Pharmacokinetics and safety evaluation in healthy Chinese volunteers of alkaloids from leaf of Alstonia scholaris: A multiple doses phase I clinical trial
Pharmacokinetics and safety evaluation in healthy Chinese volunteers of alkaloids from leaf of Alstonia scholaris: A multiple doses phase I clinical trial
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红花叶生物碱在中国健康志愿者中的药代动力学和安全性评价：多剂量I期临床试验
DOI：
10.1016/j.phymed.2019.152828
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发表时间：
2019-08-01
期刊：
影响因子：
7.9
通讯作者：
Gao, Rui
中科院分区：
文献类型：
--
作者：
Li, Rui;Zi, Ming-Jie;Gao, Rui
背景：罗布麻科植物罗布麻属植物中含有丰富的吲哚类生物碱，具有显著的生物活性。苦参叶已被用于治疗呼吸系统疾病的民族药物，确定的苦参叶吲哚生物碱已被中国食品药品监督管理局批准为植物新药研究用药(编号：2011L01436)。目的：评价苦参叶生物碱胶囊不同剂量口服给药的安全性及给药频度与药代动力学的关系。方法：采用随机、开放、单中心临床试验方法，对苦参叶生物碱胶囊进行安全性评价，探讨不同剂量苦参叶生物碱胶囊给药频度与药代动力学的关系。中国健康受试者口服不同剂量的CALAS，评价其安全性和药动学。每名志愿者(每组10人)口服CALAS 20 mg、40 mg、80 mg至120 mg。采用LC-MS/MS法研究了CALAS在健康受试者血浆中的药代动力学。在整个研究过程中，对安全性进行了生化和临床评估，并进行了药物再激发研究，以验证研究产品与轻微不良事件之间的相关性。该试验于2015年8月26日注册(http://www.chictr.Org.cn/showproj.aspx？proj=11736)，Numbers ChiCTR-IPR-15006976。结果：40名受试者在健康志愿者中的血药浓度最高，各化合物的AUC暴露水平由高到低依次为：Vallesamine>；Searicine>；19-epischolaricine>；Piclinine。对于CALAS的安全性评价，在试验过程中观察到两例轻微不良事件，但药物再激发研究表明，这两种不良事件与个体的生理变化有关。结论：各成分的药代动力学特征不同。19-表胆碱碱、伐拉西明和苦参碱符合线性药动学特征，而苦参碱符合非线性药动学特征。在目前的剂量方案下，CALAS在健康受试者中是安全的。
Background: Alstonia scholaris (Apocynaceae) was reported to be a rich source of indole alkaloids, which exhibited remarkably bioactivities. The leaf of A. scholaris has been used in 'dai' ethno-medicine for treatment of respiratory diseases, and the defined indole alkaloids from leaf of A. scholaris has been registered as investigational new botanical drug (No. 2011L01436) and was approved for phase I/II clinical trials by China Food and Drug Administration (CFDA).Purpose: The aim of the trial is to evaluate the safety and explore the relationship of dosing frequency and pharmacokinetics after oral administration of capsule of alkaloids from leaf of A. scholaris (CALAS) at different doses.Methods: In this randomized, open-labelled, single-center clinical trial, the safety and pharmacokinetics of CALAS were assessed in eligible healthy Chinese volunteers after oral administration of different doses. Each volunteer (n = 10 per group) received single dose of CALAS from 20 mg, 40 mg, 80 mg to 120 mg orally. The pharmacokinetics of CALAS was investigated in healthy Chinese subjects' plasma by a fully-validated LC-MS/MS method. Safety was assessed biochemically and clinically throughout the study, and drug re-excitation research was conducted to verify the correlation between investigational product and minor adverse events. The trial was registered on August 26, 2015 (http://www.chictr. org.cn/showproj.aspx?proj = 11736), number ChiCTR-IPR-15006976.Results: 40 subjects completed the study, and as a result, vallesamine had the highest concentration in plasma of healthy volunteers, and the AUC exposure level in each compounds in turn is vallesamine > scholaricine > 19-epischolaricine > picrinine. For the safety evaluation of CALAS, two cases of minor adverse events were observed during the trial, but the drug re-excitation research indicated that these two adverse events were related to the individual's physiological variation.Conclusion: Pharmacokinetic characteristics of each ingredient showed different patterns. 19-epischolaricine, vallesamine and picrinine were match to the linear pharmacokinetic characteristics, but scholaricine conformed to the characteristics of nonlinear pharmacokinetics. The CALAS was safe in healthy subjects under the current dose regimen.