Influence of Mycophenolic Acid Pharmacogenomics on Lung Transplant Outcomes

霉酚酸药物基因组学对肺移植结果的影响

• 批准号: 10408666
• 负责人: Laneshia K Tague
• 金额: $ 14.9万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10408666
• 关键词: Acute; Adaptive Immune System; Adverse drug effect; Adverse effects; Adverse event; Affect; Algorithms; Allografting; Anions; Area Under Curve; Award; Bioinformatics; Cell physiology; Chronic; Clinical; Clinical Data; Clinical Management; Clinical Trials; Communication; Data; Development; Development Plans; Dose; Drug Kinetics; Drug Monitoring; Family; Functional disorder; Funding; Future; Gene Expression; Genes; Genetic; Genetic Medicine; Genetic Polymorphism; Goals; Gold; Graft Survival; Grant; Granulopoiesis; Heritability; Hour; Immune; Immune Tolerance; Immunologic Surveillance; Immunosuppression; Immunosuppressive Agents; Impairment; Infection; Infrastructure; Lead; Life; Link; Lung; Lung Transplantation; Lung diseases; Malignant Neoplasms; Master of Science; Measurement; Measures; Medical Genetics; Mentors; Metabolism; Methodology; Methods; Mycophenolic Acid; Neutropenia; Opportunistic Infections; Organ Transplantation; Outcome; Patient-Focused Outcomes; Patients; Pharmacogenetics; Pharmacogenomics; Phenotype; Recommendation; Research; Research Personnel; Resources; Risk; Safety; Sampling; Secure; Single Nucleotide Polymorphism; Solid; Stress; Tacrolimus; Testing; Therapeutic; Therapeutic Effect; Time; Training; Transplant Recipients; Transplantation; Transplantation Immunology; Treatment Efficacy; Universities; Variant; Washington; Work; adverse outcome; allograft rejection; antiproliferative agents; career development; clinical effect; clinical implementation; clinical investigation; clinical practice; cohort; cytopenia; cytotoxicity; drug efficacy; evidence base; genetic epidemiology; genome wide association study; healthy volunteer; immune activation; immunogenic; improved; individual patient; lung allograft; negative affect; neutrophil; organ transplant recipient; polygenic risk score; precision medicine; preservation; response; side effect; solute; targeted treatment; tool; translational medicine

PROJECT ABSTRACT Lung transplantation is a life-extending therapy for end-stage lung disease, but necessitates life-long immunosuppression with agents that have narrow therapeutic windows and inevitable side effects. Mycophenolic acid (MPA) is the antiproliferative agent of choice. Unlike other agents, routine therapeutic drug monitoring (TDM) is not performed for MPA because it is challenging to measure area under the curve from 0–12 hours (AUC) to accurately assess pharmacokinetics (PK). MPA levels vary widely among transplant recipients, and excess levels are associated with adverse outcomes such as neutropenia, which affects >40% of lung transplant recipients receiving MPA and negatively affects outcomes. This variability is due in part to differences in genes involved in MPA metabolism and affects outcomes. We previously identified a link between single nucleotide polymorphisms in SLCO1B3, a key gene in MPA metabolism, and acute rejection and survival in lung transplant recipients. Although this and other associations are now known, there has been no attempt to incorporate genetic data into TDM strategies for MPA or develop an evidence-based therapeutic range for MPA in lung transplant recipients. We are developing a tool that integrates PK, genetic, and clinical data to predict dose-normalized AUC for lung transplant recipients receiving MPA. This tool will require a single time-point PK measurement and will provide an easily available tool for MPA PK research and clinical management. Unfortunately, target MPA AUC ranges have not been defined due to the lack of routine MPA TDM in lung transplant recipients. We hypothesize that an optimal MPA concentrations provides adequate immunosuppression while preserving immune cell function, and that MPA level variability has a strong genetic component. Therefore, we will achieve three aims in this K01 study. (1) Determine a target therapeutic range for MPA in lung transplant recipients. (2) Identify genetic factors that influence dose-normalized MPA concentration. (3) Establish the relationships between MPA exposure, genetic polymorphisms, and neutrophil function, which are key factors in innate and adaptive immune systems. This will improve clinical practice and outcomes in lung transplant recipients by enhancing drug efficacy and reducing adverse effects. This experimental work is integrated with a comprehensive career development plan that builds on Dr. Tague’s previous training (MD, Master of Science in Clinical Investigation, research in genetics and translational medicine) to become an independent investigator in pharmacogenetics, bioinformatics, statistical genetics, and genetic epidemiology in lung transplantation. The stated goals will be achieved through excellent mentoring, premium coursework, and training in scientific communication. The unique resources and infrastructure of Washington University are ideal for the proposed plan. This K01 will provide the necessary tools to develop into an independent clinician-investigator focused on the pharmacogenetics of lung transplant immunology who can secure R01 funding.

项目摘要 肺移植是一种延长生命的末期肺部疾病的疗法，但必要的终身疗法 具有狭窄治疗窗户和不可避免的副作用的药物的免疫抑制。肉芽素 酸（MPA）是选择的抗增殖剂。与其他药物不同，常规治疗药物监测（TDM） 不针对MPA执行，因为它挑战曲线下的面积从0-12小时（AUC）到 准确评估药代动力学（PK）。 MPA水平在移植受者中差异很大，并且超过 水平与不良结果（例如中额减少）有关，该结果影响> 40％的肺移植 接收MPA并负面影响结果的接收者。这种变异性部分归因于基因的差异 参与MPA代谢并影响结果。我们先前确定了单核苷酸之间的联系 SLCO1B3中的多态性，MPA代谢中的关键基因以及肺移植中的急性排斥和存活率 收件人。尽管现在已经知道了这一和其他关联，但没有尝试纳入通用 将MPA的TDM策略数据与肺移植中MPA的循证治疗范围开发 收件人。我们正在开发一种整合PK，遗传和临床数据以预测剂量归一化的工具 AUC用于接收MPA的肺移植接受者。此工具将需要一个时间点PK测量和 将为MPA PK研究和临床管理提供易于使用的工具。不幸的是，目标MPA 由于肺移植受者缺乏常规MPA TDM，因此未定义AUC范围。我们 假设最佳MPA浓度可提供足够的免疫抑制 免疫细胞功能，MPA水平变异性具有很强的遗传成分。因此，我们将实现 这项K01研究的三个目标。 （1）确定肺移植受体中MPA的靶标治疗范围。 （2） 确定影响剂量归一化MPA浓度的遗传因素。 （3）建立关系 在MPA暴露，遗传多态性和中性粒细胞功能之间，这是先天和 自适应免疫系统。这将通过 提高药物有效性并降低不良反应。这项实验工作与 全面的职业发展计划是基于Tague博士先前的培训（MD，科学硕士， 临床研究，遗传学和翻译医学研究）成为独立研究者 肺移植中的药物遗传学，生物信息学，统计遗传学和遗传流行病学。这 陈述的目标将通过出色的心理，高级课程和科学培训来实现 沟通。华盛顿大学的独特资源和基础设施非常适合拟议 计划。该K01将提供必要的工具，以发展为专注于独立的临床评估器 可以获得R01资金的肺移植免疫学的药物遗传学。