Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria.
Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria.
复制标题
DOI：
10.1016/j.ebiom.2023.104805
复制
发表时间：
2023-10
期刊：
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
目前尚无单一低剂量伯氨喹 (SLDPQ) 在患有急性恶性疟原虫和葡萄糖-6-磷酸脱氢酶缺乏症 (G6PDd) 的非洲儿童中阻断传播的药代动力学数据。年龄剂量 SLDPQ 的伯氨喹药代动力学（之前显示具有杀配子细胞作用，与安慰剂具有相似的耐受性）在 6 个月至 11 岁的恶性疟原虫感染乌干达和刚果儿童中进行了表征，入院时接受标准 3 天双氢青蒿素-哌喹或蒿甲醚-本芴醇加 SLDPQ 治疗：6 m–<1 年： 1.25 毫克，1-5 岁：2.5 毫克，6-9 岁：5 毫克，10-11 岁：7.5 毫克。通过非房室分析对 LC-MS/MS 测量的血浆伯氨喹和羧基伯氨喹（基线、1、1.5、2、4、8、12、24 小时）进行分析。多变量线性回归建模了协变量之间的关联，包括细胞色素-P450 2D6 代谢状态和结果。对 258 名儿童（中位年龄 5 [四分位距 (IQR) 3-7]）进行了抽样； 8 名（3.1%）早期呕吐者被排除。 0.10–0.40（中位数 0.21，IQR 0.16–0.25）mg 碱/kg 的伯氨喹剂量导致 1.0 至 8.0（中位数 2）小时（Tmax）之间的伯氨喹最大血浆浓度（Cmax）为 2.3–447（中位数 103.0，IQR 72.1–140.0）ng/mL药物浓度曲线下面积中位数 (AUC0-last) 730.2 (6 m–<1 y, n = 12)、582.8 (1–5 y, n = 126)、871.1 (6–9 y, n = 80) 和 931.0 (10–11 y, n = 32) ng*h/mL。中位消除半衰期 (T½) 为 4.7 (IQR 3.8–5.6) 小时。伯氨喹清除率/公斤在 18 个月时达到峰值，在 4 岁时达到稳定水平。 CYP2D6代谢活性评分[差(3/250)、中等(52/250)、正常(150/250)、超快速(5/250)、不确定(40/250)]和基线血红蛋白的增加与较低的伯氨喹AUC0-last显着相关，该AUC0-last随着mg/kg剂量和年龄的增加而增加，但与所用青蒿素治疗无关。年龄剂量的 SLDPQ 导致不同的伯氨喹暴露量，具体取决于体重调整剂量、年龄、基线血红蛋白和 CYP2D6 代谢状态，但不取决于双氢青蒿素-哌喹或蒿甲醚-本芴醇。这些数据支持年龄剂量的 SLDPQ 在撒哈拉以南非洲地区的传输阻断。这项工作由 、 和英国援助署通过（拨款参考号 MR/P006973/1）共同资助。资助者在研究设计、执行、分析和出版决策中没有任何作用。
There are no pharmacokinetic data of single low dose primaquine (SLDPQ) as transmission blocking in African children with acute Plasmodium falciparum and glucose-6-phosphate dehydrogenase deficiency (G6PDd). Primaquine pharmacokinetics of age-dosed SLDPQ (shown previously to be gametocytocidal with similar tolerability as placebo) were characterised in falciparum-infected Ugandan and Congolese children aged 6 months to 11 years, treated on admission with standard 3-day dihydroartemisinin-piperaquine or artemether-lumefantrine plus SLDPQ: 6 m–<1 y: 1.25 mg, 1–5 y: 2.5 mg, 6–9 y: 5 mg, 10–11 y: 7.5 mg. LC-MS/MS-measured plasma primaquine and carboxyprimaquine (baseline, 1, 1.5, 2, 4, 8, 12, 24 h) were analysed by noncompartmental analysis. Multivariable linear regression modelled associations between covariates, including cytochrome-P450 2D6 metaboliser status, and outcomes. 258 children (median age 5 [interquartile range (IQR) 3–7]) were sampled; 8 (3.1%) with early vomiting were excluded. Primaquine doses of 0.10–0.40 (median 0.21, IQR 0.16–0.25) mg base/kg resulted in primaquine maximum plasma concentrations (Cmax) of 2.3–447 (median 103.0, IQR 72.1–140.0) ng/mL between 1.0 and 8.0 (median 2) hours (Tmax) and median areas under the drug concentration curves (AUC0-last) 730.2 (6 m–<1 y, n = 12), 582.8 (1–5 y, n = 126), 871.1 (6–9 y, n = 80), and 931.0 (10–11 y, n = 32) ng∗h/mL. Median elimination half-live (T½) was 4.7 (IQR 3.8–5.6) hours. Primaquine clearance/kg peaked at 18 months, plateauing at 4 y. Increasing CYP2D6 metaboliser activity score [poor (3/250), intermediate (52/250), normal (150/250), ultrarapid (5/250), indeterminate (40/250)] and baseline haemoglobin were significantly associated with a lower primaquine AUC0-last,which increased with increasing mg/kg dose and age but was independent of the artemisinin treatment used. Age-dosed SLDPQ resulted in variable primaquine exposure that depended on bodyweight-adjusted dose, age, baseline haemoglobin and CYP2D6 metaboliser status, but not on dihydroartemisinin-piperaquine or artemether-lumefantrine. These data support age-dosed SLDPQ for transmission blocking in sub-Saharan Africa. This work was cofunded by the , , and UK Aid through the (grant reference MR/P006973/1). The funders had no role in the study design, execution, and analysis and decisions regarding publication.
登录
查看更多内容
影响因子：
3
作者：
Hanpithakpong, Warunee;Day, Nicholas P. J.;White, Nicholas J.;Tarning, Joel
通讯作者：
Tarning, Joel
影响因子：
4.9
作者：
Hanboonkunupakarn, Borimas;Ashley, Elizabeth A.;White, Nicholas J.
通讯作者：
White, Nicholas J.
影响因子：
--
作者：
KLAINER, AS;GILLILAND, PF;BEISEL, WR
通讯作者：
BEISEL, WR
影响因子：
4.9
作者：
Goncalves, Bronner P.;Pett, Helmi;ter Heine, Rob
通讯作者：
ter Heine, Rob
影响因子：
56.3
作者：
Dicko, Alassane;Brown, Joelle M.;Gosling, Roly
通讯作者：
Gosling, Roly