Open-Label Crossover Study of Primaquine and Dihydroartemisinin-Piperaquine Pharmacokinetics in Healthy Adult Thai Subjects
Open-Label Crossover Study of Primaquine and Dihydroartemisinin-Piperaquine Pharmacokinetics in Healthy Adult Thai Subjects
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DOI：
10.1128/aac.03704-14
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发表时间：
2014-12-01
影响因子：
4.9
通讯作者：
White, Nicholas J.
中科院分区：
文献类型：
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作者：
Hanboonkunupakarn, Borimas;Ashley, Elizabeth A.;White, Nicholas J.
双氢青蒿素-哌喹是世卫组织推荐用于治疗无并发症恶性疟原虫疟疾的一种以青蒿素为基础的联合疗法，它正越来越多地用于需要与伯氨喹联合根治的耐药间日疟疾。世卫组织最近加强了其建议，即在以青蒿素为基础的联合行动中增加一剂伯氨喹，以减少恶性疟原虫在低传播环境中的传播。在一项随机交叉研究中，评估了伯氨喹和双氢青蒿素-哌喹在16名健康泰国成年志愿者中的药代动力学。志愿者被随机分为两组，每组3人依次入院，接受30毫克（基础）伯氨喹、3片双氢青蒿素-哌喹（120/960毫克），并以相同剂量同时服用。在服用伯氨喹后3天和服用双氢青蒿素-哌喹后36天分别进行血样采集。药代动力学评估采用非区室方法进行。这些药物耐受性良好。双氢青蒿素和哌喹的药代动力学在加或不加伯氨喹时无统计学差异。双氢青蒿素-哌喹联合用药显著提高血浆伯氨喹水平；最大浓度（C-max）、0 h至研究结束时浓度-时间曲线下面积（AUC(0-last)）和0 h至无穷远时浓度-时间曲线下面积（AUC（0-无穷远））的几何平均比（90%置信区间[CI]）分别为148%（117 ~ 187%）、129%（103 ~ 163%）和128%（102 ~ 161%）。这种相互作用类似于最近描述的与氯喹的相互作用，可能导致增强的根治效果。
Dihydroartemisinin-piperaquine is an artemisinin-based combination treatment (ACT) recommended by the WHO for uncomplicated Plasmodium falciparum malaria, and it is being used increasingly for resistant vivax malaria where combination with primaquine is required for radical cure. The WHO recently reinforced its recommendations to add a single dose of primaquine to ACTs to reduce P. falciparum transmission in low-transmission settings. The pharmacokinetics of primaquine and dihydroartemisinin-piperaquine were evaluated in 16 healthy Thai adult volunteers in a randomized crossover study. Volunteers were randomized to two groups of three sequential hospital admissions to receive 30 mg (base) primaquine, 3 tablets of dihydroartemisinin-piperaquine (120/960 mg), and the drugs together at the same doses. Blood sampling was performed over 3 days following primaquine and 36 days following dihydroartemisinin-piperaquine dosing. Pharmacokinetic assessment was done with a noncompartmental approach. The drugs were well tolerated. There were no statistically significant differences in dihydroartemisinin and piperaquine pharmacokinetics with or without primaquine. Dihydroartemisinin-piperaquine coadministration significantly increased plasma primaquine levels; geometric mean ratios (90% confidence interval [CI]) of primaquine combined versus primaquine alone for maximum concentration (C-max), area under the concentration-time curve from 0 h to the end of the study (AUC(0-last)), and area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)) were 148% (117 to 187%), 129% (103 to 163%), and 128% (102 to 161%), respectively. This interaction is similar to that described recently with chloroquine and may result in an enhanced radical curative effect.