他非诺喹对感染恶性疟原虫的健康志愿者血期抗疟活性的研究

Bridget E. Barber, Azrin N. Abd-Rahman, Rebecca Webster, A. Potter, S. Llewellyn, L. Marquart, Nischal Sahai, Indika Leelasena, G. Birrell, M. Edstein, G. Shanks, D. Wesche, Joerg J. Moehrle, J. McCarthy
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Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48+/-2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population. Results Twelve participants were inoculated and administered 200 mg (n=3), 300 mg (n=4), 400 mg (n=2), or 600 mg (n=3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 h and 4.2 h respectively) was faster than with 200 mg or 300 mg (11.8 h and 9.6 h respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants), but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 10^6 and 10^9, respectively, in a 60 kg adult. 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引用次数: 3

摘要

如果长效8-氨基喹啉他非诺喹在足够低的剂量下表现出足够的血期抗疟疾活性,使葡萄糖6-磷酸脱氢酶(G6PD)缺乏的个体能够耐受,那么他非诺喹可能是一个很好的大规模药物给药候选者。方法g6pd正常成人在第0天接种恶性疟原虫3d7感染红细胞。第8天给予不同剂量的他非诺喹单次口服。测定了血浆/全血/尿液中他非诺喹和5,6-正醌代谢物的寄生虫血症和浓度,并进行了标准的安全性评估。如果发生寄生虫再生,或在第48天+/-2天给予治疗性蒿甲醚-氨芳碱治疗。结果是寄生虫清除动力学、药代动力学和药代动力学/药效学(PK/PD)参数的建模,以及理论上流行人群的剂量模拟。结果12名受试者分别接种200 mg (n=3)、300 mg (n=4)、400 mg (n=2)、600 mg (n=3)他非诺喹。400 mg或600 mg的半衰期(分别为5.4 h和4.2 h)比200 mg或300 mg的半衰期(分别为11.8 h和9.6 h)快。在给药200毫克(3/3参与者)和300毫克(3/4参与者)后出现了寄生虫再生,但在400毫克或600毫克后没有出现。使用PK/PD模型的模拟预测,460毫克和540毫克对60公斤成人的寄生虫病清除作用分别为10^6和10^9倍。结论:尽管单剂量或他非诺喹显示出有效的恶性疟原虫血期抗疟活性,但有效清除无性疟原虫的估计剂量需要事先筛查以排除G6PD缺乏症。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Characterizing the Blood-Stage Antimalarial Activity of Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum
Background The long acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD) deficient individuals. Methods Healthy G6PD-normal adults were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia, and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48+/-2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population. Results Twelve participants were inoculated and administered 200 mg (n=3), 300 mg (n=4), 400 mg (n=2), or 600 mg (n=3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 h and 4.2 h respectively) was faster than with 200 mg or 300 mg (11.8 h and 9.6 h respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants), but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 10^6 and 10^9, respectively, in a 60 kg adult. Conclusions Although a single dose or tafenoquine exhibits potent P. falciparum blood stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency.
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