Dosing & safety trials using csA in severe head injury

剂量

• 批准号: 6317137
• 负责人: Alfred Byron Young
• 金额: $ 39.94万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6317137
• 关键词: biomarker; blood brain barrier; blood chemistry; brain injury; cerebrospinal fluid; clinical trials; computed axial tomography; computer data analysis; cyclosporines; drug administration rate /duration; drug screening /evaluation; enzyme linked immunosorbent assay; high performance liquid chromatography; human subject; human therapy evaluation; longitudinal human study; outcomes research; patient oriented research; pharmacokinetics; trauma; urinalysis

Description: Head injury is a complex disease where the primary injury initiates a chemical cascade of central mediator release leading to secondary insults within the central nervous system and systemically. Morbidity and mortality rates remain high despite advances in guidelines for clinical management. Several potential mechanisms of secondary injury have been identified and therapeutic strategies for intervention have been tested in animal and human trials. Despite preliminary evidence of efficacy in small clinical trials, no drug has shown significant benefit when tested in larger well designed randomized investigations. Lack of pharmacokinetic data to guide dosing for specific pharmacodynamic endpoints is one of several possible reasons for failure of investigational drugs to demonstrate benefit. Recent evidence from animal research suggests a protective effect of Cyclosporin A (CsA) in neural trauma. CsA given to mice and rats following severe cortical contusion reduced neuronal injury by approximately 50%. CsA is a difficult drug to model and predict response. Our preliminary data from two TBI patients demonstrates a marked variability in serum trough concentrations of CsA. The systemic effects of head injury and the requirement for adequate delivery of drug to the injured brain mandate preliminary dose finding studies prior to progressing into clinical trials. In this pilot clinical trial, we will systematically define CsA pharmacokinetic and pharmacodynamic endpoints in a homogenous population of patients with traumatic brain injury. We will measure serum and cerebrospinal fluid (CSF) concentrations of drug and surrogate biochemical markers of secondary injury to identify potential pharmacodynamic endpoints useful in designing optimal drug dosing strategies. This dose-finding proposal will characterize the pharmacokinetic profile of CsA and provide preliminary safety data in patients with TBI. Information from this pilot study will be used to establish a dosing strategy for a future Phase 11 prospective randomized trial. We will test the hypothesis that clinically approved doses of CsA can be safely administered to patients with TBI and achieve measurable concentrations in the CSF and serum.

描述：头部受伤是一种复杂的疾病 启动一个化学级联中央介体释放，导致次级 中枢神经系统和系统地侮辱。发病率和 尽管临床指南进展，但死亡率仍然很高 管理。继发性损伤的几种潜在机制已经 已确定的干预策略已在 动物和人类试验。尽管初步证据表明小小的有效性 临床试验，在较大的较大 精心设计的随机调查。缺乏指导药代动力学数据 特定药效终点的剂量是几种可能的 研究药物未能证明利益的原因。 动物研究的最新证据表明 神经创伤中的环孢菌素A（CSA）。 CSA给了小鼠和大鼠 严重的皮质挫伤使神经元损伤减少了约50％。 CSA是 难以建模和预测反应的困难药物。我们的初步数据来自两个 TBI患者表现出血清槽浓度的明显变化 CSA。头部受伤的系统性影响和对足够的要求 将药物输送到受伤的大脑授权初步剂量发现研究 在进行临床试验之前。 在这项试验临床试验中，我们将系统地定义CSA药代动力学 以及同质患者的药效动力学终点 创伤性脑损伤。我们将测量血清和脑脊液（CSF） 药物的浓度和替代生化标志物的继发性损伤 确定潜在的药效终点，可用于设计最佳药物 给药策略。该剂量调查的建议将表征 CSA的药代动力学特征并提供患者的初步安全数据 与TBI。该试点研究的信息将用于建立剂量 未来11阶段的前瞻性随机试验的策略。我们将测试 假设临床批准的CSA可以安全地给予 TBI患者并在CSF和血清中达到可测量的浓度。