Clinical Pharmacology of Malaria Control and Elimination: Pharmacodynamics ofArtemisinin-based Combination Agents and their Barriers to Drug Resistance

项目摘要/摘要 背景资料。建议的指导性研究计划是对疟疾化疗药物的调查。 在抗寄生虫专家Theresa Shapiro博士的指导下，由Matthew Ippolito博士领导的消除 药理学，以及其他。该项目将把临床药理学分析与分子和遗传学结合起来。 建立药物动力学(PK，药物暴露)和药效学(PD，药物效应)的方法 用于清除配子体和防止再次感染的一线抗疟疾药物，并表征 他们对抗药性的相对障碍。伊波利托博士将获得先进的PK/PD方法和 进行临床试验。在获奖期结束时，他将准备作为一名独立人士从事职业生涯 调查员，专注于现有和现有抗疟疾药物的现场临床药理学研究 小说。 候选人。Ippolito博士是一名获得董事会认证的内科医生、传染病专家和临床药理学家 约翰霍普金斯大学医学院，约翰霍普金斯大学博士生 具有疟疾相关研究背景的临床调查研究生培训计划。 研究。拟议的研究将利用研究中现有和即将进行的临床试验样本。 参与者使用两种抗疟疾药物组合中的一种治疗简单疟疾，蒿甲醚- 鲁米芬或双氢青蒿素-哌喹。将对样本进行处理以生成PK数据(药物 浓度)和PD数据(寄生虫学结果、耐药基因)。PK和PD变量将 使用分区和非线性混合效应模型进行分析。 环境和资金。研究活动将在约翰·霍普金斯大学和 合作者的机构。主要导师Theresa Shapiro，医学博士，博士的抗寄生虫实验室- 约翰·霍普金斯大学临床药理学分部前主任和临床分部前负责人 药理分析实验室-包含用于液-质联用的必要仪器 光谱PK分析；约翰霍普金斯疟疾研究所的实验室及其 合作伙伴拥有最先进的疟疾分子诊断和基因测序仪器 寄生虫。 与公共卫生的相关性。疟疾仍然是一个主要的公共卫生问题，有近50万人死亡 每年有超过2亿人感染。如果没有足够有效的疫苗，抗疟疾药物 仍然是疟疾控制项目的重要组成部分。他们不完全表征的PK/PD曲线和 未知的耐药性障碍转化为进一步研究的机会，为药物优化提供信息。这个 拟议的培训计划和分析方法也可能适用于新的抗疟疾药物，如 它们出现在药物开发管道中。

Project Summary/Abstract Background. The proposed mentored research program is an investigation of chemotherapeutics for malaria elimination led by Dr. Matthew Ippolito under the mentorship of Dr. Theresa Shapiro, an expert in antiparasitic pharmacology, and others. The project will join clinical pharmacology analytics with molecular and genetic approaches to establish the pharmacokinetics (PK, drug exposure) and pharmacodynamics (PD, drug effect) of first-line antimalarial agents for gametocyte clearance and protection against reinfection, and characterize their relative barriers to drug resistance. Dr. Ippolito will acquire expertise in advanced PK/PD methods and clinical trial conduct. At the end of the award period, he will be prepared to pursue a career as an independent investigator with a focus on field-based clinical pharmacology studies of antimalarial drugs both extant and novel. Candidate. Dr. Ippolito is a board-certified internist, infectious disease specialist, and clinical pharmacologist at the Johns Hopkins University School of Medicine, and PhD candidate in the Johns Hopkins University Graduate Training Program in Clinical Investigation with a background in malaria-related research. Research. The proposed research will leverage existing and forthcoming clinical trial specimens from study participants treated for uncomplicated malaria with one of two antimalarial drug combinations, artemether- lumefantrine or dihydroartemisinin-piperaquine. Specimens will be processed to generate PK data (drug concentration) and PD data (parasitological outcomes, drug resistance genotypes). PK and PD variables will be analyzed using compartmental and nonlinear mixed effects models. Environment and Funding. The research activities will be carried out at Johns Hopkins University and collaborators' institutions. The antiparasitic laboratories of the primary mentor, Theresa Shapiro, MD, PhD— former director of the Johns Hopkins Division of Clinical Pharmacology and previous head of its Clinical Pharmacology Analytical Laboratory—contain the requisite instrumentation for liquid chromatography-mass spectrometry PK analyses; and the laboratories of the Johns Hopkins Malaria Research Institute and its partners have state-of-the-art instruments for molecular diagnostics and genetic sequencing of malaria parasites. Relevance to Public Health. Malaria remains a major public health issue, with nearly a half-million deaths each year arising from over 200 million infections. Absent a sufficiently effective vaccine, antimalarial drugs remain a vital component of malaria control programs. Their incompletely characterized PK/PD profiles and unknown barriers to resistance translate to opportunities for further research to inform drug optimization. The proposed training plan and analytic approaches also have potential applications to new antimalarial agents as they emerge from the drug development pipeline.