Phase 2 Studies of AQ-13, an Investigative Antimalarial

描述（由申请人提供）： 这项建议的广泛、长期目标是改善对抗药性疟疾的治疗。 其具体目标是在成人（AIM 1）和儿童（AIM 2）中进行候选氨基喹啉抗疟药AQ-13的2期人体研究（疗效）。 先前的工作可能已经表明，这些AQ（包括先导化合物AQ-13）在体外对氯喹（CQ）抗性和多重抗性恶性疟原虫具有活性，并且在人类感染CQ抗性恶性疟原虫的松鼠猴模型中对CQ抗性恶性疟原虫具有体内活性。 基于这些信息和临床前毒理学和药理学研究，正在对AQ-13进行人体研究。 进行的I期人体研究可能显示AQ-13和CQ之间的毒性无显著差异。 该提案要求支持在马里进行AQ-13人体2期（疗效）研究。 这些研究将开始，在患有无并发症的恶性疟原虫疟疾的半免疫成人中进行随机对照试验剂量探索研究（比较AQ-13剂量为1400、1750和2100毫克的碱与Coartem，Coartem是目前推荐的马里无并发症恶性疟原虫疟疾治疗方法）。使用成人中发现的有效和安全的AQ-13剂量，这些研究将转移到研究6-14岁的儿童（在马里也是半免疫的），随后是5岁以下的儿童（不是半免疫的）。 在6-14岁儿童中的研究将开始，从成人剂量外推每千克剂量的毫克碱（这可能已经成功地使用了接近结构的类似物CQ），并根据疗效（治愈率）和药代动力学（PK）参数（如基于曲线下面积（AUC）的生物利用度）-AIM 2的A部分-根据需要修改这些剂量。 然后将根据在年龄较大儿童中发现的有效剂量，研究年龄较小的非免疫儿童（≥ 5岁）（AIM 2的B部分）。 这些研究有可能确定新一代具有抗CQ耐药和多重耐药恶性疟原虫活性的AQ的临床疗效和安全性，这些AQ口服给药，与CQ一样安全，并且与CQ一样经济，可以为数百万患有CQ耐药恶性疟原虫的个体生产（例如，三剂治疗，每剂约0.03美元）。

DESCRIPTION (provided by applicant): The broad, long-term objective of this proposal is to improve the treatment of drug-resistant malaria. Its specific aims are to perform Phase 2 human studies (efficacy) of a candidate aminoquinoline antimalarial, AQ-13, in adults (AIM 1) and children (AIM 2). Previous work may have shown that these AQs (including the lead compound, AQ-13) are active in vitro against chloroquine (CQ) resistant and multiresistant P. falciparum, and in vivo against CQ resistant P. falciparum in the squirrel monkey model of human infection with CQ-resistant P. falciparum. Based on that information and preclinical toxicologic and pharmacologic studies, AQ-13 is being studied in humans. The Phase 1 Human Studies performed may have revealed no significant differences in toxicity between AQ-13 and CQ. This proposal requests support to perform Phase 2 (efficacy) studies of AQ-13 in humans in Mali. These studies will begin with a randomized controlled trial dose-finding study in semi-immune adults with uncomplicated P. falciparum malaria (comparing AQ-13 doses of 1400, 1750 and 2100 milligrams of base to Coartem, the currently recommended treatment for uncomplicated P. falciparum malaria in Mali). Using the doses of AQ-13 found effective and safe in adults, these studies will move to studying children 6-14 years of age (who are also semi-immune in Mali), and subsequently to children = 5 years of age (who are not semi-immune). The studies in children 6-14 years of age will begin with milligrams of base per kilogram dose extrapolations from the adult dose (which may have been successful with the close structural analog CQ) and modify those doses as needed based on efficacy (cure rates) and pharmacokinetic (PK) parameters such as bioavailability based on Area Under the Curve (AUC)--part A of AIM 2. Younger non-immune children (= 5 years of age) (part B of AIM 2) will then be studied based on the dose(s) found effective in older children. These studies have the potential to establish clinical efficacy and safety for a new generation of AQs with activity against CQ-resistant and multiresistant P. falciparum, which are administered orally, are as safe as CQ, and would be as economical as CQ to produce for the millions of individuals suffering from CQ-resistant P. falciparum (for example, three dose treatment at roughly $0.03 per dose).