CORE--PHARMACOKINETIC ANALYSES

核心--药代动力学分析

• 批准号: 6325792
• 负责人: PANKAJ B DESAI
• 金额: $ 40.85万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6325792
• 关键词: biomedical facility; clinical research; cocaine; cooperative study; drug screening /evaluation; human tissue; monoclonal antibody; pharmacokinetics

The role of the Core D is to serve as a resource to this SPIRCAP project for pharmacokinetic analyses in order to attain expeditious Investigational New Drug (IND) approval of an identified human anti- cocaine antibody and second, to aid in the clinical assessment of its safety and efficiency. The goals of the analyses are to establish the pharmacokinetic basis for the antibody efficacy and recommend a dosing regimen for further clinical trials. The hypothesis of the proposed study is that by sequestering cocaine in plasma, a human anti-cocaine antibody significantly alters the pharmacokinetics of cocaine resulting in a marked reduction in the peak brain concentration and area under the concentration curve (AUC) of cocaine. Our preliminary studies on cocaine disposition in rats indicate that the plasma AUC, systemic clearance (CL/s) and the steady state volume of distribution (V/ss) of cocaine were 60 microgram.min/ml, 167 ml/(min.Kg) and 1.3 L/Kg, respectively, following an i.v. bolus dose of 10 microgram/Kg. During the first stage of the proposed pre-clinical pharmacokinetic investigations, following an i.v. bolus dose of 10 microgram/Kg. During the first stage of the proposed pre-clinical pharmacokinetic investigations, detailed studies on the influence of a murine anti-cocaine antibody (B4E10) on the plasma disposition and urinary excretion of cocaine and its metabolites, in rats will be evaluated (Project 2). To gain further insight into the antibody-mediated changes, this Core will conduct an in vitro investigation of cocaine disposition in human blood. Second, the disposition of several human anti-cocaine antibodies and their influence on the plasma clearance and brain uptake of cocaine will be evaluated (Project 2). The most efficacious antibody will be further screened for toxicity in accordance with FDA guidelines. Following IND approval of the human antibody, Phase I clinical trials will be initiated. This Core Unit will aid Project 3 in the pharmacokinetic evaluation of the antibody following single and multiple dose administration in humans. Subsequently, changes in the cocaine pharmacokinetics in the presence of the antibody will be examined. This will include an assessment of the plasma clearance as well as urinary and salivary excretion of cocaine and its metabolites in human subjects (Project 4). In general, the pharmacokinetic analyses will include determination of distribution and elimination half-lives, AUC, CL/s, V/ss and other parameters of the antibody, cocaine and its metabolites. The investigators have prior experience in such analyses and are well- qualified to aid this program project in the rapid development of a human anti-cocaine antibody.

核心D的作用是作为SPIRCAP项目的资源 用于药代动力学分析，以快速 一种已鉴定的人抗- 可卡因抗体和第二，以帮助其临床评估， 安全高效。分析的目标是建立 抗体效力的药代动力学基础，并推荐给药 用于进一步临床试验。拟议研究的假设 通过将可卡因隔离在血浆中， 显著改变可卡因的药代动力学， 脑峰浓度和浓度下面积减少 可卡因的AUC曲线。我们对可卡因处置的初步研究 大鼠表明，血浆AUC、全身清除率（CL/s）和 可卡因稳态分布容积（V/ss）为60 微克/分钟/毫升，167毫升/（分钟.千克）和1.3升/千克，分别为后， 静脉推注剂量为10微克/千克。在拟议的第一阶段 静脉推注给药后的临床前药代动力学研究 10微克/公斤。在拟定临床前研究的第一阶段， 药代动力学研究，详细研究的影响， 鼠抗可卡因抗体（B4 E10）对血浆处置和尿 将评价大鼠中可卡因及其代谢物的排泄 （项目2）。为了进一步了解抗体介导的变化， 该核心将对可卡因处置进行体外调查， 人血第二，处置几个反可卡因的人 抗体及其对血浆清除率和脑摄取的影响 将对可卡因进行评价（项目2）。最有效的抗体 根据FDA指南进一步筛选毒性。 在人抗体的IND批准之后，I期临床试验将 被启动。该核心单元将在药代动力学方面帮助项目3 单次和多次给药后的抗体评价 人类的管理。随后，可卡因的变化 将检查抗体存在下的药代动力学。这 将包括对血浆清除率以及尿液和 可卡因及其代谢物在人体中的唾液排泄 （项目4）。一般而言，药代动力学分析将包括 分布和消除半衰期、AUC、CL/s、V/ss的测定 以及抗体、可卡因及其代谢物的其他参数。的 调查人员在这类分析方面有经验，而且- 有资格帮助这个项目在人类的快速发展 抗可卡因抗体