Essential PK/PD Relationships of Antimalarial and Antitrypanosomal Drugs

 描述(由申请人提供)：众所周知，患有疟疾和死于疟疾的人数惊人，抗药性的持续传播也是如此。尽管患有非洲锥虫病(昏睡病)的患者要少得多，但如果不进行治疗，这种感染通常是致命的，而且目前的治疗方法有毒、昂贵，需要非肠道给药。迫切需要对这两种疾病进行安全有效的治疗。鉴于可用于解决这些问题的资源有限，确定最大限度地提高疗效、最大限度地减少耐药性的可能性并减少开发新制剂所需的时间的战略至关重要。所有这一切的关键是合理应用药代动力学/药效学(PK/PD)关系。这项拟议的工作将利用一种新的体外灌流系统，使恶性疟原虫或布氏锥虫暴露于不断变化的药物浓度，类似于体内的动态药代动力学。利用这种仪器的实验表明，抗疟疾活动可能以全班的方式受到浓度或暴露时间的控制，并且这种控制独立于‘静态或’杀灭活动。类似的发现也适用于抗锥虫药物。目的1用传统的综合分析方法来确定实验药物在动物体内的成功(或失败)是否可以至少部分地通过PK的治理与体内动力学的匹配(或不匹配)来解释。目的2探讨临床上重要的抗疟疾和抗锥虫联合治疗的药代动力学因素，以更好地了解联合治疗疗效的主要PK驱动因素。目的3PK/PD模拟实验将在体外单独和联合应用实验性抗恶性疟药物。寄生虫将暴露在I期临床试验衍生的动态方案中动态变化的药物浓度中。PD终点将包括时间-杀灭曲线、滞后时间、99.9%清除时间和存活寄生虫的药物敏感性。这些研究的完全参数分析将包括药物相互作用的蒙特卡罗模拟。后者将确定第二阶段疗效试验的最佳剂量方案。虽然体外动态PK/PD是新的抗原虫药物，实验方法也是创新的，但该项目的交付几乎是有保证的。这项工作的结果将为药物开发的许多方面提供有价值的指导，也可以导致现有药物更合理的剂量。

 DESCRIPTION (provided by applicant): The staggering number of people afflicted with and dying from malaria is well-recognized, as is the ongoing spread of drug-resistance. Although many fewer patients have African trypanosomiasis (sleeping sickness), this infection is uniformly fatal if not treated and current therapies are toxic, expensive, and require parenteral administration. Safe and effective treatments for both diseases are urgently needed. Given the limited resources available to tackle these problems it is critical to identify strategies that maximize efficacy, minimize the likelihood of resistance, and reduce the time required to develop new agents. Pivotal in all of this is the rational application of pharmacokinetic/pharmacodynamic (PK/PD) relationships. The proposed work will utilize a novel in vitro perfusion system that exposes Plasmodium falciparum or Trypanosoma brucei brucei to constantly changing drug concentrations, akin to dynamic pharmacokinetics in vivo. Experiments utilizing this apparatus have revealed that antimalarial activity may be governed in a class-wide fashion by either concentration or time of exposure, and that this governance is independent of 'static or 'cidal activity. Similar findings pertain for antitrypanosomals. Aim 1 wil use traditional integrative analysis to determine whether the reported success (or failure) of experimental drug leads in animals can be explained, at least in part, by match (or mismatch) of PK governance with obtained in vivo kinetics. Aim 2 will explore the pharmacokinetic factors that regulate the efficacy of clinically important antimalarial and antitrypanosomal combination therapies, to obtain a better understanding of the overarching PK drivers of combination efficacy. Aim 3 PK/PD modeling experiments will deploy, solo and in combination, experimental antimalarial drugs against P. falciparum in vitro. Parasites will be exposed to dynamically changing drug concentrations in kinetic regimens derived from Phase I clinical trials. PD endpoints will include time-kill curves, lag time, 99.9 percent clearance time, and drug sensitivit of surviving parasites. Fully parametric analysis of these studies will include drug interaction an Monte Carlo simulation. The latter will identify optimum dosing regimens for Phase 2 efficacy trials. Although in vitro dynamic PK/PD is new to antiprotozoals, and the experimental methods are innovative, the deliverables of this project are near-guaranteed. Results of this work will provide valuable direction to many aspects of drug development and can also lead to the more rational dosing of existing drugs.