Optimizing MMF therapy in pediatric transplant patients

优化儿科移植患者的 MMF 治疗

• 批准号: 7221247
• 负责人: Alexander A Vinks
• 金额: $ 13.63万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-13 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7221247
• 关键词: Address; Adverse event; Area Under Curve; Attention; Biological Markers; Blood; Caring; Cellcept; Child; Childhood; Clinical; Clinical Pharmacology; Clinical Trials; Communities; Coupled; Data; Development; Discipline; Dose; Drug Kinetics; IL2RA gene; Immunology; Immunosuppressive Agents; Inosine; Kidney Transplantation; Leadership; Learning; Mentors; Modeling; Outcome; Outcome Measure; Outcomes Research; Oxidoreductase; Pharmaceutical Preparations; Pharmacodynamics; Population; Research; Role; Site; Stimulation of Cell Proliferation; Toxic effect; Transplant Recipients; Transplantation; age related; base; clinical effect; design; fluorouracil/methotrexate/mitoxantrone protocol; interest; mycophenolate mofetil; pharmacodynamic model; programs; response; simulation

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.

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免疫抑制药物的剂量浓度和不良事件关系。小儿移植群落缺少一个重要的机会来优化结果，主要将血液浓度的曲线浓度和曲线（AUC）下的面积（作为血液浓度的曲线（AUC））作为与拒绝经验证据相关的最重要参数。该应用的重点是基于机制的药代动力学 - 剂量动力学（PK-PD）模型的开发，这些模型表征了免疫抑制药物在验证效果和临床结果指标上的全部浓度效应关系。结构性PK-PD模型将允许在目标部位的反应和替代免疫学生物标志物与计算浓度相关联。拟议的PPRU网络研究旨在解决有关小儿肾移植受者中霉酚酸酯莫菲尔（MMF，Cellcept（r））的当前信息差距，及其对暴露反应和毒性关系的潜在影响。在此应用中，制定了研究，高级学习和指导议程，以描述K24的附加值。研究议程包括一项针对小儿肾脏移植患者的人群PK-PD研究。特别注意K24在促进次级分析中的作用，特别是使用生物标志物（肌苷一磷酸酶脱氢酶抑制，CD25表达和有丝分裂发生）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果数据合理化试验设计。 MMF模型所说明的核心PK-PD内容在小儿护理中广泛应用，并提供了范式来启动类似的研究和指导跨学科的机会的范式。因此，PI的高级学习议程集中在基于机理的建模和临床试验模拟上。 PI在儿科临床药理学方面的领导能力将为指导议程提供服务，并为PI领导的认可的临床药理学计划提供精力。综上所述，研究，高级学习和指导议程协同促进了对药物研究的实践和理论贡献，以优化在小儿移植和小儿护理中更好地治疗MMF。