Phase 2 Studies of AQ-13, an Investigative Antimalarial

描述(由申请人提供)： 这项提议的广泛、长期目标是改善抗药性疟疾的治疗。它的具体目标是在成人(AIM 1)和儿童(AIM 2)中进行候选氨基喹啉抗疟疾药物AQ-13的第二阶段人体研究(有效性)。以前的工作可能表明，这些AQS(包括先导化合物AQ-13)在体外对氯喹(CQ)耐药和多重耐药恶性疟原虫具有活性，在松鼠猴感染耐CQ恶性疟原虫模型中对CQ耐药恶性疟原虫具有体内抗CQ活性。基于这些信息以及临床前的毒理学和药理学研究，AQ-13正在进行人体研究。进行的第一阶段人体研究可能没有显示AQ-13和CQ在毒性方面的显著差异。该提案请求支持在马里对人类进行AQ-13的第二阶段(疗效)研究。这些研究将首先在患有无并发症恶性疟的半免疫成人中进行一项随机对照试验剂量发现研究(将1400、1750和2100毫克的AQ-13剂量与目前在马里推荐用于治疗无并发症恶性疟疾的Coartem进行比较)。利用在成人中发现有效和安全的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)，然后研究=5岁的儿童(他们不是半免疫的)。这项针对6-14岁儿童的研究将首先从成人剂量(使用接近结构的类比CQ可能已经成功)推算出每千克基础剂量，然后根据疗效(治愈率)和药代动力学(PK)参数，如基于曲线下面积的生物利用度(AUC)，根据需要修改这些剂量--AUC--AIM 2的A部分。较小的非免疫儿童(=5岁)(AIM 2的B部分)将基于在较大儿童中发现有效的剂量(S)进行研究。这些研究有可能确定新一代AQS的临床有效性和安全性，这些AQS具有对抗CQ耐药和多重耐药恶性疟原虫的活性，口服给药与CQ一样安全，并将与CQ一样经济，为数百万耐CQ恶性疟原虫患者生产(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).