CORE--PHARMACOKINETIC ANALYSES

核心--药代动力学分析

• 批准号: 6104206
• 负责人: PANKAJ B DESAI
• 金额: --
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6104206
• 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的作用是作为该SPIRCAP项目的资源 用于药代动力学分析，以便快速获得 研究用新药(IND)批准一种已鉴定的人抗病毒药物 第二，协助临床评估可卡因抗体。 安全和高效。分析的目标是建立 抗体效价的药代动力学基础及推荐剂量 用于进一步临床试验的方案。拟议研究的假设 是通过将可卡因隔离在血浆中，一种人类抗可卡因抗体 显著改变可卡因的药代动力学，导致显著的 大脑峰值浓度和浓度下面积的减少 可卡因的曲线(AUC)。我国青少年可卡因倾向的初步研究 大鼠血浆尿酸排泄率、全血清除率(CL/S)和 可卡因的稳态分布体积(V/ss)为60 微克·分/毫升、167ml/(分·公斤)和1.3g·L/公斤。 静脉注射。推注剂量为10微克/公斤。在建议的第一阶段 静脉注射后的临床前药代动力学研究。团注剂量 10微克/公斤。在拟议的临床前阶段的第一阶段 药代动力学研究，详细研究了一种 小鼠抗可卡因抗体(B4E10)对血浆和尿液的影响 将评估可卡因及其代谢物在大鼠体内的排泄 (项目2)。为了进一步了解抗体介导的变化， 该中心将进行可卡因处置的体外调查。 人血。二、人体几种反可卡因的处置 抗体及其对血清白蛋白清除和脑摄取的影响 将评估可卡因(项目2)。最有效的抗体会 根据FDA指南进行进一步的毒性筛查。 在IND批准人类抗体后，I期临床试验将 被启动。该核心单位将协助项目3的药代动力学 单剂和多剂免疫后抗体的检测 人类的管理。随后，可卡因的变化 在抗体存在的情况下，将检查药代动力学。这 将包括评估血浆清除量以及尿液和 受试者唾液中可卡因及其代谢物的排泄 (项目4)。一般而言，药代动力学分析将包括 分布和消除半衰期的测定、AUC、CL/S、V/SS 以及抗体、可卡因及其代谢物的其他参数。这个 调查人员在这类分析方面有过经验，而且- 有资格帮助这一计划项目在人类的快速发展 抗可卡因抗体。