健康受试者中甲状腺激素受体激动剂Elunetirom液体口服制剂与固体制剂在空腹及进食条件下的比较。
完整摘要 · 中文译文
Elunetirom（ABX-002）是一种靶向大脑的口服前体药物，正在开发用于重性抑郁障碍和双相抑郁的辅助治疗。其活性部分LL-340001是一种甲状腺激素受体激动剂，对β型甲状腺激素受体的选择性略高于α型。在进入大脑（预期作用部位）后，elunetirom被脂肪酸酰胺水解酶水解为LL-340001。在本项三向、随机、交叉、生物等效性研究中，比较了早期临床开发中使用的口服液体制剂与计划用于后期开发和潜在商业化的口服固体制剂在空腹和进食条件下的药代动力学（PK）和安全性。健康成年受试者分别接受单剂量的elunetirom（45 μg），包括空腹条件下给予液体制剂、空腹条件下给予固体制剂，以及在高脂餐后30分钟给予固体制剂。空腹条件下给予固体制剂所产生的elunetirom和LL-340001暴露量与液体制剂观察到的结果相似，因此被认为具有相当的生物利用度。与空腹状态相比，进食增加了elunetirom的总暴露量（AUC），但未影响最大暴露量（Cmax）。相反，与空腹状态相比，进食降低了LL-340001的Cmax，但未影响AUC。进食延迟了elunetirom和LL-340001达到Cmax的时间（Tmax）。Elunetirom以液体和固体制剂形式口服给药是安全的，且耐受性良好。 在进食和空腹条件下均耐受良好。
完整摘要 · 英文原文
Elunetirom (ABX-002) is a brain-targeted, oral prodrug being developed for the adjunctive treatment of major depressive disorder and bipolar depression. The active moiety, LL-340001, is a thyroid hormone receptor agonist with modest selectivity for beta over alpha thyroid hormone receptors. Upon entering the brain, the intended site of action, elunetirom is hydrolyzed by fatty acid amide hydrolase to LL-340001. In this 3-way randomized, crossover, bioequivalence study, the pharmacokinetics (PK) and safety of an oral liquid formulation used in early clinical development were compared with those of an oral solid formulation intended for later-stage development and potential commercialization, under fasted and fed conditions. Healthy adult participants received single doses of elunetirom (45 μg) as a liquid formulation under fasted conditions and as a solid formulation under fasted conditions and 30 min after consumption of a high-fat meal. Administration of the solid formulation under fasted conditions resulted in elunetirom and LL-340001 exposures similar to those observed with the liquid formulation and is therefore considered to have comparative bioavailability. Food intake increased elunetirom total exposure (AUC) compared with the fasted state but did not affect maximum exposure (Cmax). In contrast, administration with food reduced LL-340001 Cmax compared with the fasted state but did not affect AUC. Food intake delayed the time to reach Cmax (Tmax) for both elunetirom and LL-340001. Elunetirom, administered orally as a liquid and as a solid formulation, was safe and well tolerated under fed and fasted conditions.