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 肺移植是终末期肺病的一种延长生命的治疗方法，但需要终身 使用具有狭窄治疗窗和不可避免的副作用的药剂进行免疫抑制。霉酚 醋酸（MPA）是抗增殖剂的选择。与其他药物不同，常规治疗药物监测（TDM） 由于难以测量0-12小时曲线下面积（AUC）， 准确评估药代动力学（PK）。MPA水平在移植受者之间差异很大， 水平与不良结局相关，如中性粒细胞减少症，其影响>40%的肺移植 接受MPA并对结果产生负面影响的接受者。这种变异性部分是由于基因的差异 参与MPA代谢并影响结局。我们之前发现了一个单核苷酸 MPA代谢关键基因SLCO 1B 3多态性与肺移植急性排斥反应和存活 受惠人士虽然这种关联和其他关联现在已经知道了，但还没有尝试将遗传因素纳入其中。 将数据纳入MPA的TDM策略或制定肺移植中MPA的循证治疗范围 受惠人士我们正在开发一种整合PK、遗传和临床数据的工具，以预测剂量标准化 接受MPA的肺移植受者的AUC。该工具将需要单个时间点PK测量， 将为MPA PK研究和临床管理提供一个易于获得的工具。不幸的是，目标MPA 由于缺乏肺移植受者的常规MPA TDM，尚未定义AUC范围。我们 假设最佳MPA浓度提供了足够的免疫抑制，同时保留了 免疫细胞功能和MPA水平变异性具有很强的遗传成分。因此，我们将实现 K 01研究的三个目标。(1)确定肺移植受者MPA的目标治疗范围。（二） 确定影响剂量标准化MPA浓度的遗传因素。(3)建立关系 MPA暴露、遗传多态性和中性粒细胞功能之间的关系，这些是先天性和 适应性免疫系统这将改善肺移植受者的临床实践和结果， 提高药效，减少副作用。这项实验工作是与一个 全面的职业发展计划，建立在塔格博士以前的培训（医学博士，理学硕士， 临床研究，遗传学和转化医学研究），成为一名独立的研究者， 药物遗传学、生物信息学、统计遗传学和肺移植中的遗传流行病学。的 将通过优秀的指导、优质的课程和科学培训来实现既定目标。 通信华盛顿大学独特的资源和基础设施是理想的建议 计划该K 01将提供必要的工具，以发展成为一名独立的临床研究者，重点是 肺移植免疫学的药物遗传学谁可以确保R 01资金。