A Phase 1 Study of Ensitrelvir Fumaric Acid Tablets Evaluating the Safety, Pharmacokinetics and Food Effect in Healthy Adult Populations,Clinical Drug Investigation

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A Phase 1 Study of Ensitrelvir Fumaric Acid Tablets Evaluating the Safety, Pharmacokinetics and Food Effect in Healthy Adult Populations
Clinical Drug Investigation ( IF 2.9 ) Pub Date : 2023-10-05 , DOI: 10.1007/s40261-023-01309-z
Ryosuke Shimizu ₁ , Takuhiro Sonoyama ₂ , Takahiro Fukuhara ₃ , Aya Kuwata ₃ , Yumiko Matsuo _{1,

4} , Ryuji Kubota ₁

Affiliation

Background

A reported clinical pharmacokinetics and safety study of suspension formulation of ensitrelvir, a therapeutic agent used in severe acute respiratory syndrome coronavirus 2 infection, demonstrated favorable pharmacokinetics and was well tolerated in healthy male Japanese and White participants. Understanding the safety and pharmacokinetic features of ensitrelvir (using the formulation approved for clinical use) in various populations, and the effect of food, is crucial for optimal clinical use.

Objectives

The objectives of this study were to (1) assess the safety, tolerability, and pharmacokinetics of ensitrelvir following multiple-dose administration of ensitrelvir tablets in populations with different races, ages, and sex; and (2) assess the effect of food on the pharmacokinetics of ensitrelvir tablets in the fasted or fed state.

Methods

A phase 1, multicenter, double-blinded, randomized, placebo-controlled study was conducted to evaluate the safety and pharmacokinetics of once-daily ensitrelvir tablets at loading/maintenance doses of 375/125 mg or 750/250 mg for 5 days in healthy Japanese females, Japanese elderly (only 375/125 mg), and White male and female participants. An open-label, two-group, two-period crossover study was also conducted to estimate the effect of food on the pharmacokinetics of ensitrelvir at single dose of 375 mg. The nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded in safety assessments in both studies.

Results

The maximum plasma concentration (C_max) and area under the plasma concentration-time curve (AUC) were similar within these populations. The geometric mean half-life of ensitrelvir following multiple-dose administration was 48.7–58.9 h across all cohorts. The C_max and AUC increased in a dose-proportional manner in Japanese female participants, and increased in a less than dose-proportional manner in White participants. Furthermore, there was no clear relationship between the dose and geometric mean half-life of ensitrelvir. The plasma concentration at 24 h (C₂₄) after an initial dose of 375/125 mg exceeded the target plasma concentration (6.09 µg/mL) in all populations. Regarding the effect of food on the pharmacokinetics of ensitrelvir, although time to C_max in the fed state was delayed, there was no clinically meaningful difference in the exposure levels (C_max and AUC) of ensitrelvir between the fasted and fed states. Most treatment-emergent adverse events were mild in nature and had resolved.

Conclusion

Ensitrelvir (375/125 mg and 750/250 mg tablet formulation) was well tolerated, without any major safety concerns. The pharmacokinetics of ensitrelvir between all populations in the study were similar and C₂₄ exceeded the target plasma concentration at 375/125 mg. These results suggest that ensitrelvir can be effectively administered with no necessity for dose adjustment for age, sex, and race without food restriction.

Clinical Trial Registration

Japan Registry of Clinical Trials identifier: jRCT2031210202, registered on 16 July 2021.

中文翻译：

Ensitrelvir 富马酸片的 1 期研究评估健康成人人群的安全性、药代动力学和食物影响

背景

一项报道的恩西瑞韦悬浮液制剂的临床药代动力学和安全性研究（一种用于严重急性呼吸综合征冠状病毒 2 感染的治疗剂）显示出良好的药代动力学，并且在健康的日本男性和白人参与者中具有良好的耐受性。了解恩西瑞韦（使用批准临床使用的制剂）在不同人群中的安全性和药代动力学特征以及食物的影响对于最佳临床使用至关重要。

目标

本研究的目的是（1）评估不同种族、年龄和性别人群多次剂量服用恩西瑞韦片后的安全性、耐受性和药代动力学； (2) 评估空腹或进食状态下食物对恩西瑞韦片药代动力学的影响。

方法

进行了一项 1 期、多中心、双盲、随机、安慰剂对照研究，以评估每日一次恩西瑞韦片剂在健康受试者中的安全性和药代动力学，负荷/维持剂量为 375/125 mg 或 750/250 mg，持续 5 天。日本女性、日本老年人（仅 375/125 毫克）以及白人男性和女性参与者。还进行了一项开放标签、两组、两期交叉研究，以评估食物对单剂量 375 mg 恩西瑞韦药代动力学的影响。这两项研究的安全性评估中均评估并记录了治疗引起的不良事件的性质、频率和严重程度。

结果

这些人群中的最大血浆浓度 ( C _max ) 和血浆浓度-时间曲线下面积 (AUC) 相似。所有队列中多剂量给药后恩西瑞韦的几何平均半衰期为 48.7-58.9 小时。日本女性参与者的C max 和 AUC 以与剂量成比例的方式增加，而白人参与者的 C _max和 AUC 以低于剂量比例的方式增加。此外，恩西瑞韦的剂量和几何平均半衰期之间没有明确的关系。在所有人群中，初始剂量375/125 mg后24小时（ C ₂₄ ）的血浆浓度超过目标血浆浓度（6.09 µg/mL）。关于食物对恩西瑞韦药代动力学的影响，尽管进食状态下达到C _max的时间延迟，但空腹和进食状态之间恩西瑞韦的暴露水平（ C _max和AUC）没有临床意义的差异。大多数治疗引起的不良事件性质轻微并且已经解决。

结论

Ensitrelvir（375/125 mg 和 750/250 mg 片剂配方）耐受性良好，没有任何重大安全问题。研究中所有人群之间的 enitrelvir 药代动力学相似， C ₂₄超过目标血浆浓度 375/125 mg。这些结果表明，恩西瑞韦可以有效给药，无需根据年龄、性别和种族调整剂量，且不限制食物。