Essential PK/PD relationships of antimalarial drugs

抗疟药物的基本 PK/PD 关系

• 批准号: 10463678
• 负责人: Theresa A Shapiro
• 金额: $ 43.83万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10463678
• 关键词: Address; Affect; African; Animal Model; Anti-Bacterial Agents; Anti-Infective Agents; Antimalarials; Antimycobacterial Agents; Antiprotozoal Agents; Artemisinins; Budgets; Cells; Chloroguanide; Clinical; Clinical Trials; Combination Drug Therapy; Consumption; Data; Dose; Drug Approval; Drug Combinations; Drug Design; Drug Exposure; Drug Kinetics; Drug resistance; Drug usage; Elements; Evaluation; Exposure to; Fiber; Foundations; Funding; Genotype; Glass; Goals; Grant; Growth; In Vitro; Individual; Kinetics; Knowledge; Malaria; Measures; Medicine; Methods; Mus; Parasite resistance; Parasites; Parents; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phenotype; Physiologic pulse; Plasmodium falciparum; Population; Predictive Value; Public Health; Publishing; Regimen; Reporting; Resistance; Resources; Role; Source; Study models; System; Techniques; Testing; Time; Trypanosoma; Work; atovaquone; benflumetol; cell type; clinically relevant; cost; drug action; drug candidate; drug discovery; drug-sensitive; experimental study; human model; improved; individual patient; mouse model; mutant; novel; novel therapeutics; pharmacodynamic model; preference; pressure; prospective

The ever-pressing problem of drug resistance harms individual patients, threatens public health control efforts, and drives costly and time-consuming new drug discovery. For antibacterial and antimycobacterial drugs, dynamic in vitro pharmacokinetic/pharmacodynamic (hollow fiber PK/PD) studies have proven exceedingly valuable for predicting efficacy and selection of resistance and are now an expected component of drug approval packages. This proposal investigates drug therapies, including combinations, for malaria. With previous funding from this grant we established methods that allow dynamic in vitro PK/PD for antiprotozoal drugs, and for several dozen agents have discovered an unambiguous governance by either concentration or time, that is constant over logs of drug exposure. The kinetic driver for an antiprotozoal was not a priori predictable, was unrelated to static/cidal activity or time kill curves and was independent of reversible or irreversible drug action. It was, however, class-wide (e.g., all tested trioxanes were concentration-driven). In vitro findings were prospectively confirmed in murine models (supported by other sources) and retrospectively consistent with published clinical trials data. Methods for deploying two drugs simultaneously, each by its own kinetic pattern, have been established and validated. The proposed experiments will build on this foundation, addressing issues surrounding drug resistance and combination therapies. Studies will feature experimental agents, dihydroartemisinin with additive partner lumefantrine, and atovaquone with synergistic partner proguanil. Resistance studies will be conducted with well- characterized isogenic pairs of wild type cells and their clinically relevant drug resistant mutants and will include mutants with high as well as low degrees of resistance. Aim 1 studies will assess the impact of drugs applied singly, questioning whether, for the same total dose, the pattern of drug pressure (short-lived high pulse vs. constant lower concentration) differentially impacts growth of resistant vs. wild type cells. Aim 2 will feature wild type cells exposed to drug combinations, asking how the pattern of individual partner kinetics affects efficacy of the combination. Aim 3 will then examine the role of partner kinetics against resistant cells, probing the importance of maintaining their concentrations at constant ratio over time, and evaluating the consequence of matching (or not) drug kinetics to their drivers. Results from these inaugural PK/PD studies of antimalarial drug combinations and drug resistance will provide a window into the fundamental PK governance of efficacy (and resistance selection), will provide a template for similar study of other antiprotozoals, will set the stage for dynamic in vitro PK/PDs that model human kinetics vs. parasites, and will provide a new metric for judging experimental and clinically used antiprotozoals.

不断迫在眉睫的耐药性问题伤害了个体患者，威胁着公共卫生控制努力，并推动了昂贵而耗时的新药发现。对于抗菌药物和抗分枝杆菌药物，动态的体外药代动力学/药效学(中空纤维PK/PD)研究已被证明在预测疗效和选择耐药性方面非常有价值，现在已成为药物批准包的预期组成部分。该提案调查疟疾的药物疗法，包括联合疗法。利用之前来自这笔赠款的资金，我们建立了允许动态体外PK/PD用于抗原虫药物的方法，并对数十种药物已经发现了一种通过浓度或时间的明确控制，即在药物暴露的对数上是恒定的。抗原虫的动力学驱动力不是先验可预测的，与静态/杀灭活性或时间杀灭曲线无关，与可逆或不可逆的药物作用无关。然而，它是全类的(例如，所有被测试的三恶烷都是由浓度驱动的)。体外研究结果在小鼠模型中得到了前瞻性的证实(得到了其他来源的支持)，并与已发表的临床试验数据回顾一致。已经建立并验证了同时释放两种药物的方法，每种药物都有其自己的动力学模式。拟议的实验将建立在这一基础上，解决围绕耐药性和联合疗法的问题。研究将以实验药物为特色，双氢青蒿素与添加剂鲁米芬配伍，阿托瓦酮与增效伙伴普罗瓜尼配伍。耐药性研究将使用具有良好特性的野生型细胞等基因对及其临床相关的耐药突变株进行，并将包括耐药程度高和低的突变株。目的1研究将评估单独应用药物的影响，质疑在相同的总剂量下，药物压力模式(短暂的高脉冲与恒定的低浓度)是否会对耐药细胞与野生型细胞的生长产生不同的影响。AIM 2将以暴露在药物组合中的野生型细胞为特色，询问个体伴侣动力学模式如何影响组合的疗效。目标3随后将研究伙伴动力学对耐药细胞的作用，探索随着时间的推移将其浓度保持在恒定比率的重要性，并评估与其驱动因素匹配(或不匹配)的药物动力学的结果。这些首创的抗疟疾药物组合和耐药性PK/PD研究的结果将为疗效(和耐药性选择)的基本PK控制提供一个窗口，将为其他抗原虫的类似研究提供模板，将为体外动态PK/PD模拟人类对寄生虫的动力学奠定基础，并将为判断实验和临床使用的抗原虫药物提供新的衡量标准。