Single‐Dose Safety, Pharmacokinetics, and Food Effects Studies of Compound Naphthoquine Phosphate Tablets in Healthy Volunteers
Single‐Dose Safety, Pharmacokinetics, and Food Effects Studies of Compound Naphthoquine Phosphate Tablets in Healthy Volunteers
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DOI：
10.1177/0091270009356296
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发表时间：
2010-11
期刊：
影响因子：
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通讯作者：
Hengyan Qu;Hong-zhi Gao;Guang-tao Hao;Yuanyuan Li;Hai-yan Li;Jin Chao Hu;Xiao Fang Wang;Wei Liu;Ze-yuan Liu
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文献类型：
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作者：
Hengyan Qu;Hong-zhi Gao;Guang-tao Hao;Yuanyuan Li;Hai-yan Li;Jin Chao Hu;Xiao Fang Wang;Wei Liu;Ze-yuan Liu
复方磷酸萘酚喹是一种新型抗疟药物片剂，含有磷酸萘酚喹和青蒿素的固定剂量组合，比例为1：2.5。在28名健康男性志愿者中进行了一项关于安全性和耐受性的随机、开放研究，单次口服350 mg、700 mg、1400 mg或2100 mg青蒿素-磷酸氯喹。在30名志愿者中检查了最后3次给药的药代动力学。还确定了食物的影响。使用经验证的高效液相色谱-串联质谱法分析单次经口给药后长达216小时的系列血样的血浆浓度。该化合物在高达2100 mg的单次剂量下耐受性良好。磷酸萘酚喹和青蒿素的暴露增加比例小于剂量比例，呈线性。磷酸萘酚喹的半衰期约为255小时。与单药治疗相比，联合用药使青蒿素（71%和49%）和磷酸萘酚喹（135%和104%）的AUC 0 ‐t和Cmax增加。摄食使青蒿素的AUC 0-t显著增加，增加比例为77%，使磷酸萘酚喹的AUC 0-t从空腹状态下的955 ± 352 μg·h/L降至餐后状态下的446 ± 231 μg·h/L。药物的药代动力学和安全性特征支持其在未来临床研究中继续研究。
The compound naphthoquine phosphate is a novel antimalaria drug tablet containing a fixed‐dose combination of naphthoquine phosphate and artemisinin in a 1:2.5 ratio. A randomized, open study on the safety and tolerability was conducted in 28 healthy male volunteers using a single oral dose of 350 mg, 700 mg, 1400 mg, or 2100 mg of artemisinin‐naphthoquine phosphate. Pharmacokinetics at the last 3 doses were examined in 30 volunteers. Food effects were also determined. Serial blood samples up to 216 hours after single oral dose administration were analyzed for plasma concentrations using a validated high‐performance liquid chromatography‐tandem mass spectrometry assay. The compound was well tolerated at single doses up to 2100 mg. Increased exposure to naphthoquine phosphate and artemisinin was less than dose proportional and linear. The half‐life of naphthoquine phosphate was approximately 255 hours. The combination increased the AUC0‐t and Cmax of both artemisinin (by 71% and 49%) and naphthoquine phosphate (by 135% and 104%) compared with monotherapy. Food intake greatly increased the AUC0‐t of artemisinin with a ratio of 77% and reduced that of naphthoquine phosphate from 955 ± 352 μg·h/L under the fasted state to 446 ± 231 μg·h/L in the fed condition. The pharmacokinetics and safety profile of the drug support its continued investigation in future clinical studies.