Optimizing MMF therapy in pediatric transplant patients

描述（由申请人提供）： 存在未满足的临床需求和广泛的研究兴趣，以更好地了解移植患者中免疫抑制药物的剂量浓度-反应和不良事件关系。儿科移植界错过了一个重要的机会，以优化结果，主要集中在谷浓度和曲线下面积（AUC）的血液浓度作为最重要的参数，与排斥反应的经验证据相关。本申请侧重于开发基于机制的药代动力学-药效学（PK-PD）模型，该模型表征免疫抑制药物在验证效果和临床结局指标上的完整浓度-效应关系。结构PK-PD模型将允许应答和替代免疫学生物标志物与靶部位的计算浓度相关。拟定的PPRU网络研究旨在解决目前关于儿童肾移植受者中霉酚酸酯（MMF，CellCept（r））的年龄依赖性分布及其对疗效-反应和毒性关系的潜在影响的信息缺口。在这个应用程序中，研究，高级学习和指导议程制定描述的K24的附加值。研究议程包括在儿童肾移植患者中进行的群体PK-PD研究。特别注意K24在促进二次分析中的作用，特别是使用生物标志物（肌苷单磷酸酶脱氢酶抑制，CD 25表达和有丝分裂）进行间接反应建模。这些模型将有助于优化每个孩子的治疗。这些分析与试验模拟相结合，可以更好地预测研究结果，并使用PK-PD研究的生物标志物和结局数据使试验设计合理化。由MMF模型说明的核心PK-PD内容在儿科护理中具有广泛的应用，并提供了跨学科开展类似研究和指导机会的范例。因此，Pi的高级学习议程专注于基于机制的建模和临床试验模拟。PI在儿科临床药理学方面的领导力将服务于指导议程，并激励PI领导的经认证的临床药理学项目。总之，研究，高级学习和指导议程协同作用，以促进药物研究的优化，以更好地治疗MMF在儿科移植和儿科护理广泛的实践和理论贡献。

DESCRIPTION (provided by applicant): There exists an unmet clinical need and widespread research interest to better understand the dose concentration- response and adverse events relationships of immunosuppressive medications in transplant patients. The pediatric transplant community is missing a significant opportunity to optimize outcomes by focusing predominantly on trough concentrations and the area under the curve (AUC) of the blood concentrations as the most important parameters to correlate with empirical evidence of rejection. This application focuses on the development of mechanism based pharmacokinetic-pharmacodynamic (PK-PD) models that characterize the full concentration-effect relationship of immunosuppressive drugs on validated effect and clinical outcome measures. The structural PK-PD models will allow correlation of response and surrogate immunology biomarkers with computed concentrations at the target site. The proposed PPRU network study is designed to address the current information gap regarding age dependent disposition of mycophenolate mofetil (MMF, CellCept(r)) in pediatric renal transplant recipients and its potential impact on the exposure-response and toxicity relationships. In this application, research, advanced learning and mentoring agendas are formulated to describe the added value of the K24. The research agenda includes a population PK-PD study in pediatric kidney transplant patients. Particular attention is paid to the role of the K24 in facilitating secondary analyses particularly using biomarkers (Inosine Monophosphatase Dehydrogenase inhibition, CD25 expression and mitogenesis) for indirect response modeling. These models will serve to optimize therapy for each child. These analyses coupled with trial simulation can better predict research outcomes and rationalize trial design using biomarker and outcome data of the PK-PD study. The core PK-PD content illustrated by the MMF model has broad application in pediatric care and offers a paradigm to launch similar studies and mentoring opportunities across disciplines. The Pi's advanced learning agenda therefore is focused in mechanism based modeling and clinical trial simulation. The Pi's leadership in pediatric clinical pharmacology will serve the mentoring agenda and energize an accredited Clinical Pharmacology Program which the PI leads. Taken together, the research, advanced learning, and mentoring agendas synergize to promote practical and theoretical contributions to the optimization of drug studies for better treatment of MMF in pediatric transplant and pediatric care broadly.