Sulfadoxine-pyrimethamine pharmacokinetics in malaria: Pediatric dosing implications
Sulfadoxine-pyrimethamine pharmacokinetics in malaria: Pediatric dosing implications
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DOI：
10.1016/j.clpt.2006.08.016
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发表时间：
2006-12-01
影响因子：
6.7
通讯作者：
White, Nicholas J.
中科院分区：
文献类型：
--
作者：
Barnes, Karen I.;Little, Francesca;White, Nicholas J.
目的：我们的目的是描述磺胺嘧啶-乙胺嘧啶在非洲成人和儿童急性恶性疟疾的药代动力学特性。尽管几十年的广泛使用，有很少的数据，以告知剂量recommendations.Methods：在一项前瞻性的多中心药代动力学研究，在307例急性恶性疟疾，毛细血管血中磺胺嘧啶和乙胺嘧啶浓度测定在9个访问超过一段时间的42 days。经剂量调整后，2 ~ 5岁儿童的磺胺嘧啶和乙胺嘧啶的浓度-时间曲线下面积（AUC）均为成人的一半（中位AUC，410 μ g/mL d [四分位距（IQR），126-705 μ g/mL d]对比816 μ g/mL d [IQF，磺胺嘧啶为536-1150 μ g/mL d] [P= 0.0001]，乙胺嘧啶为620 ng/mL d [IQF，229-1399 ng/mL d] vs 1518 ng/mL - d [IQR，1117-2013 ng/mL - d]）。与成人相比，年龄对磺胺嘧啶和乙胺嘧啶AUC的影响反映了2至5岁儿童的清除率较高，表观分布容积较大（中位清除率，64.5 mL kg（-1）d（-1）[IQF，46.2-132.6 mL kg（-1）d（-1）]对比32.7 mL kg（-1）d（-1）[IQR，22.3-52.2 mL kg（-1）d（-1）]，磺胺嘧啶[P=.0001]和1.77 L kg（-1）d（-1）[IQR，1.0-3.0 L kg（-1）d（-1）]对比0.85 L kg（-1）d（-1）[IQR，乙胺嘧啶为0.62-1.21 L kg（-1）d（-1）][P=.0001];中位分布容积为413 mL/kg [IQR，299-711 mL/kg]，硫代嘌呤为372 mL/kg [IQR，267-488 mL/kg][P=.0021]，3.83-11.24 L/kg]对比乙胺嘧啶的3.83 L/kg [IQF，2.73-5.11 L/kg][P=.0001]）。第7天磺胺嘧啶和乙胺嘧啶的浓度提供了其各自AUC的良好替代测量（R-2 >= 0.72）。药代动力学因素可能会导致婴幼儿磺胺嘧啶-乙胺嘧啶抗疟治疗失败的风险增加。目前的剂量建议需要修订。我们预测，2至5岁的儿童应与1克磺胺嘧啶/50毫克乙胺嘧啶治疗，以达到药物浓度相当于成人。
Objective: Our objective was to characterize the pharmacokinetic properties of sulfadoxine-pyrimethamine in African adults and children with acute falciparum malaria. Despite decades of widespread use, there are few data to inform dose recommendations.Methods: In a prospective multicenter pharmacokinetic study in 307 patients with acute falciparum malaria, capillary blood concentrations of sulfadoxine and pyrimethamine were determined at 9 visits over a period of 42 days by mass spectrometry.Results. After adjustment for dose, the area under the concentration-time curves (AUCs) of sulfadoxine and pyrimethamine in children aged 2 to 5 years were half of those in adults (median AUC, 410 mu g/mL d [interquartile range (IQR), 126-705 mu/mL d] versus 816 mu g/mL d [IQF, 536-1150 mu g/mL d] [P=.0001] for sulfadoxine and 620 ng/mL d [IQF, 229-1399 ng/mL d] versus 1518 ng/mL - d [IQR, 1117-2013 ng/mL - d] for pyrimethamine). The effect of age on the AUC of sulfadoxine and pyrimethamine reflected higher clearance rates and larger apparent volumes of distribution in children aged 2 to 5 years when compared with adults (median clearance, 64.5 mL kg(-1) d(-1) [IQF, 46.2-132.6 mL kg(-1) d(-1)] versus 32.7 mL kg(-1) d(-1) [IQR, 22.3-52.2 mL kg(-1) d(-1)] for sulfadoxine [P=.0001] and 1.77 L kg(-1) d(-1) [IQR, 1.0-3.0 L kg(-1) d(-1)] versus 0.85 L kg(-1) d(-1) [IQR, 0.62-1.21 L kg(-1) d(-1)] for pyrimethamine [P=.0001]; median volume of distribution, 413 mL/kg [IQR, 299-711 mL/kg] versus 372 mL/kg [IQR, 267-488 mL/kg] for sulfadoxine [P=.0021] and 6.28 L/kg [IQR, 3.83-11.24 L/kg] versus 3.83 L/kg [IQF, 2.73-5.11 L/kg] for pyrimethamine [P=.0001]). Day 7 concentrations of both sulfadoxine and pyrimethamine provided good surrogate measures (R-2 >= 0.72) of their respective AUCs.Conclusions. Pharmacokinetic factors may contribute to the increased risk of sulfadoxine-pyrimethamine antimalarial treatment failure in young children. The current dose recommendations need revision. We predict that children aged 2 to 5 years should be treated with I g sulfadoxine/50 mg pyrimethamine to achieve drug concentrations equivalent to those in adults.