Efficacy of artemether-lumefantrine in relation to drug exposure in children with and without severe acute malnutrition: an open comparative intervention study in Mali and Niger.
Efficacy of artemether-lumefantrine in relation to drug exposure in children with and without severe acute malnutrition: an open comparative intervention study in Mali and Niger.
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DOI：
10.1186/s12916-016-0716-1
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发表时间：
2016-10-24
期刊：
影响因子：
9.3
通讯作者：
Etard JF
中科院分区：
文献类型：
--
作者：
Denoeud-Ndam L;Dicko A;Baudin E;Guindo O;Grandesso F;Diawara H;Sissoko S;Sanogo K;Traoré S;Keita S;Barry A;de Smet M;Lasry E;Smit M;Wiesner L;Barnes KI;Djimde AA;Guerin PJ;Grais RF;Doumbo OK;Etard JF
严重急性营养不良(SAM)几乎影响所有器官，并与肠道药物吸收减少有关。然而，关于抗疟疾药物在这一脆弱人群中的药代动力学特性的信息非常有限。我们评估了蒿甲醚-鲁米芬(AL)对患有SAM的儿童和没有SAM的儿童的临床疗效。2013年11月至2015年1月期间，马里和尼日尔登记了患有简单恶性疟原虫的5岁以下儿童，其中三分之一患有简单SAM，三分之二没有。SAM儿童在直接观察下服用由即食治疗性食物(RUTF-Plumpy‘Nut®)组成的脂肪摄入量，在3天内每天两次。对儿童进行了42天的跟踪调查，主要结果是在第28天进行了聚合酶链式反应校正后的充分临床和寄生虫学反应(ACPR)。在不同的时间点对一组参与者的鲁米芬浓度进行了评估，包括在第7天进行系统测量。共有399名儿童(马里360名，尼日尔39名)参加了试验。患有SAM的儿童比非SAM儿童年轻(P <； 0.0001，平均17个月比28个月)。经聚合酶链式反应校正后的ACPR值在第28天和42天分别为100%(95%CI，96.8-100%)和98.8%(96.4-99.7%)，而非SAM组分别为98.8%(96.4-99.7%)和98.3%(95.6-99.4%)(P = 分别为0.236和0.168)。与年龄较小的儿童相比，21个月以上的儿童经历了更多的再感染，直到第28天，SAM与再感染的风险更大(调整后的危险比 = 为2.10(1.04-4.22)，P = 0.038)。SAM患者第7天的鲁米芬浓度显著低于非SAM患者(中位数251vs.365 ng/m L，P = 0.049)。这项研究表明，在没有SAM的儿童中，AL与RUTF联合使用时，对SAM儿童和SAM儿童的疗效相当，但在患有SAM的年龄较大的儿童中，再感染的风险更高。这可能与较差的抗疟疾药物暴露有关，根据第7天较低的Lumefantrine浓度记录。ClinicalTrials.gov：NCT01958905，注册日期：2013年10月7日。本文的在线版本(doi：10.1186/s12916-0160716-1)包含补充材料，授权用户可以使用。
Severe acute malnutrition (SAM) affects almost all organs and has been associated with reduced intestinal absorption of medicines. However, very limited information is available on the pharmacokinetic properties of antimalarial drugs in this vulnerable population. We assessed artemether-lumefantrine (AL) clinical efficacy in children with SAM compared to those without. Children under 5 years of age with uncomplicated P. falciparum malaria were enrolled between November 2013 and January 2015 in Mali and Niger, one third with uncomplicated SAM and two thirds without. AL was administered under direct observation with a fat intake consisting of ready-to-use therapeutic food (RUTF – Plumpy’Nut®) in SAM children, twice daily during 3 days. Children were followed for 42 days, with PCR-corrected adequate clinical and parasitological response (ACPR) at day 28 as the primary outcome. Lumefantrine concentrations were assessed in a subset of participants at different time points, including systematic measurements on day 7. A total of 399 children (360 in Mali and 39 in Niger) were enrolled. Children with SAM were younger than their non-SAM counterparts (mean 17 vs. 28 months, P < 0.0001). PCR-corrected ACPR was 100 % (95 % CI, 96.8–100 %) in SAM at both day 28 and 42, versus 98.8 % (96.4–99.7 %) at day 28 and 98.3 % (95.6–99.4 %) at day 42 in non-SAM (P = 0.236 and 0.168, respectively). Compared to younger children, children older than 21 months experienced more reinfections and SAM was associated with a greater risk of reinfection until day 28 (adjusted hazard ratio = 2.10 (1.04–4.22), P = 0.038). Day 7 lumefantrine concentrations were significantly lower in SAM than non-SAM (median 251 vs. 365 ng/mL, P = 0.049). This study shows comparable therapeutic efficacy of AL in children without SAM and in those with SAM when given in combination with RUTF, but a higher risk of reinfection in older children suffering from SAM. This could be associated with poorer exposure to the antimalarials as documented by a lower lumefantrine concentration on day 7. ClinicalTrials.gov: NCT01958905, registration date: October 7, 2013. The online version of this article (doi:10.1186/s12916-016-0716-1) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Isanaka S;Guesdon B;Labar AS;Hanson K;Langendorf C;Grais RF
通讯作者：
Grais RF
影响因子：
3.6
作者：
Treluyer, JM;Roux, A;Lagardere, B
通讯作者：
Lagardere, B
影响因子：
56.3
作者：
Phiri, Kamija;Esan, Michael;ter Kuile, Feiko O.
通讯作者：
ter Kuile, Feiko O.
影响因子：
4.4
作者：
Su, XZ;Wellems, TE
通讯作者：
Wellems, TE
影响因子：
3
作者：
Checchi, Francesco;Piola, Patrice;Guthmann, Jean-Paul
通讯作者：
Guthmann, Jean-Paul