Essential PK/PD Relationships of Antimalarial and Antitrypanosomal Drugs

描述（由申请人提供）：受疟疾折磨和死于疟疾的人数惊人，这是众所周知的，抗药性疟疾的持续传播也是如此。虽然患非洲锥虫病（昏睡病）的患者少得多，但如果不加以治疗，这种感染通常是致命的，目前的治疗方法有毒、昂贵，并且需要肠外给药。目前迫切需要安全有效的疟疾和昏睡病治疗方案。鉴于可用于解决这一问题的资源有限，至关重要的是确定能够最大限度地提高疗效和最大限度地减少耐药性可能性的策略，并减少开发新药物所需的时间。关键是要清楚地了解基本的药代动力学/药效学（PK/PD）关系。对于一般的抗感染药物，给定药物暴露的功效（浓度-时间曲线下的面积，AUC）由峰值浓度（CMAX）或最小有效浓度（TMIC）的时间来调节。此属性是类范围的，不可预测。深入了解这种基本的PK/PD关系可以为药物开发计划的许多方面提供信息，也可以使已上市药物的剂量更合理。值得注意的是，对于控制抗疟疾和抗锥虫药物作用的基本PK/ pd几乎一无所知。拟议的工作将利用一种新的体外灌注系统，将恶性疟原虫或布鲁氏锥虫暴露于不断变化的药物浓度中，模拟药物给药后在人体中遇到的情况。该仪器可以编程，以提供给定的AUC在任何所需的PK配置文件，包括极端的CMAX或TMIC。试点研究表明，严格的概念验证PK/PD研究现在是可能的。在Aim 1中，这个新系统将用于描述所选抗疟药的基本PK/PD，以确定这些关系是否在类范围内存在，它们是否与细菌的PK/PD关系相关，以及PK/PD关系如何受到耐药性的影响，以及它本身如何影响耐药性。目的2将重点关注抗锥虫药物的基本PK/ pd。虽然CMAX或tmic介导的疗效对抗原虫来说是一个新的概念，实验方法也是创新的，但本项目的可交付成果几乎是有保证的。这项工作的结果将包括确定基本PK/PD关系的鲁棒性良好的表征方法；首次描述了大多数临床有用的抗疟疾和抗锥虫药物以及一些实验药物的PK/PD要求；并初步了解PKs在抗疟疾药物耐药性中的可能作用。也许最重要的是，它将提供一个迄今为止缺失的框架，在这个框架内，可以判断和合理使用抗疟疾和抗锥虫药物。

DESCRIPTION (provided by applicant): The staggering numbers of people afflicted with and dying from malaria are well-recognized, as is the ongoing spread of drug-resistant malaria. 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 regimens for malaria and sleeping sickness are urgently needed. Given the limited resources available to tackle this problem it is critical to identify strategies that maximize efficacy and minimize the likelihood of resistance, and that reduce the time required to develop new agents. Pivotal in this is a clear understanding of essential pharmacokinetic/pharmacodynamic (PK/PD) relationships. For anti-infectives in general, the efficacy of a given drug exposure (area under the concentration-time curve, AUC) is mediated either by peak concentration (CMAX) or by time over a minimum effective concentration (TMIC). This property is class-wide and not predictable. Insight into this essential PK/PD relationship can inform many aspects of a drug development program, and also lead to more rational dosing of already-marketed drugs. Remarkably, almost nothing is known about the essential PK/PDs that govern antimalarial and antitrypanosomal drug action. The proposed work will utilize a novel in vitro perfusion system that exposes Plasmodium falciparum or Trypanosoma brucei to constantly changing drug concentrations, mimicking those encountered in humans after drug dosing. The apparatus can be programmed to deliver a given AUC in any desired PK profile, including extremes of CMAX or TMIC. Pilot studies demonstrate that rigorous proof-of-concept PK/PD studies are now possible. In Aim 1 this new system will be used to describe the essential PK/PDs for selected antimalarials, to determine whether these relationships are class-wide, if they correlate with those for bacteria, and how the PK/PD relationship is affected by, and itself affects, drug resistance. Aim 2 will focus on the essential PK/PDs of antitrypanosomal drugs. Though the concept of CMAX- or TMIC-mediated efficacy is new to antiprotozoals, and the experimental method is innovative, the deliverables of this project are near-guaranteed. Results of this work will include a robust well-characterized method for determining the essential PK/PD relationships; first-ever descriptions of the PK/PD requirements for most classes of clinically useful antimalarial and antitrypanosomal drugs and a few experimental agents; and preliminary insights into the possible role of PKs in antimalarial drug resistance. Perhaps most important, it will provide a heretofore missing framework within which antimalarial and antitrypanosomal agents can be judged and used rationally.