫克) valemetostat片剂的安全性、耐受性和药代动力学 (PK)，以及胶囊和片剂之间的相对生物利用度，以及高脂或低脂食物对valemetostat片剂的PK的影响。在剂量递增研究中，valemetostat的最大血浆浓度(Cmax)和浓度-时间曲线下区域 (AUC)与剂量成比例增加。单剂量200毫克后，valemetostat的血浆PK参数在胶囊和片剂配方中相似。进食后用valemetostat，200毫克的血浆Cmax降低了50%-60%，AUC降低了30%-50%，相对于禁食的给药，Tmax延迟了2.5-3小时。valemetostat在健康受试者中耐受性良好；治疗相关的不良事件的临床表现轻微 (1级)。根据这些试验，valemetostat片剂配方适用于进一步的临床试验，并应在禁食条件下给药以避免食物效应的负面影响。© 2023作者。临床药物发展出版由Wiley Periodicals LLC代表美国临床药理学会发表。

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 (Cmax ) 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 Cmax , 30%-50% lower AUC, and a median Tmax 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.© 2023 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.