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: 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
• 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

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 肺移植是终末期肺部疾病的一种延长生命的疗法，但需要终生。 治疗窗口狭窄且不可避免的副作用的药物的免疫抑制。麦考酚醛 酸(MPA)是首选的抗增生剂。与其他药物不同，常规治疗药物监测(TDM) 由于测量曲线下的0-12小时(AUC)至 准确评估药代动力学(PK)。移植受者之间的甲孕酮水平差异很大，而且过量 血药浓度与不良后果有关，例如影响40%肺移植的中性粒细胞减少症。 接受者接受MPA，并对结果产生负面影响。这种差异部分归因于基因的差异。 参与了甲孕酮的代谢并影响结果。我们之前发现单核苷酸之间存在联系 甲孕酮代谢关键基因SLCO1B3基因多态性与肺移植急性排斥反应及存活的关系 收件人。尽管这种关联和其他关联现在已为人所知，但还没有人尝试将基因 将数据纳入肺移植中MPA的TDM策略或开发基于证据的治疗范围 收件人。我们正在开发一种集成PK、遗传和临床数据以预测剂量归一化的工具 接受甲孕酮的肺移植受者的AUC。此工具将需要单个时间点PK测量和 将为MPA PK研究和临床管理提供一个容易获得的工具。不幸的是，目标是MPA 由于肺移植受者缺乏常规的MPATDM，AUC范围尚未确定。我们 假设最优的甲孕酮浓度可提供足够的免疫抑制，同时保存 免疫细胞功能，而甲孕酮水平的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)确定肺移植受者MPA的靶向治疗范围。(2) 确定影响剂量标准化的甲孕酮浓度的遗传因素。(3)建立关系 在MPA暴露、遗传多态性和中性粒细胞功能之间，这些是先天和后天的关键因素 适应性免疫系统。这将通过以下方式改善肺移植受者的临床实践和预后 提高药物疗效，减少不良反应。这项实验工作与一个 全面的职业发展计划，建立在泰格博士之前的培训基础上(医学博士，理科硕士 临床调查、遗传学和转化医学研究)成为#年的独立调查员 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。这个 所述目标将通过出色的指导、优质的课程和科学方面的培训来实现 沟通。华盛顿大学独特的资源和基础设施是拟议中的 计划。该K01将提供必要的工具，以发展成为一个独立的临床医生-研究员专注于 肺移植免疫学的药物遗传学谁能获得R01资金。

项目成果

Translational Science 22 conference proceedings.

• DOI: 10.1017/cts.2022.427
• 发表时间: 2022
• 期刊: JOURNAL OF CLINICAL AND TRANSLATIONAL SCIENCE
• 影响因子: 2.6
• 作者: Pliakos, Elina E.;Tague, Laneisha K.;Poblete, Roy E.
• 通讯作者: Poblete, Roy E.

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

胸部X射线肺高度测量和肺移植的尺寸匹配的不确定性分析。

• DOI: 10.21037/jtd-21-1755
• 发表时间: 2022-04
• 期刊: JOURNAL OF THORACIC DISEASE
• 影响因子: 2.5
• 作者: Guillamet, Rodrigo Vazquez;Guillamet, Maria C. Vazquez;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;Hachem, Ramsey;Trulock, Elbert P.
• 通讯作者: Trulock, Elbert P.

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

• DOI: 10.1016/j.healun.2021.06.016
• 发表时间: 2021-10
• 期刊: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
• 作者: Tague LK;Bedair B;Witt C;Byers DE;Vazquez-Guillamet R;Kulkarni H;Alexander-Brett J;Nava R;Puri V;Kreisel D;Trulock EP;Gelman A;Hachem RR
• 通讯作者: Hachem RR