Artemisinin-Naphthoquine Combination Therapy for Uncomplicated Pediatric Malaria: a Pharmacokinetic Study
Artemisinin-Naphthoquine Combination Therapy for Uncomplicated Pediatric Malaria: a Pharmacokinetic Study
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DOI：
10.1128/aac.06250-11
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发表时间：
2012-05-01
影响因子：
4.9
通讯作者：
Davis, Timothy M. E.
中科院分区：
文献类型：
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作者：
Batty, Kevin T.;Salman, Sam;Davis, Timothy M. E.
青蒿素-萘酚喹(ART-NQ)是一种联合配方的抗疟疾疗法，在巴布亚新几内亚和其他热带国家作为单剂疗法销售。基于对这些成分的药代动力学特性的有限了解，特别是四氨基喹啉NQ，我们研究了巴布亚新几内亚患有简单疟疾的5至12岁儿童的ART-NQ处置，比较了单次剂量(15和6 mg/kg体重)与水(第1组；n=13)、单次剂量(22和9 mg/kg)与牛奶(n=17)以及每天两次剂量22和9 mg/kg加水(第3组；n=16)。用高效液相色谱法测定血浆NQ浓度，用液-质联用法测定血浆ART浓度。建立了NQ和ART的基于群体的多室药代动力学模型。NQ的分布符合三室模型，平均吸收半衰期(t(1/2))为1.0h，第二次给药后预测的最大血药浓度中位数为57mUg/L，平均消除时间t(1/2)为22.8天，相对生物利用度(CL/F)为1.1升/小时/公斤，稳态时相对生物利用度(V-ss/F)为710升/公斤。与水相比，添加脂肪(8.5g；615kJ)的NQ可使生物利用度提高25%。ART倾向符合两室模型，其平均CL/F(4.1升/小时/公斤)和V/F(21升/公斤)与以前的研究结果相似。第二次ART剂量的生物利用度降低了77%(第3组)。NQ具有药代动力学特性，证实了其作为青蒿素伙伴药物治疗简单儿童疟疾的潜力。
Artemisinin-naphthoquine (ART-NQ) is a coformulated antimalarial therapy marketed as a single-dose treatment in Papua New Guinea and other tropical countries. To build on limited knowledge of the pharmacokinetic properties of the components, especially the tetra-aminoquinoline NQ, we studied ART-NQ disposition in Papua New Guinea children aged 5 to 12 years with uncomplicated malaria, comparing a single dose (15 and 6 mg/kg of body weight) administered with water (group 1; n = 13), a single dose (22 and 9 mg/kg) with milk (group 2) (n = 17), and two daily doses of 22 and 9 mg/kg with water (group 3; n = 16). The plasma NQ concentration was assayed by high-performance liquid chromatography, and the plasma ART concentration was assayed using liquid chromatography-mass spectrometry. Population-based multicompartment pharmacokinetic models for NQ and ART were developed. NQ disposition was best characterized by a three-compartment model with a mean absorption half-life (t(1/2)) of 1.0 h and predicted median maximum plasma concentrations that ranged as high as 57 mu g/liter after the second dose in group 3. The mean NQ elimination t(1/2) was 22.8 days; clearance relative to bioavailability (CL/F) was 1.1 liters/h/kg; and volume at steady state relative to bioavailability (V-ss/F) was 710 liters/kg. Administration of NQ with fat (8.5 g; 615 kJ) versus water was associated with 25% increased bioavailability. ART disposition was best characterized by a two-compartment model with a mean CL/F (4.1 liters/h/kg) and V/F (21 liters/kg) similar to those of previous studies. There was a 77% reduction in the bioavailability of the second ART dose (group 3). NQ has pharmacokinetic properties that confirm its potential as an artemisinin partner drug for treatment of uncomplicated pediatric malaria.