Pharmacodynamics of Antimalarial Chemoprevention

 描述（由申请人提供）：恶性疟疾仍然是世界上最重要的传染病之一，非洲的儿童和孕妇面临的问题最严重。控制并最终消除疟疾的关键手段之一是间歇性预防治疗，即定期向高危人群提供完整的疗程。 组在非洲，耐药性严重影响了IPT。在治疗恶性疟疾方面，以青蒿素为基础的复方疗法取代了旧的疗法。对于IPT，有必要进行类似的改变，并且合乎逻辑的选择是双氢青蒿素/哌喹（DHA/PQ），其受益于DHA对大多数寄生虫的快速杀死以及由于PQ的半衰期长而在治疗后数周内的保护。我们现在正在乌干达开始一项试验，探索怀孕期间和婴儿每月服用DHA/PQ的预防效果和对免疫反应的影响。我们期望DHA/PQ能提供良好的预防效果。然而，DHA/PQ用于IPT的成功受到3个问题的挑战。首先，该方案的药代动力学（PK），特别是PQ，没有得到很好的表征，特别是在孕妇和幼儿中，以及在IPT的背景下。提高认识是至关重要的，因为现有证据表明，DHA/PQ在幼儿中的剂量不足，并且缺乏怀孕指南。其次，DHA/PQ的药效学不确定。什么样的给药方案能最大限度地提高目标人群的抗疟预防效果？第三，对DHA的耐药性正在东南亚蔓延，更直接的问题是对PQ的耐药性。我们描述的实验，以更好地表征DHA/PQ的PK在孕妇和幼儿接受IPT和表征接触DHA/PQ和疟疾的风险和耐药性的选择之间的关联。我们假设a）DHA/PQ组分的PK在我们的目标人群和非妊娠成年人之间不同，B）PQ的阈值浓度将与预防疟疾相关，以及c）第二个较低的阈值将定义允许疟疾感染但选择耐药寄生虫的PQ浓度。为了验证这些假设，我们将利用我们在乌干达托罗罗（Tororo）进行疟疾研究的出色基础设施，并与我们资助的评估DHA/PQ预防效果的试验相联系。我们将增加试验研究，以提高我们对DHA/PQ的全面影响的理解，这是预防疟疾的最重要的新方案。我们的具体目标是（1）确定DHA/PQ用作乌干达孕妇和儿童IPT时的PK，（2）描述暴露于PQ与孕妇和儿童的循环寄生虫血症、胎盘疟疾和临床疟疾之间的关联，以及（3）描述暴露于DHA和PQ与药物敏感性改变风险之间的关联。总的来说，我们的主要目标是优化孕妇和儿童的IPT与DHA/PQ的给药方案，以在不选择耐药性的情况下预防疟疾。

 DESCRIPTION (provided by applicant): Falciparum malaria remains one of the most important infectious diseases in the world, and the problem is greatest in children and pregnant women in Africa. Among key tools to control and eventually eliminate malaria is intermittent preventive therapy (IPT), the provision of full treatment courses at regular intervals to high risk groups. In Africa, IPT is severely compromised by drug resistance. For treatment of falciparum malaria, older regimens have been replaced by artemisinin-based combination therapies (ACTs). For IPT, a similar change is warranted, and the logical choice is dihydroartemisinin/piperaquine (DHA/PQ), which benefits from rapid killing of most parasites by DHA and protection for weeks after therapy due to the long half-life of PQ. We are now beginning a trial in Uganda that will explore the preventive efficacy and impacts on immune responses of monthly DHA/PQ administered during pregnancy and to infants. We expect that DHA/PQ will offer good preventive efficacy. However, the success of DHA/PQ for IPT is challenged by 3 concerns. First, the pharmacokinetics (PKs) of the regimen, in particular PQ, is not well characterized, especially in pregnant women and young children, and also in the context of IPT. Improved understanding is critical, as available evidence suggests that DHA/PQ is not adequately dosed in young children, and guidelines for pregnancy are lacking. Second, the pharmacodynamics of DHA/PQ are uncertain. What dosing regimens will maximize antimalarial preventive efficacy in target populations? Third, resistance to DHA is spreading in Southeast Asia, and of more immediate concern is resistance to PQ. We describe experiments to better characterize the PKs of DHA/PQ in pregnant women and young children receiving IPT and to characterize associations between exposure to DHA/PQ and risks of malaria and of selection of drug resistance. We hypothesize a) that the PKs of the components of DHA/PQ differ between our target populations and non-pregnant adults, b) that a threshold concentration of PQ will be associated with protection against malaria, and c) that a second lower threshold will define concentrations of PQ that permit malaria infection but select for drug resistant parasites. To test these hypotheses, we will leverage our outstanding infrastructure for malaria research in Tororo, Uganda and link with our funded trial that will assess the preventive efficacy of DHA/PQ. We will add to the trial studies to improve our understanding of the full impact of DHA/PQ, the most important new regimen for the prevention of malaria. Our specific aims will be (1) to define the PKs of DHA/PQ when used as IPT for Ugandan pregnant women and children, (2) to characterize associations between exposure to PQ and circulating parasitemia, placental malaria, and clinical malaria in pregnant women and children, and (3) to characterize associations between exposure to DHA and PQ and risk of altered drug sensitivity. Overall, our primary goal will be to optimize dosing regimens for IPT with DHA/PQ in pregnant women and children to enable protection against malaria without selection of drug resistance.