Salman Sam, Bendel Daryl, Lee Toong C, Templeton David, Davis Timothy M E
University of Western Australia, School of Medicine and Pharmacology, Fremantle Hospital, Fremantle, Western Australia, Australia.
Xidea Solutions Limited, Watford, Hertfordshire, England.
Antimicrob Agents Chemother. 2015;59(6):3208-15. doi: 10.1128/AAC.05014-14. Epub 2015 Mar 23.
The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in 91 young African children with severe malaria or who could not tolerate oral antimalarial therapy. Each received 3.0 mg/kg of body weight of artemether at 0, 8, 24, 36, 48, and 60 h or until the initiation of oral treatment. Few blood samples were drawn postdose. Plasma artemether and dihydroartemisinin (DHA) levels were measured using liquid chromatography-mass spectrometry, and the data were analyzed using established population compartmental pharmacokinetic models. Parasite clearance was prompt (median parasite clearance time, 24 h), and there were no serious adverse events. Consistent with studies in healthy adults (S. Salman, D. Bendel, T. C. Lee, D. Templeton, and T. M. E. Davis, Antimicrob Agents Chemother 59:3197-3207, 2015, http://dx.doi.org/10.1128/AAC.05013-14), the absorption of sublingual artemether was biphasic, and multiple dosing was associated with the autoinduction of the metabolism of artemether to DHA (which itself has potent antimalarial activity). In contrast to studies using healthy volunteers, pharmacokinetic modeling indicated that the first absorption phase did not avoid first-pass metabolism, suggesting that the drug is transferred to the upper intestine through postdose fluid/food intake. Simulations using the present data and those from an earlier study in older Melanesian children with uncomplicated malaria treated with artemether-lumefantrine tablets suggested that the bioavailability of sublingual artemether was at least equivalent to that after conventional oral artemether-lumefantrine (median [interquartile range] areas under the concentration-time curve for artemether, 3,403 [2,471 to 4,771] versus 3,063 [2,358 to 4,514] μg · h/liter, respectively; and for DHA, 2,958 [2,146 to 4,278] versus 2,839 [1,812 to 3,488] μg · h/liter, respectively; P ≥ 0.42). These findings suggest that sublingual artemether could be used as prereferral treatment for sick children before transfer for definitive management of severe or moderately severe malaria.
在91名患有严重疟疾或无法耐受口服抗疟治疗的非洲儿童中研究了舌下含服蒿甲醚（ArTiMist）的药代动力学。每名儿童在0、8、24、36、48和60小时时接受3.0mg/kg体重的蒿甲醚，或直至开始口服治疗。给药后采集少量血样。使用液相色谱-质谱法测量血浆蒿甲醚和双氢青蒿素（DHA）水平，并使用既定的群体房室药代动力学模型分析数据。寄生虫清除迅速（中位寄生虫清除时间为24小时），且无严重不良事件。与健康成人中的研究一致（S. Salman、D. Bendel、T. C. Lee、D. Templeton和T. M. E. Davis，《抗菌药物化疗》59:3197 - 3207，2015年，http://dx.doi.org/10.1128/AAC.05013 - 14），舌下含服蒿甲醚的吸收是双相的，多次给药与蒿甲醚代谢为DHA的自身诱导相关（DHA本身具有强大的抗疟活性）。与使用健康志愿者的研究不同，药代动力学建模表明第一个吸收阶段并未避免首过代谢，这表明药物通过给药后液体/食物摄入转移至上段肠道。使用本研究数据以及早期一项针对使用蒿甲醚-本芴醇片治疗的无并发症疟疾的美拉尼西亚大龄儿童的研究数据进行的模拟表明，舌下含服蒿甲醚的生物利用度至少等同于传统口服蒿甲醚-本芴醇后的生物利用度（蒿甲醚浓度-时间曲线下面积的中位数[四分位间距]分别为3403[2471至4771]与3063[2358至4514]μg·h/升；DHA分别为2958[2146至4278]与2839[1812至3488]μg·h/升；P≥0.42）。这些发现表明，舌下含服蒿甲醚可作为患病儿童在转诊前的治疗用药，以便在转诊后对严重或中度严重疟疾进行确定性治疗。
