Background and Objectives

Currently, there are no US FDA-approved therapies for eosinophilic esophagitis (EoE). Budesonide oral suspension (BOS; SHP621, TAK-721) is a viscous, muco-adherent, oral formulation of budesonide that is in phase III development for the treatment of EoE. BOS 2 mg twice daily was studied in 12- and 36-week phase III studies for the induction and maintenance of clinical remission in adults and adolescents with EoE (NCT02605837 and NCT02736409). ENTOCORT EC is a gelatin capsule formulation of budesonide that is FDA-approved for the treatment of mild-to-moderate active Crohn’s disease (CD) in adults and children. This study compared the systemic exposure to budesonide from BOS with that from ENTOCORT EC, aiming to provide the pharmacokinetic (PK) bridge to the safety data of ENTOCORT EC.

Methods

Healthy adult volunteers (n = 22) were enrolled in an open-label, single-center, crossover study. Participants received a single oral dose of BOS 2 mg and a single oral dose of ENTOCORT EC 9 mg under fasting conditions in a randomized sequence, with a 48-h washout period between treatments. PK parameters were calculated by non-compartmental analysis and compared between treatments using a mixed-effects model with sequence and treatment as fixed effects and individuals within sequence as a random effect.

Results

Plasma budesonide concentrations showed that budesonide was absorbed significantly faster from BOS 2 mg than from ENTOCORT EC 9 mg, with peak concentrations reached at 1.5 and 4 h, respectively (p < 0.001). Systemic exposure to budesonide after a single oral dose of BOS 2 mg was lower than that observed after a single oral dose of ENTOCORT EC 9 mg; the least squares geometric mean maximum plasma concentration and the area under the concentration–time curve from the time of dosing to infinity and from the time of dosing to the last measurable concentration of budesonide after BOS 2 mg were 71.1%, 33.5%, and 33.6% of those after ENTOCORT EC 9 mg, respectively. No notable differences in treatment-emergent adverse events were observed between individuals treated with either drug; all events were mild and none resulted in discontinuation from the study.

Conclusions

This study demonstrated that systemic exposure to budesonide after a single oral dose of BOS 2 mg was lower than that after a single oral dose of ENTOCORT EC 9 mg. These results provide PK bridging data to compare BOS with therapeutic doses of ENTOCORT EC with respect to safety information.

中文翻译：

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比较健康个体布地奈德口服混悬液和 ENTOCORT EC 全身暴露于布地奈德的药代动力学桥接研究

背景和目标

目前，没有美国 FDA 批准的嗜酸性粒细胞性食管炎 (EoE) 疗法。布地奈德口服混悬液（BOS；SHP621，TAK-721）是一种粘性、黏膜粘附的布地奈德口服制剂，处于 III 期开发阶段，用于治疗 EoE。在 12 周和 36 周的 III 期研究中，每天两次 BOS 2 mg 用于诱导和维持 EoE 成人和青少年的临床缓解（NCT02605837 和 NCT02736409）。ENTOCORT EC 是一种布地奈德的明胶胶囊制剂，经 FDA 批准用于治疗成人和儿童的轻度至中度活动性克罗恩病 (CD)。本研究比较了 BOS 与 ENTOCORT EC 布地奈德的全身暴露，旨在为 ENTOCORT EC 的安全性数据提供药代动力学 (PK) 桥梁。

方法

健康成年志愿者 ( n  = 22) 参加了一项开放标签、单中心、交叉研究。参与者在禁食条件下以随机顺序接受单次口服 BOS 2 mg 和单次口服 ENTOCORT EC 9 mg，治疗之间有 48 小时的清除期。PK 参数是通过非房室分析计算的，并使用混合效应模型在治疗之间进行比较，序列和治疗作为固定效应，序列内的个体作为随机效应。

结果

血浆布地奈德浓度显示布地奈德从 BOS 2 mg 吸收比从 ENTOCORT EC 9 mg 吸收明显更快，峰值浓度分别在 1.5 和 4 小时达到（p < 0.001)。单次口服 BOS 2 mg 后布地奈德的全身暴露低于单次口服 ENTOCORT EC 9 mg 后观察到的暴露；最小二乘几何平均最大血浆浓度和从给药时间到无穷大以及从给药时间到 BOS 2 mg 后布地奈德的最后可测量浓度的浓度-时间曲线下面积分别为 71.1%、33.5% 和 33.6 ENTOCORT EC 9 mg 后的百分比。两种药物治疗的个体之间未观察到治疗中出现的不良事件的显着差异；所有事件都是轻微的，没有任何事件导致研究中止。

结论

该研究表明，单次口服 BOS 2 mg 后布地奈德的全身暴露低于单次口服 ENTOCORT EC 9 mg 后的全身暴露。这些结果提供了 PK 桥接数据，以在安全性信息方面比较 BOS 与治疗剂量的 ENTOCORT EC。