Population pharmacokinetics of mefloquine, piperaquine and artemether-lumefantrine in Cambodian and Tanzanian malaria patients.
Population pharmacokinetics of mefloquine, piperaquine and artemether-lumefantrine in Cambodian and Tanzanian malaria patients.
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DOI：
10.1186/1475-2875-12-235
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发表时间：
2013-07-10
期刊：
影响因子：
3
通讯作者：
Csajka C
中科院分区：
文献类型：
--
作者：
Staehli Hodel EM;Guidi M;Zanolari B;Mercier T;Duong S;Kabanywanyi AM;Ariey F;Buclin T;Beck HP;Decosterd LA;Olliaro P;Genton B;Csajka C
血药浓度-时间曲线的个体间差异可能有助于抗疟疾治疗反应的差异。这项研究调查了三种不同形式的青蒿素联合疗法(ACT)在坦桑尼亚和柬埔寨的药代动力学，以量化和确定潜在的可变性来源。对坦桑尼亚的143名患者(青蒿甲醚、双氢青蒿素、鲁米芬和地丁基-鲁米芬)、柬埔寨的63名患者(青蒿琥酯、双氢青蒿素和甲氟喹)和60名患者(双氢青蒿素和哌喹)进行了药物浓度测定。评估药代动力学参数的个体间和个体内变异，并使用非线性混合效应建模方法(NONMEM®)量化人口统计学和其他协变量的贡献。胃肠道一级吸收的一室模型符合除哌喹(两室)以外的所有药物的数据。浓度暴露的个体间变异约为40%，甲氟喹为12%。在所有测试的协变量中，只有体重(对所有抗疟药)和伴随治疗(仅对蒿甲醚)对这些药物的药代动力学特征有显著影响。由于数据点不足，青蒿琥酯和双氢青蒿素不能在柬埔寨患者中进行研究。模拟的Lumefantrine动力学显示，在相当大比例的患者中，第7天的目标浓度可能无法达到。不同形式的ACT处置的显著差异在很大程度上仍不能用现有的协变量来解释。体重上的剂量似乎是合理的。不受管制的药物使用(入院时发现的残留水平)和次优暴露(变异性)可能会产生较低的血浆水平，这有助于选择耐药寄生虫。
Inter-individual variability in plasma concentration-time profiles might contribute to differences in anti-malarial treatment response. This study investigated the pharmacokinetics of three different forms of artemisinin combination therapy (ACT) in Tanzania and Cambodia to quantify and identify potential sources of variability. Drug concentrations were measured in 143 patients in Tanzania (artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine), and in 63 (artesunate, dihydroartemisinin and mefloquine) and 60 (dihydroartemisinin and piperaquine) patients in Cambodia. Inter- and intra-individual variabilities in the pharmacokinetic parameters were assessed and the contribution of demographic and other covariates was quantified using a nonlinear mixed-effects modelling approach (NONMEM®). A one-compartment model with first-order absorption from the gastrointestinal tract fitted the data for all drugs except piperaquine (two-compartment). Inter-individual variability in concentration exposure was about 40% and 12% for mefloquine. From all the covariates tested, only body weight (for all antimalarials) and concomitant treatment (for artemether only) showed a significant influence on these drugs’ pharmacokinetic profiles. Artesunate and dihydroartemisinin could not be studied in the Cambodian patients due to insufficient data-points. Modeled lumefantrine kinetics showed that the target day 7 concentrations may not be achieved in a substantial proportion of patients. The marked variability in the disposition of different forms of ACT remained largely unexplained by the available covariates. Dosing on body weight appears justified. The concomitance of unregulated drug use (residual levels found on admission) and sub-optimal exposure (variability) could generate low plasma levels that contribute to selecting for drug-resistant parasites.
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影响因子：
3
作者：
Hodel EM;Ley SD;Qi W;Ariey F;Genton B;Beck HP
通讯作者：
Beck HP
影响因子：
6.7
作者：
Barnes, Karen I.;Little, Francesca;White, Nicholas J.
通讯作者：
White, Nicholas J.
DOI：
10.1016/j.jchromb.2009.02.006
发表时间：
2009-04-01
影响因子：
3
作者：
Hodel, E. M.;Zanolari, B.;Decosterd, L. A.
通讯作者：
Decosterd, L. A.
影响因子：
6.4
作者：
Hodel, Eva Maria;Genton, Blaise;Ariey, Frederic
通讯作者：
Ariey, Frederic
影响因子：
3.9
作者：
Ilett, KF;Ethell, BT;Edwards, G
通讯作者：
Edwards, G