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: 10453203
• 负责人: Michele Spring
• 金额: $ 28.5万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453203
• 关键词: Address; Adult; Affect; Aminoquinolines; Antimalarials; Area; Biological Assay; Blood; Blood specimen; CYP2D6 gene; Cambodia; Carbon Monoxide; Cell Fraction; Chloroquine; Clinical; Clinical Trials; 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; In Vitro; Individual; Infection; Knowledge; Lead; Liver; Malaria; Maryland; Measures; Mediating; Medical Research; Metabolism; Modeling; Monkeys; Oxidation-Reduction; Parents; Pathway interactions; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Plasma; Plasmodium vivax; Policies; Primaquine; Production; Reactive Oxygen Species; Reading; 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; base; cohort; community transmission; cost; efficacy clinical trial; efficacy evaluation; efficacy study; follow-up; improved; malaria infection; 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 虽然大多数抗疟药对间日疟原虫血液期感染有效，但只有两种FDA批准的8- 氨基喹啉类药物可有效消除休眠的肝催眠虫阶段，如果 如果得不到治疗，可能导致疟疾的多次复发。自1952年以来批准的伯氨喹是主要药物 用于催眠虫清除（根治），并且成本低且广泛可用。伯氨喹（PQ）自由基 治愈失败并不罕见，最常见的原因是两周疗程的给药/依从性，直到 人类肝脏CYP 450 2D 6酶的多态性可导致无效的 伯氨喹代谢成其活性代谢物。药代动力学研究现已发现几种 通过CYP 2D 6途径产生的羟基化代谢物以及5，6邻醌（5，6 OQ）， 假定活性代谢物5-羟基伯氨喹的稳定替代物。这项研究的长期目标是 了解伯氨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， 以成功治疗所有间日疟原虫感染。本提案的目标将决定是否将5，6 OQ可用于预测伯氨喹代谢是否充分，因此可用作即时检测 在治疗过程中评估根治效果，而不是等待数月再次复发。本 最后，拟议的研究将从在泰国和柬埔寨进行的母公司临床试验中获得尿样 将招募并用伯氨喹治疗感染间日疟原虫的成年人，以确定6个月期间的PQ疗效。 还将根据CYP 2D 6状态对尿液5，6 OQ的PK特征和参数进行分类。的 泰国研究还将采集血液样本，以进行血浆和红细胞中的PK，后者是因为它是 怀疑PQ治疗期间红细胞内可能有5，6 OQ蓄积， 一个额外的关联。还将根据各种血液杀肿瘤剂的PQ测量5，6 OQ 这是因为已经发现某些杀寄生虫剂提高或降低功效。如果5，6 OQ可以 提供预测治疗结果的初步证据，进一步的研究可以验证这些发现， 最终找到一条前进的道路，为5，6 OQ测试的治愈，让医疗保健专业人员预测激进的 治愈效果，而不是只有在没有复发的临床证据时才做出决定。