在健康的泰国志愿者体内测试肠外青蒿琥酯新制剂的安全性和药代动力学特性。

IF 2.4 3区 医学 Q3 INFECTIOUS DISEASES
Joel Tarning, Borimas Hanboonkunupakarn, Richard M Hoglund, Kesinee Chotivanich, Mavuto Mukaka, Sasithon Pukrittayakamee, Nicholas P J Day, Nicholas J White, Arjen M Dondorp, Podjanee Jittamala
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引用次数: 0

摘要

背景:肠外青蒿琥酯是治疗重症疟疾的一线疗法。青蒿琥酯的现有配方必须在给药前立即制备,首先溶解在碳酸氢钠溶液中,然后用生理盐水稀释。最近开发出一种新型溶剂,用于快速、稳定地一步复溶青蒿琥酯,其溶解度和稳定性均有改善。本研究旨在比较目前可用的青蒿琥酯肠外制剂和新开发的青蒿琥酯肠外制剂在泰国健康志愿者中的安全性和药代动力学特性:这是一项开放标签、随机、4 期、4 治疗、24 顺序、单剂量、交叉研究,在 72 名男性和女性泰国健康志愿者中进行。在每次给药时,对所有志愿者频繁采集药代动力学样本。观察到的浓度-时间曲线采用非室分析法进行分析,然后进行生物等效性评价:结果:肌肉注射和静脉注射新的青蒿琥酯肠外制剂均安全且耐受性良好,与目前使用的制剂相比没有额外的安全信号。青蒿琥酯及其活性代谢物双氢青蒿素的药代动力学特性特征良好,表明青蒿琥酯可快速转化为双氢青蒿素。肌肉注射新配制的青蒿琥酯后,双氢青蒿素的生物利用度几乎完全达到。新旧制剂的药代动力学特性相似:结论:与目前使用的青蒿琥酯制剂相比,更容易制备的青蒿琥酯新制剂安全且耐受性良好,药代动力学特性相似。静脉注射和肌肉注射青蒿琥酯后,青蒿琥酯的二氢青蒿素(抗疟作用的主要活性代谢产物)的暴露量相当,这表明这两种给药途径产生的治疗效果相当:该研究已在 clinicaltrials.gov 上注册(#TCTR20170907002)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Safety and pharmacokinetic properties of a new formulation of parenteral artesunate in healthy Thai volunteers.

Background: Parenteral artesunate is the first-line therapy for severe malaria. Artesunate, in its current formulation, must be prepared immediately before administration by first dissolving in sodium bicarbonate solution and then diluting in saline. A novel solvent for rapid and stable single step reconstitution of artesunate was recently developed showing improved solubility and stability. This study aimed to compare the safety and pharmacokinetic properties of the currently available and newly developed parenteral formulation of artesunate in healthy Thai volunteers.

Methods: This was an open-label, randomized, 4 periods, 4-treatments, 24-sequence, single-dose, cross-over study in 72 male and female healthy Thai volunteers. Frequent pharmacokinetic samples were collected in all volunteers at each dose occasion. Observed concentration-time profiles were analysed with a non-compartmental approach followed by a bioequivalence evaluation.

Results: Both intramuscular and intravenous administrations of the new parenteral formulation of artesunate were safe and well-tolerated, with no additional safety signals compared to the currently used formulation. The pharmacokinetic properties of artesunate and its active metabolite, dihydroartemisinin, were well-characterized, and showed rapid conversion of artesunate into dihydroartemisinin. Intramuscular administration of the newly formulated artesunate resulted in almost complete bioavailability of dihydroartemisinin. The pharmacokinetic properties were similar between the old and new formulation.

Conclusions: The new and more easily prepared formulation of artesunate was safe and well-tolerated, with similar pharmacokinetic properties compared to the currently used formulation. Dihydroartemisinin, the active metabolite responsible for the majority of the anti-malarial effect, showed equivalent exposure after both intravenous and intramuscular administration of artesunate, suggesting that both routes of administration should generate comparable therapeutic effects.

Trial registration: The study was registered to clinicaltrials.gov (#TCTR20170907002).

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来源期刊
Malaria Journal
Malaria Journal 医学-寄生虫学
CiteScore
5.10
自引率
23.30%
发文量
334
审稿时长
2-4 weeks
期刊介绍: Malaria Journal is aimed at the scientific community interested in malaria in its broadest sense. It is the only journal that publishes exclusively articles on malaria and, as such, it aims to bring together knowledge from the different specialities involved in this very broad discipline, from the bench to the bedside and to the field.
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