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

基本信息

批准号：
10655552
负责人：
Laneshia K Tague
金额：
$ 14.88万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10655552
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 Genetic Predisposition to Disease Goals Graft Survival Grant Granulopoiesis Heritability Hour Immune Immune Tolerance Immunologic Surveillance Immunosuppression Immunosuppressive Agents Impairment Infection Infrastructure Innate Immune System Life Link Lung Lung Transplantation Lung diseases Malignant Neoplasms Master of Science Measurement Measures 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 Assessment 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 conventional dosing 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

项目摘要

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.

项目摘要肺移植是治疗终末期肺病的一种延长生命的疗法，但需要终生治疗使用具有狭窄治疗窗和不可避免的副作用的免疫抑制药物。与其他药物不同，常规治疗药物监测 (TDM) 是首选的抗增殖药物。不针对 MPA 执行，因为测量 0-12 小时 (AUC) 的曲线下面积具有挑战性准确评估移植受者之间的药代动力学 (PK) 水平差异很大，并且过量。水平与不良后果相关，例如中性粒细胞减少症，影响超过 40% 的肺移植接受 MPA 并对结果产生负面影响的部分原因是基因差异。我们之前发现了单核苷酸之间的联系。 MPA 代谢关键基因 SLCO1B3 的多态性与肺移植中的急性排斥反应和存活尽管现在已知这种关联和其他关联，但尚未尝试将遗传因素纳入其中。将数据纳入 MPA 的 TDM 策略或开发肺移植中 MPA 的循证治疗范围我们正在开发一种整合 PK、遗传和临床数据来预测剂量标准化的工具。接受 MPA 的肺移植受者的 AUC 该工具需要单时间点 PK 测量和不幸的是，目标 MPA 将为 MPA PK 研究和临床管理提供一个易于使用的工具。由于肺移植受者缺乏常规 MPA TDM，AUC 范围尚未确定。认为最佳 MPA 浓度可提供足够的免疫抑制，同时保留免疫细胞功能，并且 MPA 水平变异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) 确定肺移植受者的 MPA 目标治疗范围 (2)。 (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，这些是先天性和中性粒细胞功能的关键因素这将通过以下方式改善肺移植受者的临床实践和结果。这项实验工作与增强药物疗效和减少不良反应相结合。以 Tague 博士之前的培训（医学博士、理学硕士）为基础的全面职业发展计划临床研究、遗传学和转化医学研究）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。既定目标将通过出色的指导、优质课程和科学培训来实现华盛顿大学独特的资源和基础设施非常适合拟议的项目。该 K01 计划将提供必要的工具，以发展成为专注于以下方面的独立临床医生-研究者。肺移植免疫学的药物遗传学谁可以获得 R01 资金。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pseudomonas aeruginosa and acute rejection independently increase the risk of donor-specific antibodies after lung transplantation.

铜绿假单胞菌和急性排斥反应独立增加肺移植后供体特异性抗体的风险。

DOI：
发表时间：
2020-04
期刊：
影响因子：
0
作者：
Kulkarni, Hrishikesh S;Tsui, Kevin;Sunder, Suraj;Ganninger, Ale;Tague, Laneshia K;Witt, Chad A;Byers, Derek E;Trulock, Elbert P;Nava, Ruben;Puri, Varun;Kreisel, Daniel;Mohanakumar, Thalachallour;Gelman, Andrew E;Hachem, Ramsey R
通讯作者：
Hachem, Ramsey R

Uncertainty analysis of chest X-ray lung height measurements and size matching for lung transplantation.

胸部X线肺高度测量和肺移植尺寸匹配的不确定性分析。

DOI：
发表时间：
2022-04
期刊：
影响因子：
0
作者：
Vazquez Guillamet, Rodrigo;Vazquez Guillamet, Maria C;Rjob, Ashraf;Bierhals, Andrew;Bello, Irene;Abularach, Alberto Jauregui;Tague, Laneshia;Wallendorf, Michael;Marklin, Gary F;Witt, Chad;Byers, Derek E;Kreisel, Daniel;Nava, Ruben;Puri, Varun
通讯作者：
Puri, Varun

Lung protective ventilation based on donor size is associated with a lower risk of severe primary graft dysfunction after lung transplantation.

基于供体大小的肺保护性通气与肺移植后严重原发性移植物功能障碍的较低风险相关。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Tague, Laneshia K;Bedair, Bahaa;Witt, Chad;Byers, Derek E;Vazquez;Kulkarni, Hrishikesh;Alexander;Nava, Ruben;Puri, Varun;Kreisel, Daniel;Trulock, Elbert P;Gelman, Andrew;Hachem, Ramsey R
通讯作者：
Hachem, Ramsey R

Translational Science 22 conference proceedings.

转化科学 22 会议论文集。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Pliakos, Elina E;Tague, Laneisha K;Poblete, Roy E
通讯作者：
Poblete, Roy E

Potential Role of Computed Tomography Volumetry in Size Matching in Lung Transplantation.

计算机断层扫描体积测量在肺移植尺寸匹配中的潜在作用。

DOI：
发表时间：
2023-03
期刊：
影响因子：
0.9
作者：
Vazquez Guillamet, Rodrigo;Rjob, Ashraf;Bierhals, Andrew;Tague, Laneshia;Marklin, Gary;Halverson, Laura;Witt, Chad;Byers, Derek;Hachem, Ramsey;Gierada, David;Brody, Steven L;Takahashi, Tsuyoshi;Nava, Ruben;Kreisel, Daniel;Puri, Varun;Truloc
通讯作者：
Truloc