Essential PK/PD relationships of antimalarial drugs

日益紧迫的耐药性问题危害到个体患者，威胁到公共卫生控制工作，并推动昂贵和耗时的新药发现。对于抗菌和抗真菌药物，动态体外药代动力学/药效学（中空纤维PK/PD）研究已被证明对预测疗效和耐药性选择非常有价值，现在是药物审批包的预期组成部分。这项提议调查了疟疾的药物治疗，包括联合治疗。在此之前的资助下，我们建立了方法，允许对抗原虫药物进行动态的体外PK/PD，并且在几十种药物中发现了浓度或时间的明确治理，这在药物暴露的记录中是恒定的。原生体的动力学驱动不是先验的可预测的，与静态/杀灭活性或时间杀伤曲线无关，与可逆或不可逆药物作用无关。然而，它是全类的（例如，所有测试的三氧环都是浓度驱动的）。体外研究结果在小鼠模型中得到前瞻性证实（有其他来源支持），并与已发表的临床试验数据回顾性一致。已经建立并验证了两种药物同时部署的方法，每种药物都有自己的动力学模式。拟议的实验将建立在这个基础上，解决围绕耐药性和联合治疗的问题。研究将以实验性药物为特色，双氢青蒿素与添加剂伙伴鲁美芳碱，以及阿托伐酮与协同伙伴普罗胍。耐药性研究将用具有良好特征的等基因对野生型细胞及其临床相关的耐药突变体进行，并将包括具有高和低耐药程度的突变体。Aim 1研究将评估单独使用药物的影响，质疑在相同的总剂量下，药物压力模式（短暂的高脉冲vs持续的低浓度）对耐药和野生型细胞生长的影响是否存在差异。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模式如何影响组合的有效性。目标3随后将检查伴侣动力学对耐药细胞的作用，探索随时间保持其浓度恒定比的重要性，并评估匹配（或不匹配）药物动力学与其驱动因素的后果。这些抗疟疾药物组合和耐药性的首次PK/PD研究的结果将为药效的基本PK治理（和耐药性选择）提供一个窗口，将为其他抗原性动物的类似研究提供模板，将为体外动态PK/PD模型人类动力学与寄生虫奠定基础，并将为判断实验和临床使用的抗原性动物提供一个新的指标。

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.