恩西韦-富马酸片的1期研究,评估健康成年人群的安全性、药代动力学和食物效果。

IF 2.9 3区 医学 Q2 PHARMACOLOGY & PHARMACY Clinical Drug Investigation Pub Date : 2023-10-01 Epub Date: 2023-10-05 DOI:10.1007/s40261-023-01309-z
Ryosuke Shimizu, Takuhiro Sonoyama, Takahiro Fukuhara, Aya Kuwata, Yumiko Matsuo, Ryuji Kubota
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摘要

背景:据报道,一项用于严重急性呼吸系统综合征冠状病毒2型感染的治疗剂ensitrelvir混悬制剂的临床药代动力学和安全性研究表明,该制剂具有良好的药代动力学,在健康的日本男性和白人参与者中耐受性良好。了解ensitrelvir(使用批准用于临床的制剂)在不同人群中的安全性和药代动力学特征,以及食物的效果,对于优化临床使用至关重要。目的:本研究的目的是:(1)评估在不同种族、年龄和性别的人群中多剂量给药艾司韦片后艾司韦的安全性、耐受性和药代动力学;以及(2)评估食物对禁食或喂食状态下的恩司他韦片的药代动力学的影响。方法:进行了一项1期、多中心、双盲、随机、安慰剂对照研究,以评估在健康日本女性、日本老年人(仅375/125 mg)和白人男性和女性参与者中,每天一次、375/125毫克或750/250毫克负荷/维持剂量的阿司韦片剂持续5天的安全性和药代动力学。还进行了一项开放标签、两组、两个周期的交叉研究,以评估食物对单剂量375 mg的恩曲韦药代动力学的影响。在两项研究的安全性评估中评估并记录了治疗突发不良事件的性质、频率和严重程度。结果:在这些人群中,最大血浆浓度(Cmax)和血浆浓度-时间曲线下面积(AUC)相似。在所有队列中,多剂量给药后恩司曲韦的几何平均半衰期为48.7-58.9小时。日本女性受试者的Cmax和AUC以剂量成比例的方式增加,而白人受试者则以低于剂量成比例方式增加。此外,恩西曲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(C24)的血浆浓度均超过目标血浆浓度(6.09µg/mL)。关于食物对恩曲韦药代动力学的影响,尽管喂食状态下达到Cmax的时间延迟,但禁食状态和喂食状态下恩曲韦的暴露水平(Cmax和AUC)没有临床意义的差异。大多数治疗引发的不良事件性质轻微,已得到解决。结论:恩西韦(375/125 mg和750/250 mg片剂制剂)耐受性良好,没有任何重大安全问题。在研究中,所有人群之间的恩曲韦药代动力学相似,C24在375/125 mg时超过了目标血浆浓度。这些结果表明,恩曲韦可以有效给药,无需根据年龄、性别和种族进行剂量调整,无需食物限制。临床试验注册:日本临床试验注册标识符:jRCT203110202,于2021年7月16日注册。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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

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 (Cmax) 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 Cmax 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 Cmax in the fed state was delayed, there was no clinically meaningful difference in the exposure levels (Cmax 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.

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来源期刊
CiteScore
5.90
自引率
3.10%
发文量
108
审稿时长
6-12 weeks
期刊介绍: Clinical Drug Investigation provides rapid publication of original research covering all phases of clinical drug development and therapeutic use of drugs. The Journal includes: -Clinical trials, outcomes research, clinical pharmacoeconomic studies and pharmacoepidemiology studies with a strong link to optimum prescribing practice for a drug or group of drugs. -Clinical pharmacodynamic and clinical pharmacokinetic studies with a strong link to clinical practice. -Pharmacodynamic and pharmacokinetic studies in healthy volunteers in which significant implications for clinical prescribing are discussed. -Studies focusing on the application of drug delivery technology in healthcare. -Short communications and case study reports that meet the above criteria will also be considered. Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in Clinical Drug Investigation may be accompanied by plain language summaries to assist readers who have some knowledge, but non in-depth expertise in, the area to understand important medical advances.
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