Intrahost modeling of artemisinin resistance in Plasmodium falciparum
Intrahost modeling of artemisinin resistance in Plasmodium falciparum
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DOI：
10.1073/pnas.1006113108
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发表时间：
2011-01-04
影响因子：
11.1
通讯作者：
White, Lisa J.
中科院分区：
文献类型：
--
作者：
Saralamba, Sompob;Pan-Ngum, Wirichada;White, Lisa J.
柬埔寨西部出现了抗青蒿素恶性疟原虫疟疾。耐药的特点是青蒿琥酯治疗后体内寄生虫清除时间延长。其生物学基础尚不清楚。研究人员检验了一种假说，即寄生虫清除延迟是由于循环的年轻无性寄生虫环阶段青蒿素敏感性的阶段性降低。建立了一个数学模型，描述了宿主内寄生虫特定阶段的药代动力学-药效学关系。模型参数的估算使用了39例经青蒿琥酯治疗的无并发症恶性疟疾患者的详细药代动力学和寄生虫清除数据，这些患者分别来自帕林（柬埔寨西部）和王法（泰国西北部），分别接受青蒿素耐药性明显和疗效保持良好的治疗。数学模型以准确的拟合优度再现了每位患者观察到的寄生虫清除率（rmsd: 0.03-0.67, log（10）标度）。与体内观察数据最吻合的参数集包括滋养体和分裂体寄生虫阶段高度保守的浓度-效应关系，而环虫阶段则是可变的关系。基于模型的评估表明，青蒿琥酯对白林环期寄生虫的效果显著降低。这一结果支持了青蒿素耐药性主要反映环期敏感性降低的假设，并预测加倍给药频率将加速对青蒿素耐药寄生虫的清除。
Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia. Resistance is characterized by prolonged in vivo parasite clearance times (PCTs) following artesunate treatment. The biological basis is unclear. The hypothesis that delayed parasite clearance results from a stage-specific reduction in artemisinin sensitivity of the circulating young asexual parasite ring stages was examined. A mathematical model was developed, describing the intrahost parasite stage-specific pharmacokinetic-pharmacodynamic relationships. Model parameters were estimated using detailed pharmacokinetic and parasite clearance data from 39 patients with uncomplicated falciparum malaria treated with artesunate from Pailin (western Cambodia) where artemisinin resistance was evident and 40 patients from Wang Pha (northwestern Thailand) where efficacy was preserved. The mathematical model reproduced the observed parasite clearance for each patient with an accurate goodness of fit (rmsd: 0.03-0.67 in log(10) scale). The parameter sets that provided the best fits with the observed in vivo data consist of a highly conserved concentration-effect relationship for the trophozoite and schizont parasite stages, but a variable relationship for the ring stages. The model-derived assessment suggests that the efficacy of artesunate on ring stage parasites is reduced significantly in Pailin. This result supports the hypothesis that artemisinin resistance mainly reflects reduced ring-stage susceptibility and predicts that doubling the frequency of dosing will accelerate clearance of artemisinin-resistant parasites.