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）：为了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，存在未满足的临床需求和广泛的研究兴趣。儿科移植界错过了一个通过主要关注谷浓度和血液浓度曲线下面积 (AUC) 作为与排斥反应经验证据相关的最重要参数来优化结果的重要机会。该应用的重点是开发基于机制的药代动力学-药效（PK-PD）模型，该模型描述了免疫抑制药物在验证效果和临床结果指标上的完整浓度-效应关系。结构 PK-PD 模型将允许将反应和替代免疫学生物标志物与靶位点的计算浓度相关联。拟议的 PPRU 网络研究旨在解决目前关于儿科肾移植受者中吗替麦考酚酯（MMF、CellCept(r)）的年龄依赖性处置及其对暴露反应和毒性关系的潜在影响的信息差距。在此应用中，制定了研究、高级学习和指导议程来描述 K24 的附加价值。研究议程包括儿童肾移植患者的群体 PK-PD 研究。特别关注 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、CD25 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，可以使用 PK-PD 研究的生物标志物和结果数据更好地预测研究结果并合理化试验设计。 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 的高级学习议程侧重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地位将为指导议程服务，并为 PI 领导的经认可的临床药理学项目注入活力。总而言之，研究、高级学习和指导议程协同作用，促进对药物研究优化的实践和理论贡献，以便在儿科移植和儿科护​​理中更好地治疗 MMF。