Pharmacodynamic Thresholds of Immunosuppression

描述(申请人提供)：发生急性排斥反应或副作用 所有接受免疫抑制的移植患者中有近一半。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)，有 对临床相关免疫抑制药物表现出敏感性 人外周血淋巴细胞在有丝分裂原刺激下的浓度 正常和移植的人类受试者。作用：浓度(药效学， Pd)生物标志物和药物浓度之间的关系也表明 能够衡量组合中的单因素和多因素影响 并预测抑制一定剂量所需的药量 对于患者群体和个人都是如此。然而，在此之前 用来衡量免疫抑制效果的生物标志物抑制量 与临床症状有关，表现为不足、过度和 必须知道是否有足够的免疫抑制。这可能定义了药物的安全量 对于儿童来说，他们经历了更高的生命威胁发生率 免疫抑制的并发症，如移植后淋巴组织增生性疾病 无序。因此，本项目的具体目标是测量生物标志物。 SRL+TAC在计划药代动力学(PK)评估中的表达 40例肝移植患儿的用药方案与用药量的关系 以确定急性排斥反应的发生、副作用是否稳定 移植后病程可能与生物标记物的阈值水平有关 抑制或与这种阈值相关的药量。在一次 赞助SRL+TAC的临床试验，我们的提案将生物标记物数据管理为 1.检测丝裂原刺激的细胞因子IL-2的表达， T细胞的肿瘤坏死因子-α和干扰素-γ以及共刺激蛋白CD54的表达 (细胞间黏附分子-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 将在临床试验计划的PK研究期间进行，以及 此外，在排斥期间，以及在12个月和24个月后，副作用 移植。2.预测生物标志物阈值或药物的PD建模 与它们相关的浓度，这与发生 急性排斥反应、副作用和移植后稳定的病程。潜力 福利可能包括未来定制的养生法，并减少 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。

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.