Population pharmacokinetics and electrocardiographic effects of dihydroartemisinin-piperaquine in healthy volunteers
Population pharmacokinetics and electrocardiographic effects of dihydroartemisinin-piperaquine in healthy volunteers
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DOI：
10.1111/bcp.13372
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发表时间：
2017-12-01
影响因子：
3.4
通讯作者：
Tarning, Joel
中科院分区：
文献类型：
--
作者：
Chotsiri, Palang;Wattanakul, Thanaporn;Tarning, Joel
目的评价双氢青蒿素(DHA)和哌喹在健康志愿者体内的药代动力学特性、与伯喹联合用药的药物-药物相互作用以及哌喹对心电图的影响。方法采用开放、随机、交叉研究方法，评价DHA和哌喹在泰国健康成人中的群体药代动力学特性。用非线性混合效应模型对药物浓度-时间数据和心电数据进行了评价。结果所建立的模型准确地描述了DHA和哌喹的群体药代动力学。同时使用伯喹并不影响DHA或哌喹的药代动力学特性。线性药代动力学-药效学模型令人满意地描述了单独校正的QT间期与哌喹浓度之间的关系；群体平均QT间期每增加100 ng ml(-1)哌喹血药浓度增加4.17ms。最终模型的模拟显示，健康受试者每月和两个月集体给药会导致QT间期延长的中位数分别为18.9ms和16.8ms，而不太可能导致超过50ms的延长。在恶性疟多药耐药的地区，可以在现有的DHA-哌喹治疗方法中安全地添加一剂小剂量的伯氨喹。在健康成年志愿者中的malaria.ConclusionsPharmacokinetic-pharmacodynamic模型和模拟表明，在预防或治疗恶性疟的治疗剂量中，DHA-哌喹不太可能与危险的QT延长有关。
AimsThe aims of the present study were to evaluate the pharmacokinetic properties of dihydroartemisinin (DHA) and piperaquine, potential drug-drug interactions with concomitant primaquine treatment, and piperaquine effects on the electrocardiogram in healthy volunteers.MethodsThe population pharmacokinetic properties of DHA and piperaquine were assessed in 16 healthy Thai adults using an open-label, randomized, crossover study. Drug concentration-time data and electrocardiographic measurements were evaluated with nonlinear mixed-effects modelling.ResultsThe developed models described DHA and piperaquine population pharmacokinetics accurately. Concomitant treatment with primaquine did not affect the pharmacokinetic properties of DHA or piperaquine. A linear pharmacokinetic-pharmacodynamic model described satisfactorily the relationship between the individually corrected QT intervals and piperaquine concentrations; the population mean QT interval increased by 4.17ms per 100ng ml(-1) increase in piperaquine plasma concentration. Simulations from the final model showed that monthly and bimonthly mass drug administration in healthy subjects would result in median maximum QT interval prolongations of 18.9ms and 16.8ms, respectively, and would be very unlikely to result in prolongation of more than 50ms. A single low dose of primaquine can be added safely to the existing DHA-piperaquine treatment in areas of multiresistant Plasmodium falciparum malaria.ConclusionsPharmacokinetic-pharmacodynamic modelling and simulation in healthy adult volunteers suggested that therapeutic doses of DHA-piperaquine in the prevention or treatment of P. falciparum malaria are unlikely to be associated with dangerous QT prolongation.