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: 8604131
• 负责人: Theresa A Shapiro
• 金额: $ 28.35万
• 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 2015-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8604131
• 关键词: Academia; Address; Affect; African; African Trypanosomiasis; Anti-Bacterial Agents; Anti-Infective Agents; Anti-malarial drug resistance; Antimalarials; Antiparasitic Agents; Antiprotozoal Agents; Area; Artemisinins; Bacteria; Chloroquine; Clinical; DL-alpha-Difluoromethylornithine; Development; Diamidine; Dose; Drug Exposure; Drug Kinetics; Drug effect disorder; Drug resistance; Goals; Half-Life; Human; In Vitro; Industry; Infection; Knowledge; Lead; Malaria; Mediating; Melarsoprol; Methods; Minimum Inhibitory Concentration measurement; Molecular; New Agents; Outcome; Parasite resistance; Parasites; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Pharmacodynamics; Pilot Projects; Plasma; Plasmodium falciparum; Property; Public Health; Regimen; Resistance; Resources; Role; Safety; Suramin; System; Thinking; Time; Trypanosoma; Trypanosoma brucei brucei; Work; artemisinine; cost; drug candidate; drug development; drug efficacy; drug market; improved; innovation; insight; interest; new technology; novel; programs; prospective; research study; success

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.

描述（由申请人提供）：被疟疾困扰和死亡的人数惊人的人被广泛认可，耐药疟疾的持续传播也是如此。尽管较少的患者患有非洲锥虫病（睡眠疾病），但这种感染是统一致命的，如果不接受治疗，当前的疗法有毒，昂贵，需要肠胃外治疗。迫切需要安全有效的疟疾和睡眠治疗方案。鉴于可用于解决此问题的有限资源，至关重要的是要确定最大化疗效并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。在这一点中，关键是对必需药代动力学/药效学（PK/PD）关系的清晰理解。 对于一般的抗感染物，给定药物暴露（浓度时间曲线下的面积，AUC）的疗效是由峰浓度（CMAX）介导的，或在最低有效浓度（TMIC）上介导的。该属性在整个班级，不可预测。对这种基本PK/PD关系的洞察力可以为药物开发计划的许多方面提供信息，并导致已经销售的药物的更合理的剂量。值得注意的是，几乎一无所知，对控制抗疟疾和抗胰蛋白酶药物作用的基本PK/PDS一无所知。 拟议的工作将利用一种新型的体外灌注系统，该系统将恶性疟原虫或Brucei锥虫暴露于不断变化的药物浓度，模仿药物给药后人类遇到的人。可以对该设备进行编程，以在任何所需的PK曲线（包括极端CMAX或TMIC）中提供给定的AUC。试点研究表明，现在有可能进行严格的概念验证PK/PD研究。在AIM 1中，该新系统将用于描述选定的抗疟药的必需PK/PD，以确定这些关系是否与细菌相关，以及PK/PD关系如何受到抗药性的影响。 AIM 2将重点放在抗胰腺药物的必需PK/PD上。尽管CMAX或TMIC介导的疗效的概念是抗植物的新功能，并且实验方法具有创新性，但该项目的可交付成果几乎保证。这项工作的结果将包括一种可靠的良好特征化方法来确定基本PK/PD关系；首先，对大多数类别的临床有用抗疟疾和抗胰腺药物以及一些实验剂的PK/PD要求进行了描述；以及对PK在抗疟疾耐药性中可能作用的初步见解。也许最重要的是，它将提供一个迄今缺失的框架，在该框架中，可以在该框架中对抗疟疾和抗丙糖体剂进行合理的判断和使用。