MICA: A bioequivalent study to WHO prequalify a new 15 mg primaquine tablet.

MICA：世界卫生组织对新型 15 毫克伯氨喹片进行了生物等效性研究。

• 批准号: MR/V027522/1
• 负责人: Walter Taylor
• 金额: $ 44.1万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV027522%2F1
• 关键词: MICA; bioequivalent; study; WHO; prequalify

Primaquine is an old drug and is recommended for treating malaria, a disease that affects millions of people who live mostly in tropical countries, by targeting different stages of its development. The two main malaria species, Plasmodium falciparum and Plasmodium vivax, are transmitted to humans by infected mosquitoes which inject sporozoites when they bite humans. The sporozoites develop further in the liver and are injected back into the blood to infect red blood cells. In vivax malaria, some parasites stay in the liver as sleeping forms called hypnozoites, which periodically reactivate to set off new cycles of infection, called relapses. The parasites in the red blood cells divide to cause illness but some are programmed to develop male and female sexual forms, called gametocytes. When mosquitoes feed, the gametocytes are taken up and undergo sexual reproduction to produce sporozoites. Primaquine is recommended by the World Health Organization (WHO) to kill hypnozoites to prevent relapses, and block transmission in falciparum patients by killing gametocytes. It's remarkable that primaquine is barely used by malaria control programmes to eliminate malaria even though it is so cheap. One key reason is that few drug companies show interest because profits are small and explains why we only have two tablet strengths on the market, 7.5 and 15 mg, that have been approved by stringent drug regulatory authorities. Such approval gives the public and malaria control programmes confidence that primaquine is of high quality. Another issue is that children need small doses e.g. 2.5 and 5 mg and child-friendly formulations like granules or dispersible tablets but there are none so tablet fractions must be used which are inconvenient and inaccurate. Also, primaquine is very bitter and children don't that. What can be done to remedy this unhappy situation? Our research group is striving to increase the number of approved primaquine tablets by WHO prequalification, equivalent to approval by a stringent drug regulatory authority. We have consulted the WHO on the necessary steps. First, we must produce a generic 15 mg primaquine to high standards and conduct a bioequivalence study where by our test primaquine is given to healthy human adults, then, after it is no longer in the blood, reference 15 mg primaquine, produced by Sanofi. The concentrations of both primaquine formulations are compared and ours must be within 80-125% of the reference primaquine to be accepted by the WHO. When bioequivalence is confirmed, we will prequalify 2.5, 3.75, 5, and 7.5 mg tablets by demonstrating in laboratory tests that they dissolve and have the same distribution of primaquine within the tablet as our prequalified generic 15 mg tablet. In parallel, we plan to work on developing tasteless granules and flavoured dispersible tablets to make swallowing much easier in children. We have partnered with an enthusiastic, Indian drug company, IPCA, which will produce our high quality generic primaquine for the bioequivalence study (and future studies in patients) and help put together the dossier for submission to the WHO. Success in prequalifying primaquine is linked closely to our other work on designing the correct doses of primaquine for transmission blocking and preventing relapses and packaging so that one tablet equals one dose. All we need our funds to carry out our work.

伯氨喹是一种古老的药物，被推荐用于治疗疟疾，这种疾病影响着数百万主要生活在热带国家的人，针对其发展的不同阶段。恶性疟原虫和间日疟原虫这两种主要的疟疾物种通过受感染的蚊子传播给人类，蚊子叮咬人类时会注入子孢子。子孢子在肝脏中进一步发育，并被注射回血液以感染红细胞。在间日疟中，一些寄生虫以休眠形式留在肝脏中，称为催眠虫，它们周期性地重新激活，引发新的感染周期，称为复发。红细胞中的寄生虫会分裂导致疾病，但有些寄生虫会发育成雄性和雌性的性形式，称为配子体。当蚊子进食时，配子体被吸收并进行有性繁殖以产生子孢子。世界卫生组织（WHO）推荐使用伯氨喹杀死催眠虫以防止复发，并通过杀死配子体阻断恶性疟原虫患者的传播。值得注意的是，伯氨喹几乎没有被疟疾控制项目用来消灭疟疾，尽管它是如此便宜。一个关键原因是，由于利润很小，很少有制药公司表现出兴趣，这也解释了为什么我们在市场上只有两种片剂规格，7.5和15 mg，这两种规格已经得到了严格的药品监管机构的批准。这种批准使公众和疟疾控制方案相信伯氨喹是高质量的。另一个问题是，儿童需要小剂量，例如2.5和5 mg，以及儿童友好型制剂，如颗粒剂或分散片，但没有，因此必须使用片剂部分，这是不方便和不准确的。此外，伯氨喹是非常苦的，孩子们不会。有什么办法可以补救这种令人不快的局面呢？我们的研究小组正在努力增加世卫组织预审批准的伯氨喹片剂数量，相当于严格的药品监管机构的批准。我们已就所需的步骤咨询世卫组织。首先，我们必须生产高标准的15毫克伯氨喹仿制药，并进行生物等效性研究，通过我们的测试，将伯氨喹给予健康的成年人，然后，在它不再存在于血液中后，参考赛诺菲生产的15毫克伯氨喹。比较两种伯氨喹制剂的浓度，我们的浓度必须在世界卫生组织接受的参考伯氨喹的80-125%范围内。当生物等效性得到确认时，我们将通过实验室试验证明2.5、3.75、5和7.5 mg片剂的溶解性和伯氨喹在片剂中的分布与我们预先合格的通用15 mg片剂相同，对这些片剂进行预先合格。与此同时，我们计划开发无味颗粒和调味分散片，使儿童更容易吞咽。我们已经与一家热情的印度制药公司IPCA合作，该公司将为生物等效性研究（以及未来的患者研究）生产我们的高质量非专利伯氨喹，并帮助整理提交给世卫组织的档案。伯氨喹资格预审的成功与我们设计伯氨喹的正确剂量以阻断传播和预防复发以及包装以使一片等于一剂的其他工作密切相关。我们只需要资金来开展工作。