Essential PK/PD relationships of antimalarial drugs

日益紧迫的耐药性问题损害了个体患者，威胁到公共卫生控制工作，并推动了昂贵而耗时的新药发现。对于抗菌和抗分枝杆菌药物，动态体外药代动力学/药效学（中空纤维PK/PD）研究已被证明对于预测疗效和选择耐药性非常有价值，现在是药物批准包的预期组成部分。该提案研究疟疾的药物疗法，包括联合疗法。利用先前来自该资助的资金，我们建立了允许抗原动物药物的动态体外PK/PD的方法，并且对于几十种药物已经发现了通过浓度或时间的明确治理，即在药物暴露的对数上恒定。抗原虫的动力学驱动因素不是先验可预测的，与静态/杀灭活性或时间杀灭曲线无关，并且不依赖于可逆或不可逆的药物作用。然而，它是全类的（例如，所有测试的三恶烷都是浓度驱动的）。体外结果在鼠模型中得到前瞻性证实（得到其他来源的支持），并与已发表的临床试验数据回顾性一致。同时部署两种药物的方法，每一种都有自己的动力学模式，已经建立和验证。拟议的实验将建立在这个基础上，解决围绕耐药性和联合疗法的问题。研究将采用实验药物，双氢青蒿素与添加剂伙伴苯芴醇，阿托伐醌与协同伙伴氯胍。将使用野生型细胞及其临床相关耐药突变体的充分表征的等基因对进行耐药性研究，并将包括具有高和低耐药性的突变体。目标1研究将评估单独应用药物的影响，质疑对于相同的总剂量，药物压力模式（短暂的高脉冲与恒定的较低浓度）是否对耐药细胞与野生型细胞的生长产生差异影响。目标2将以暴露于药物组合的野生型细胞为特征，询问个体伴侣动力学的模式如何影响组合的功效。目标3然后将检查伴侣动力学对耐药细胞的作用，探索随着时间的推移保持其浓度恒定比例的重要性，并评估药物动力学与其驱动因素匹配（或不匹配）的后果。这些抗疟药联合用药和耐药性的首次PK/PD研究的结果将为疗效（和耐药性选择）的基本PK管理提供一个窗口，将为其他抗原动物的类似研究提供模板，将为模拟人体动力学与寄生虫的动态体外PK/PD奠定基础，并将为判断实验和临床使用的抗原动物提供新的指标。

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.