Chotsiri Palang, Wattanakul Thanaporn, Hoglund Richard M, Hanboonkunupakarn Borimas, Pukrittayakamee Sasithon, Blessborn Daniel, Jittamala Podjanee, White Nicholas J, Day Nicholas P J, Tarning Joel
Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand.
Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Br J Clin Pharmacol. 2017 Dec;83(12):2752-2766. doi: 10.1111/bcp.13372. Epub 2017 Aug 16.
The 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.
The 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.
The 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 4.17 ms per 100 ng ml 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 18.9 ms and 16.8 ms, respectively, and would be very unlikely to result in prolongation of more than 50 ms. A single low dose of primaquine can be added safely to the existing DHA-piperaquine treatment in areas of multiresistant Plasmodium falciparum malaria.
Pharmacokinetic-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.
本研究旨在评估双氢青蒿素（DHA）和哌喹的药代动力学特性、与伯氨喹联合治疗时潜在的药物相互作用以及哌喹对健康志愿者心电图的影响。
采用开放标签、随机、交叉研究，对16名健康泰国成年人评估DHA和哌喹的群体药代动力学特性。使用非线性混合效应模型评估药物浓度-时间数据和心电图测量结果。
所建立的模型准确描述了DHA和哌喹的群体药代动力学。与伯氨喹联合治疗不影响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个体校正QT间期与哌喹浓度之间的关系；哌喹血浆浓度每增加100 ng/ml，群体平均QT间期增加4.17 ms。最终模型的模拟结果表明，健康受试者每月和每两个月进行大规模药物给药，QT间期最大延长中位数分别为18.9 ms和16.8 ms，且极不可能导致延长超过50 ms。在多重耐药恶性疟原虫疟疾流行地区，可将单剂量低剂量伯氨喹安全地添加到现有的DHA-哌喹治疗方案中。
在健康成年志愿者中进行的药代动力学-药效学建模和模拟表明，预防或治疗恶性疟原虫疟疾的治疗剂量的DHA-哌喹不太可能与危险的QT间期延长有关。
