Department of Clinical Trials, KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.
Department of Clinical Trials, KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya; Nuffield Department of Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK.
Int J Infect Dis. 2024 Nov;148:107236. doi: 10.1016/j.ijid.2024.107236. Epub 2024 Sep 6.
When malaria vectors consume ivermectin in a blood meal, their survival probability decreases, potentially reducing malaria transmission during mass drug administrations. However, questions remain regarding the optimal dosing. This study aimed to compare the mosquitocidal effect and pharmacokinetics of two-dose regimens of ivermectin for malaria vector control.
We conducted an open-label randomized control trial in Kenya, staggered in blocks with sequential intervention groups and parallel controls. Participants were randomly assigned (2:1:1:1) using computer random-sequence generation, unstratified, with one block of six pharmacokinetics-only participants (single-dose ivermectin) and six blocks of four participants (3:1 intervention vs control), to receive single-dose ivermectin (400 mcg/kg, n = 12), three daily doses (3-day regimen 300 mcg/kg, n = 6), albendazole (400 mg, n = 6), or no treatment (negative control, n = 6). Our primary outcome was Anopheles gambiae survival (time-to-event [days]) after blood feeding up to 10 days after drug administration. We also evaluated pharmacokinetics (peak plasma and capillary blood concentration, areas under the plasma and capillary blood concentration-time curve from time of last administration to time of last observation, time to reach peak plasma and capillary blood concentration, terminal elimination half-life) up to 7 days after treatment.
A total of 36 healthy volunteers aged 21-32 years were recruited into the study and followed up to completion, with two participants not attending the visit on day 28. All drug regimens were well-tolerated. Both regimens showed significant mosquitocidal effect in the first 7 days. At 10 days after treatment, the single dose presented superior longevity of effect (adjusted hazard ratio = 3.91; 95% confidence interval = 1.93-7.93; P <0.001) compared with the triple dose (adjusted hazard ratio = 1.79; 95% confidence interval = 0.88-3.62; P = 0.0.11). Albendazole had, overall, no mosquitocidal effect.
It is unclear why a single dose led to increased bio-efficacy compared with a triple dose. We recommend trials investigating ivermectin mass drug administrations for malaria control to consider single-dose ivermectin. A single-dose regimen is also expected to present additional operational advantages compared with a 3-day regimen, leading to improved programmatic suitability.
当疟疾病媒在一次血餐中摄入伊维菌素时，其存活概率会降低，从而有可能减少大规模药物治疗期间的疟疾传播。然而，关于最佳剂量仍存在一些问题。本研究旨在比较伊维菌素两种剂量方案对疟疾媒介控制的杀蚊效果和药代动力学。
我们在肯尼亚进行了一项开放标签随机对照试验，采用分块的方式进行，分阶段干预组和平行对照组。参与者按照 2:1:1:1 的比例随机分配（计算机随机序列生成，不分层），每组有 6 名仅进行药代动力学研究的参与者（单剂量伊维菌素）和 6 名 4 名参与者（干预组 3 天方案 300 mcg/kg 组 3 名，对照组 1 名），分别接受单剂量伊维菌素（400 mcg/kg，n = 12）、3 天疗程（3 天方案 300 mcg/kg，n = 6）、阿苯达唑（400 mg，n = 6）或不治疗（阴性对照，n = 6）。我们的主要结局是在药物治疗后 10 天内通过血餐摄入后冈比亚按蚊的存活时间（时间事件[天]）。我们还评估了药代动力学（血浆和毛细血管血峰浓度、从最后一次给药到最后一次观察的血浆和毛细血管血浓度时间曲线下面积、达到血浆和毛细血管血峰浓度的时间、终末消除半衰期），直至治疗后 7 天。
共有 36 名年龄在 21-32 岁的健康志愿者入组并完成了研究，其中 2 名参与者在第 28 天未参加随访。所有药物方案均耐受良好。两种方案在最初 7 天内均表现出显著的杀蚊效果。治疗后 10 天，单剂量的效果持续时间明显更长（校正后的危险比=3.91；95%置信区间=1.93-7.93；P <0.001），而 3 天剂量的效果持续时间较短（校正后的危险比=1.79；95%置信区间=0.88-3.62；P = 0.11）。阿苯达唑总体上没有杀蚊效果。
尚不清楚为什么单剂量会比三剂量产生更高的生物功效。我们建议针对疟疾控制进行伊维菌素大规模药物治疗的试验考虑使用单剂量伊维菌素。与 3 天疗程相比，单剂量方案预计还将具有额外的操作优势，从而提高方案的适用性。
