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（由适用提供）：被疟疾折磨和死亡的人数惊人的人被广泛认可，耐药耐药的蔓延也是如此。尽管许多患者患有非洲锥虫病（睡眠疾病），但这种感染是统一致命的，如果不治疗，当前的疗法有毒，昂贵，需要父母的给药。迫切需要对两种疾病的安全有效治疗。鉴于可用于解决这些问题的有限资源，至关重要的是确定最大化效率，最大程度地减少抵抗的可能性并减少开发新代理所需的时间的策略至关重要。在所有这些方面，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型的体外灌注系统，该系统暴露于Brucei brucei brucei plasmodium brucei brucei的药物浓度不断变化，类似于体内动态药代动力学。利用该设备的实验表明，抗疟疾活性可以通过集中或暴露时间以整个范围的方式来控制，并且该治理与“静态或'cidal活性”无关。类似的发现与抗戊糖体有关。 AIM 1 WIR将使用传统的综合分析来确定是否可以通过与体内动力学获得的PK治理匹配（或不匹配）的PK治理匹配（或不匹配）来解释动物中的实验药物铅的成功（或失败）。 AIM 2将探索调节临床上重要的抗疟疾和抗丙糖体组合疗法的有效性的药代动力学因子，以更好地了解组合效率的总体PK驱动因素。 AIM 3 PK/PD建模实验将在体外部署，独奏和组合，实验性抗疟疾药物。寄生虫将暴露于从I期临床试验中得出的动力学方案中动态变化的药物浓度。 PD端点将包括时间杀伤曲线，滞后时间，99.9％的间隙时间以及生存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和蒙特卡洛模拟。后者将确定2阶段有效试验的最佳给药方案。尽管体外动态PK/PD是抗植物的新手，并且实验方法具有创新性，但该项目的可交付成果几乎是保证的。这项工作的结果将为药物开发的许多方面提供宝贵的方向，也可以导致现有药物的更合理的剂量。