Essential PK/PD relationships of antimalarial drugs

抗疟药物的基本 PK/PD 关系

基本信息

批准号：
10682569
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
项目类别：
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/10682569
关键词：
Address Affect African Animal Model Anti-Bacterial Agents Anti-Infective Agents Anti-malarial drug resistance 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 Protozoa 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

项目摘要

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.

耐药性的不断压力问题会损害个别患者，威胁公共卫生控制工作，并驱动昂贵且耗时的新药发现。对于抗菌和抗菌药物，事实证明，动态体外药代动力学/药效动力学（中空纤维PK/PD）研究已被证明在预测耐药性和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。该提案调查了疟疾的药物疗法，包括组合。通过此赠款的先前资金，我们建立了允许在抗营养药物的体外PK/PD的方法，并且在几十个代理商中，通过浓度或时间发现了明确的治理，这在药物暴露的日志上都是持续的。抗植物的动力学驱动器不是可以预见的，而是与静态/cidal活性或时间杀伤曲线无关，并且与可逆或不可逆的药物作用无关。但是，它是整个班级的（例如，所有测试的三重视都是浓度驱动的）。前瞻性地证实了体外发现（其他来源），并回顾性地与已发表的临床试验数据一致。已经建立和验证了同时部署两种药物的方法。拟议的实验将基于该基础，解决围绕耐药性和联合疗法的问题。研究将具有实验剂，二氢甲蛋白具有添加剂lumefantrine，以及与协同合作伙伴Proguanil的Atovaquone。耐药性研究将使用良好的野生型细胞及其临床相关的耐药突变体进行良好特征的等源性对，其中包括具有较高和低耐药度的突变体。 AIM 1研究将评估单独施用的药物的影响，质疑，对于同样的总剂量，药物压力模式（短寿命高脉冲与恒定较低浓度）是否会差异地影响抗性与野生型细胞的生长。 AIM 2将具有暴露于药物组合的野生型细胞，询问单个伴侣动力学的模式如何影响组合的功效。然后，AIM 3将检查伴侣动力学对抗性细胞的作用，探测其随着时间的恒定比率保持浓度的重要性，并评估匹配（或不）对驱动因素的匹配（或不使用）药物动力学的结果。 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抗植物。