Pharmacokinetics, Safety Profile, and Tolerability of Tetramethylpyrazine Nitrone Tablets After Single and Multiple Ascending Doses in Healthy Chinese Volunteers.

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Gangzhi Zhu, Liu Wang, Shaojin Zhong, Shengnan Han, Hui Peng, Mei Tong, Xiaoai He
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引用次数: 0

Abstract

Background and objectives: Tetramethylpyrazine nitrone (TBN) is a novel tetramethylpyrazine derivative armed with a strong free radical scavenging nitrone moiety. This study aims to evaluate the pharmacokinetics, safety profile, and tolerability of TBN tablets after a single ascending dose (SAD) and multiple ascending doses (MAD) in healthy Chinese volunteers.

Methods: This phase I, single-center, open-label study was conducted in China. The SAD portion consisted of four cohorts with dose levels of 400-1800 mg. The MAD portion included three cohorts in which subjects received doses of 600-1800 mg twice daily for 7 days (13 consecutive doses). The third portion was a randomized, two-period, crossover design to assess the influence of food with a single dose of TBN tablets (1200 mg). The safety profile was evaluated by monitoring adverse events (AEs), vital signs, electrocardiograms, physical examinations, and laboratory test results.

Results: Fifty-two healthy subjects aged 18 to 45 years with a body mass index between 19.0 and 26.0 kg/m2 were enrolled. After a single dose of TBN, the median time to maximum plasma concentration (Tmax) was 2.48-3.24 h and the mean half-life (t1/2) was 1.28 to 2.10 h across all doses. In the MAD study, the median Tmax was 2.48 to 3.48 h. In the 400-1800 mg dose range, there was a tendency for less than proportional increases in the maximum plasma concentration (Cmax), the area under the concentration-time curve from 0 to time of last measurable concentration (AUC0-t), and the area under the concentration-time curve from 0 to infinity (AUC0-inf) in both single- and multiple-dose periods. A significantly higher TBN exposure was observed in females than males in both a single and multiple doses of the 600 mg and 1200 mg groups, with a geometric mean female-to-male ratio of 138.69-203.18%. Food decreased the Cmax and AUC0-t of TBN to 45.19% and 59.73%, respectively. Each dose group reached a steady state after 4 days. No drug accumulation was observed. Two subjects had drug-related AEs. A decreased neutrophil count and drug eruption in the SAD portion (1200 mg group) and an increased alanine aminotransferase level in the food effect group were found. All AEs were mild and tolerable (CTCAE grade 1) and resolved without any medical intervention.

Conclusion: TBN tablets had a good safety profile and were well tolerated in healthy Chinese volunteers. Steady-state concentrations were reached after 4 consecutive days of oral administration. The results of this phase I study will provide guidance for the design of future TBN clinical studies.

Chinese clinical trial registry: ChiCTR1900022092.

中国健康志愿者服用四甲基吡嗪硝酮片单次和多次给药后的药代动力学、安全性和耐受性研究
背景和目的:四甲基吡嗪腈酮(TBN)是一种新型的四甲基吡嗪衍生物,具有很强的清除自由基的腈基。本研究旨在评估四甲基吡嗪腈酮片在中国健康志愿者中单次递增剂量(SAD)和多次递增剂量(MAD)后的药代动力学、安全性和耐受性:这项 I 期、单中心、开放标签研究在中国进行。SAD 部分包括四个组群,剂量水平为 400-1800 毫克。MAD 部分包括三个组群,受试者接受 600-1800 毫克的剂量,每天两次,共 7 天(连续 13 次)。第三部分为随机、两阶段、交叉设计,以评估食物与单剂量 TBN 片剂(1200 毫克)的影响。通过监测不良事件(AEs)、生命体征、心电图、体格检查和实验室测试结果来评估安全性:52名健康受试者的年龄在18至45岁之间,体重指数在19.0至26.0 kg/m2之间。单剂量服用 TBN 后,达到最大血浆浓度(Tmax)的中位时间为 2.48-3.24 小时,所有剂量的平均半衰期(t1/2)为 1.28-2.10 小时。在 400-1800 毫克剂量范围内,单剂量和多剂量期间的最大血浆浓度(Cmax)、从 0 到最后可测量浓度时间的浓度时间曲线下面积(AUC0-t)以及从 0 到无穷大的浓度时间曲线下面积(AUC0-inf)的增加趋势均不成正比。在 600 毫克和 1200 毫克组的单剂量和多剂量中,观察到女性的 TBN 暴露量明显高于男性,几何平均雌雄比为 138.69-203.18%。食物使 TBN 的 Cmax 和 AUC0-t 分别降低了 45.19% 和 59.73%。各剂量组均在 4 天后达到稳态。未观察到药物蓄积。两名受试者出现了与药物相关的不良反应。在 SAD 部分(1200 毫克组)发现中性粒细胞计数下降和药物疹,在食物效应组发现丙氨酸氨基转移酶水平升高。所有不良反应均轻微且可耐受(CTCAE 1 级),无需任何医疗干预即可缓解:结论:在健康的中国志愿者中,TBN片剂具有良好的安全性和耐受性。结论:TBN 片剂在中国健康志愿者中具有良好的安全性和耐受性,连续口服 4 天后即可达到稳态浓度。本 I 期研究的结果将为今后 TBN 临床研究的设计提供指导:中国临床试验注册号:ChiCTR1900022092。
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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来源期刊
CiteScore
3.70
自引率
0.00%
发文量
64
审稿时长
>12 weeks
期刊介绍: Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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