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

基本信息

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
项目类别：
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

项目摘要

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疾治疗功效中的作用项目概要虽然大多数抗疟药对间日疟原虫血期感染有活性，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休眠子阶段，如果如果不加以治疗，可能会导致疟疾多次复发。伯氨喹自 1952 年起获得批准，是主要药物用于清除催眠体（根治），成本低且广泛使用。伯氨喹（PQ）自由基的报告治愈失败并不罕见，最常见的原因是剂量/遵守两周的疗程，直到人类肝脏 CYP450 2D6 酶的多态性可导致无效的发现，具有启发性伯氨喹代谢为其活性代谢物。目前药代动力学研究已发现多种通过 CYP2D6 途径产生的羟基化代谢物以及 5,6 邻醌 (5,6 OQ) 假定的活性代谢物 5-羟基伯氨喹的稳定替代品。这项研究的长期目标是了解伯氨喹的药物基因组学倾向，以便更好地利用它或改变治疗方案为了成功治疗所有间日疟原虫感染。该提案的目标将决定 5,6 OQ 可用于预测适当的伯氨喹代谢，因此可用作现场护理测试在治疗期间评估根治的疗效，而不是等待数月再次复发。对此最后，拟议的研究将从在泰国和柬埔寨进行的母体临床试验中获取尿液样本该项目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 个月内的 PQ 疗效。尿液 5,6 OQ 的 PK 曲线和参数也将根据 CYP2D6 状态进行分类。这泰国研究还将采集血液样本，对血浆和红细胞进行PK，后者是因为它是怀疑在 PQ 治疗期间可能有 5,6 OQ 积聚在红细胞内，并且可能是一个额外的关联。 5,6 OQ 也将根据使用各种血液裂殖剂给予的 PQ 进行测量治疗方案，因为已经发现某些裂殖剂可以提高或降低疗效。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 5,6 OQ 治愈测试的前进道路，让医疗保健专业人员能够预测根本性的治疗治愈效果，而不是仅在没有临床复发证据时才做出决定。