Role of primaquine pharmacokinetics in treatment efficacy for vivax malaria

伯氨喹药代动力学在间日疟疾治疗效果中的作用

• 批准号: 10901353
• 负责人: Michele Spring
• 金额: $ 12.23万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-10 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10901353
• 关键词: Acceleration; Adult; Affect; Aminoquinolines; Antimalarials; Area; Biological Assay; Blood; Blood specimen; CYP2D6 gene; Cambodia; Carbon Monoxide; Categories; Cell Fraction; Chloroquine; Clinical; Clinical Trials; Combined Modality Therapy; Conduct Clinical Trials; Cytochrome P450; Data; Diagnostic tests; Dose; Drug Kinetics; Enrollment; Enzymes; Erythrocytes; FDA approved; Failure; Foundations; Generations; Genetic Polymorphism; Genotype; Goals; Health Professional; Hepatic; Hour; Human; Hydroxylation; In Vitro; Individual; Infection; Knowledge; Liver; Malaria; Maryland; Measures; Mediating; Medical Research; Metabolism; Modeling; Monkeys; Oxidation-Reduction; Parents; Pathway interactions; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Plasma; Plasmodium vivax; Policies; Prediction of Response to Therapy; Primaquine; Production; Quinones; Reactive Oxygen Species; Recurrence; Regimen; Relapse; Reporting; Research; Research Institute; Research Personnel; Risk; Role; Sampling; Testing; Thailand; Treatment Efficacy; Treatment Protocols; Treatment outcome; Universities; Urine; Vivax Malaria; Volunteer Group; artesunate; cohort; community transmission; cost; efficacy clinical trial; efficacy evaluation; efficacy study; follow-up; improved; malaria infection; manufacture; non-genetic; point of care testing; relapse risk; research study; stem; synergism; therapeutic evaluation; treatment guidelines

Project Title: Role of primaquine pharmacokinetics in treatment efficacy for vivax malaria Project Summary While most anti-malarials are active against Plasmodium vivax blood stage infection, only two FDA-approved 8- aminoquinolines medications are effective in eliminating the dormant hepatic hypnozoite stage which, if untreated, can lead to multiple relapses of malaria. Primaquine, approved since 1952, is the primary medication for hypnozoite clearance (radical cure), and is low cost and widely available. Reports of primaquine (PQ) radical cure failure are not uncommon and most often attributed to dosing/compliance to the two-week course, until the illuminating discovery that polymorphisms in the human hepatic CYP450 2D6 enzyme can lead to ineffective metabolism of primaquine to its active metabolites. Pharmacokinetic studies have now detected several hydroxylated metabolites produced through the CYP2D6 pathway as well as the 5,6 orthoquinone (5,6 OQ), a stable surrogate of presumed active metabolite, 5-hydroxyprimaquine. The long-term goal of this research is to understand the pharmacogenomics liabilities of primaquine so it can be better utilized, or regimens altered, in order to to successfully treat all infections with P. vivax. The objective of this proposal will determine if the 5,6 OQ can be used to predict adequate primaquine metabolism , and as such, could be used as a point-of-care test to evaluate efficacy of radical cure during treatment, instead of waiting for months for another relapse. To this end, the proposed study will obtain urine samples from parent clinical trials conducted in Thailand and Cambodia that will enroll and treat P. vivax infected adults with primaquine to determine PQ efficacy over a 6-month period. The PK profiles and parameters of the urine 5,6 OQ will be also categorized according to CYP2D6 status. The Thai study will also collect blood samples to conduct PK in plasma and erythrocytes, the latter since it is suspected that there may be 5,6 OQ accumulating within the red blood cells during PQ treatment, and may be an additional correlate. The 5,6 OQ will also be measured according to PQ given with various blood schizonticide regimens, since it has been found that certain schizonticides either improve or reduce efficacy. If 5,6 OQ can provide initial evidence toward predicting treatment outcome, further research can validate these findings, ultimately finding a path forward for a 5,6 OQ test of cure to allow health care professionals anticipate radical cure efficacy, versus making the determination only when there has been no clinical evidence of relapse.

项目名称：伯氨喹药代动力学在间日疟疗效中的作用 项目摘要 虽然大多数抗疟疾药物对间日疟原虫血液期感染有效，但只有两种FDA批准的8- 氨基喹啉类药物有效地消除了肝脏休眠的催产素阶段，如果 如果得不到治疗，可能会导致疟疾多次复发。伯喹，自1952年被批准以来，是主要的药物 用于催眠药清除(根治)，成本低，可广泛使用。伯喹(PQ)自由基的报道 治愈失败并不少见，最常见的原因是两周疗程的服药/依从性，直到 人类肝脏细胞色素P450 2D6酶基因多态性可导致无效作用的启发性发现 伯喹对其活性代谢物的代谢。药代动力学研究现已检测到 通过CYP2D6途径产生的羟化代谢物以及5，6邻苯二酚(5，6 OQ)，a 推定的活性代谢物5-羟基伯喹的稳定替代品。这项研究的长期目标是 了解伯喹的药物基因组学责任，以便更好地利用它或改变治疗方案 为了成功治疗所有感染间日疟原虫的人。这项提案的目标将决定5，6 OQ可以用来预测伯喹的充足代谢，因此可以作为一种护理点测试。 在治疗期间评估根治性治疗的疗效，而不是等待几个月才再次复发。对这件事 最后，拟议的研究将从泰国和柬埔寨进行的父母临床试验中获得尿样 这将登记和治疗感染间日疟原虫的成年人，用伯氨喹来确定6个月内的PQ疗效。 尿5，6-OQ的PK谱和参数也将根据CYP2D6状态进行分类。这个 泰国的一项研究还将收集血液样本，以在血浆和红细胞中进行PK，后者是因为它是 怀疑在PQ治疗期间，红细胞内可能积聚了5，6 OQ，可能是 还有一个关联。5，6 OQ也将根据给予不同血液分裂素剂的PQ进行测量 治疗方案，因为已经发现某些精神分裂症药物要么提高疗效，要么降低疗效。如果5，6 OQ可以 为预测治疗结果提供初步证据，进一步的研究可以验证这些发现， 最终找到了一条5，6 OQ治愈测试的前进道路，使医疗保健专业人员能够预测激进的 治疗效果，而不是只有在没有临床证据表明复发的情况下才做出判断。