Essential PK/PD Relationships of Antimalarial and Antitrypanosomal Drugs

抗疟药和抗锥虫药物的基本 PK/PD 关系

• 批准号: 9476905
• 负责人: Theresa A Shapiro
• 金额: $ 36.45万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9476905
• 关键词: African Trypanosomiasis; Animals; Anti-Bacterial Agents; Antimalarials; Antiparasitic Agents; Area; Artemisinins; Belief; Case Study; Characteristics; Chloroguanide; Chloroquine; Clinical; Combined Modality Therapy; Data; Development; Diagnostic; Disease; Dose; Drug Combinations; Drug Interactions; Drug Kinetics; Drug resistance; Eflornithine; Exposure to; Failure; Geldanamycin; Grant; Half-Life; Human; In Vitro; Infection; Kinetics; Lead; Malaria; Medicine; Methods; Monte Carlo Method; Mus; New Agents; Nifurtimox; Outcome; Parasites; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Plasma; Plasmodium falciparum; Population; Probability; Property; Proteins; Public Health; RTN4 gene; Regimen; Reporting; Resistance; Resources; Side; System; Therapeutic Uses; Time; Trypanosoma brucei brucei; Work; atovaquone; clinical efficacy; design; drug candidate; drug development; drug efficacy; effective therapy; efficacy trial; experimental study; improved; in vitro Model; in vivo; innovation; novel; novel therapeutics; parenteral administration; pharmacodynamic model; pharmacokinetic model; preclinical development; public health relevance; success; tool

 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.

 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可能性并减少开发新制剂所需时间的策略至关重要。所有这一切的关键是药代动力学/药效学（PK/PD）关系的合理应用。拟议的工作将利用一种新的体外灌注系统，将恶性疟原虫或布氏锥虫暴露于不断变化的药物浓度，类似于体内动态药代动力学。利用该装置的实验表明，抗疟活性可能是由浓度或暴露时间的类宽的方式，这种治理是独立的“静态或”杀活性。类似的发现也适用于抗锥虫药物。目的1将使用传统的综合分析，以确定是否报告的成功（或失败）的实验药物线索在动物中可以解释，至少部分地，通过匹配（或不匹配）的PK管理与获得的体内动力学。目的2将探索调节临床重要的抗疟和抗锥虫联合治疗疗效的药代动力学因素，以更好地了解联合治疗疗效的总体PK驱动因素。目的3个药代动力学/药效学模型实验将在体外部署抗恶性疟原虫的实验性抗疟药物（单独或联合）。寄生虫将暴露于来自I期临床试验的动力学方案中动态变化的药物浓度。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Monte Carlo模拟。后者将确定II期疗效试验的最佳给药方案。虽然体外动态PK/PD对抗原动物是新的，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。这项工作的结果将为药物开发的许多方面提供有价值的方向，也可以导致现有药物的更合理的剂量。