Essential PK/PD Relationships of Antimalarial and Antitrypanosomal Drugs

描述(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的可能性的战略，并减少开发新制剂所需的时间。这其中的关键是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，给定药物暴露的有效性(浓度-时间曲线下的面积，AUC)由峰值浓度(CMAX)或超过最低有效浓度的时间(TMIC)调节。此属性是类范围的，不可预测。深入了解这种关键的PK/PD关系可以为药物开发计划的许多方面提供信息，也可以导致已经上市的药物更合理的剂量。值得注意的是，对控制抗疟疾和抗锥虫药物作用的基本PK/PD几乎一无所知。这项拟议的工作将利用一种新的体外灌流系统，使恶性疟原虫或布鲁氏锥虫暴露在不断变化的药物浓度中，模拟人类在服药后遇到的药物浓度。该设备可以编程为以任何所需的PK配置文件提供给定的AUC，包括CMAX或TMIC的极端情况。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，这一新系统将用于描述所选抗疟疾药物的基本PK/PD，以确定这些关系是否具有类别范围，它们是否与细菌的关系相关，以及PK/PD关系如何受到耐药性的影响，以及PK/PD关系本身是如何影响耐药性的。目标2将重点介绍抗锥虫药物的基本PK/PDs。尽管CMAX或TMIC介导的疗效的概念对抗原虫药物来说是新的，实验方法也是创新的，但该项目的交付几乎是有保证的。这项工作的结果将包括一种确定基本PK/PD关系的可靠的、特征良好的方法；首次描述大多数临床有用的抗疟疾和抗锥虫药物和少数实验药物的PK/PD要求；以及对PKS在抗疟疾药物耐药性中可能发挥的作用的初步见解。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。 与公共卫生有关：疟疾和非洲昏睡病构成严重的公共卫生问题，人们普遍认识到需要新的治疗方法。该项目使用一种新的实验系统来确定动态变化的药物水平如何管理抗寄生虫行动。这些信息可用于帮助开发新药和改善现有药物的使用。

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. PUBLIC HEALTH RELEVANCE: Malaria and African sleeping sickness pose substantial public health problems and the need for new treatments is widely acknowledged. This project uses a novel experimental system to determine how dynamically changing drug levels govern anti-parasitic action. This information can be used to help with the development of new drugs and to improve the use of existing drugs.