Pharmacodynamic Thresholds of Immunosuppression

描述（由申请人提供）：急性排斥反应或副作用发生在 将近一半的移植患者接受免疫抑制。在我们 西罗莫司+环孢素/他克莫司（CsA/TAC）方案（SRL）研究， 细胞因子和共刺激细胞表面蛋白（生物标志物）， 证明对临床相关免疫抑制药物敏感 在有丝分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。作用：浓度（药效学， 生物标志物和药物浓度之间的关系也表明 测量联合用药中单药和多药效应的能力 团，并预测抑制一定量的药物所需的量， 生物标志物，无论是患者群体还是个体。然而，在 作为免疫抑制作用的量度，生物标志物抑制的量 与代表不足、过度和 必须知道适当的免疫抑制。这可能会定义药物的安全量 对于儿童来说，他们经历了更高的危及生命的事件， 免疫抑制的并发症，如移植后淋巴增生 disorder.因此，本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）评价期间的表达 对40例肝移植患儿的用药方案进行了分析，并与用药量进行了相关性研究， 判断是否发生急性排斥反应，副作用稳定 移植后病程可能与生物标志物的阈值水平有关 抑制或与这种阈值相关的药物量。期间 申办的SRL+TAC临床试验，我们的提案将管理生物标志物数据， 如下：1.测量细胞因子IL-2的有丝分裂原刺激的表达， T细胞中的TNF-α和IFN-γ，以及共刺激蛋白CD 54 （细胞间粘附分子-1）、CD 86（B7.2）和CD 95（Fas抗原）在 B细胞和淋巴细胞对供体抗原的增殖反应。这 将在临床试验计划的PK研究期间进行，并且 此外，在排斥反应期间，副作用，以及在12个月和24个月后， 移植2. PD建模以预测生物标志物阈值或药物 与之相关的浓度，这些浓度与 急性排斥反应、副作用和稳定的移植后病程。潜在 好处可能包括未来的定制方案， 近40，000名新移植接受者中有一半的并发症 实体器官和骨髓移植

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.