Pharmacodynamic Thresholds of Immunosuppression

免疫抑制的药效阈值

• 批准号: 6555805
• 负责人: RAKESH K. SINDHI
• 金额: $ 23.28万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-04 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6555805
• 关键词: B lymphocyte; CD antigens; FK506; T lymphocyte; artificial immunosuppression; biomarker; child (0-11); human subject; immunopharmacology; interferon gamma; interleukin 2; liver transplantation; patient oriented research; sirolimus; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Acute rejection or side effects occur in nearly half of all transplant patients receiving immunosuppression. During our studies with regimens of (SRL) sirolimus+cyclosporine/tacrolimus (CsA/TAC), cytokine and costimulatory cell surface proteins (biomarkers), have demonstrated sensitivity to clinically relevant immunosuppressive drug concentrations in mitogen-stimulated peripheral blood lymphocytes (PBL) from normal and transplanted human subjects. Effect: concentration (pharmacodynamic, PD) relationships between biomarkers and drug concentrations also indicate ability to measure single- and multiple-agent effects within combination regiments, and to predict the amount of drug needed to inhibit a certain amount of biomarker, both for patient populations and individuals. However, prior to use as measures of immunosuppressive effect, the amount of biomarker inhibition associated with clinical conditions representing insufficient, excessive and adequate immunosuppression must be known. This may define safe amounts of drugs for children, who experience a higher incidence of life-threatening complications of immunosuppression such as post-transplant lymphoproliferative disorder. Therefore, the specific aim of this project is to measure biomarker expression during a planned pharmacokinetic (PK) evaluation of a SRL+TAC regimen in 40 children with liver transplants, relate it to amount of drug, and to determine whether the occurrence of acute rejection, side effects and stable post-transplant course can be related to threshold levels of biomarker inhibition or the amount of drug associated with such thresholds. During a sponsored clinical trial of SRL+TAC, our proposal will manage biomarker data as follows: 1. Measure mitogen-stimulated expression of the cytokines IL-2, TNF-alpha and IFN-gamma in T-cells, and of costimulatory proteins CD54 (intercellular adhesion molecule-1), CD86 (B7.2) and CD95 (Fas antigen) in B-cells, and the proliferative response of lymphocytes to donor antigen. This will be performed during PK studies planned in the clinical trial, and additionally, during rejection, side effects, and at 12, and 24 month after transplantiation. 2. PD modeling to predict biomarker thresholds or drug concentrations associated with them, which are related to the occurrence of acute rejection, side effects, and the stable post-transplant course. Potential benefits may include customized regimens in the future, and decreased complications in one-half of the nearly 40,000 new transplant recipients of solid organ and bone marrow grafts, each year.

描述（由申请人提供）： 急性排斥反应或副作用发生在 近一半的移植患者接受免疫抑制。在我们的 (SRL) 西罗莫司+环孢素/他克莫司 (CsA/TAC) 方案的研究， 细胞因子和共刺激细胞表面蛋白（生物标志物），具有 表现出对临床相关免疫抑制药物的敏感性 丝裂原刺激的外周血淋巴细胞（PBL）中的浓度 正常和移植的人类受试者。效果：浓度（药效学， PD）生物标志物和药物浓度之间的关系也表明 能够测量组合中的单药和多药效果 方案，并预测抑制一定量所需的药物量 针对患者群体和个人的生物标志物。然而，在此之前 生物标志物抑制量作为免疫抑制效果的衡量标准 与临床症状相关，表现为不足、过度和 必须了解足够的免疫抑制。这可以定义药物的安全量 对于儿童来说，他们经历的危及生命的事件发生率较高 免疫抑制并发症，例如移植后淋巴细胞增殖 紊乱。因此，该项目的具体目标是测量生物标志物 SRL+TAC 的计划药代动力学 (PK) 评估期间的表达 40例肝移植儿童的治疗方案，并将其与药物剂量相关联，以及 判断是否发生急性排斥反应、副作用及稳定 移植后病程可能与生物标志物的阈值水平有关 抑制或与此类阈值相关的药物量。期间 赞助 SRL+TAC 的临床试验，我们的提案将生物标志物数据管理为 如下： 1. 测量有丝分裂原刺激的细胞因子 IL-2 的表达， T 细胞中的 TNF-α 和 IFN-γ，以及共刺激蛋白 CD54 （细胞间粘附分子-1）、CD86 (B7.2) 和 CD95（Fas 抗原） B 细胞，以及淋巴细胞对供体抗原的增殖反应。这 将在临床试验中计划的 PK 研究期间进行，并且 此外，在排斥期间、副作用以及术后 12 和 24 个月 移植。 2. PD建模来预测生物标志物阈值或药物 与其相关的浓度，这与发生有关 急性排斥反应、副作用和稳定的移植后病程。潜在的 好处可能包括未来的定制治疗方案，以及减少 近 40,000 名新移植受者中有一半出现并发症 每年进行实体器官和骨髓移植。