Essential PK/PD Relationships of Antimalarial and Antitrypanosomal Drugs

描述（由申请人提供）：疟疾患者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。尽管患有非洲锥虫病（昏睡病）的患者少得多，但如果不治疗，这种感染是致命的，目前的治疗方法是有毒的，昂贵的，需要肠胃外给药。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，确定最大限度地提高疗效和最大限度地减少耐药性可能性并减少开发新制剂所需时间的战略至关重要。首先是对基本药代动力学/药效学（PK/PD）关系的清晰理解。 一般而言，对于抗感染药物，给定药物暴露的疗效（浓度-时间曲线下面积，AUC）由峰浓度（CMAX）或超过最小有效浓度的时间（TMIC）介导。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，也可以为已上市药物提供更合理的剂量。值得注意的是，几乎没有什么是已知的基本PK/PD的抗疟疾和抗锥虫药物的作用。 拟议的工作将利用一种新型的体外灌注系统，将恶性疟原虫或布氏锥虫暴露于不断变化的药物浓度，模仿人类在给药后遇到的药物浓度。该装置可以被编程为以任何期望的PK曲线递送给定的AUC，包括CMAX或TMIC的极值。初步研究表明，严格的概念验证PK/PD研究现在是可能的。在目标1中，该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为全类关系，是否与细菌相关，以及PK/PD关系如何受到耐药性的影响以及其本身如何影响耐药性。目标2将关注抗锥虫药物的基本PK/PD。虽然CMAX或TMIC介导的功效的概念对于抗原动物是新的，并且实验方法是创新的，但该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一个强大的充分表征的方法，用于确定基本的PK/PD关系;首次描述的PK/PD要求的大多数类别的临床有用的抗疟疾和抗锥虫药物和一些实验药物;和初步的见解可能的作用，PK在抗疟疾药物耐药性。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，抗疟药和抗锥虫药可以被合理地判断和使用。

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.