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

项目总结/摘要 背景建议的指导研究计划是一项疟疾化疗药物的调查 在抗寄生虫专家特蕾莎·夏皮罗博士的指导下，马修·伊波利托博士领导了消除工作 药理学和其他。该项目将把临床药理学分析与分子和遗传学分析结合起来， 确定药代动力学（PK，药物暴露）和药效学（PD，药物效应）的方法 用于配子体清除和防止再感染的一线抗疟药， 它们对耐药性的相对屏障。Ippolito博士将获得先进PK/PD方法的专业知识， 临床试验实施。在奖励期结束时，他将准备以独立人士的身份从事职业生涯。 研究人员，重点是对现有抗疟药物和 小说 候选人Ippolito博士是一位委员会认证的内科医生，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候选人 临床调查研究生培训计划，具有疟疾相关研究背景。 Research.拟议的研究将利用来自研究的现有和即将进行的临床试验样本 参与者接受了两种抗疟药物组合之一的无并发症疟疾治疗， 苯芴醇或双氢青蒿素-哌喹。将处理标本以生成PK数据（药物 浓度）和PD数据（寄生虫学结果，耐药基因型）。PK和PD变量将 使用房室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进行， 合作机构。主要导师Theresa Shapiro，MD，PhD的抗寄生虫实验室- 约翰霍普金斯临床药理学部前主任， 药理学分析实验室-包含液相色谱-质谱所需的仪器 以及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 与公共卫生相关。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2亿的感染病例。缺乏足够有效的疫苗、抗疟药物 仍然是疟疾控制方案的重要组成部分。其PK/PD特征不完全， 未知的耐药性障碍转化为进一步研究的机会，以告知药物优化。的 拟议的培训计划和分析方法也有可能应用于新的抗疟剂， 它们来自于药物开发管道。

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.