Precision Pharmacokinetic-Guided Tacrolimus Dosing to Improve Pediatric Heart Transplant Outcomes

精确药代动力学指导的他克莫司剂量可改善儿童心脏移植结果

• 批准号: 10618829
• 负责人: Joseph Rower
• 金额: $ 16.71万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618829
• 关键词: Age; Biological Markers; Biometry; CYP3A5 gene; Cardiomyopathies; Cessation of life; Child; Childhood; Chronic; Clinical; Clinical Research; Creatinine clearance measurement; Data; Decision Making; Disease; Dose; Drug Kinetics; Drug Monitoring; Enrollment; Genetic; Genetic Variation; Genotype; Goals; Health; Heart; Heart Transplantation; Hepatic; Immunosuppression; Immunosuppressive Agents; Individual; Kidney; Knowledge; Longevity; Maintenance; Measures; Mentors; Modeling; Modification; Nature; Organ Transplantation; Outcome; Patients; Pediatric Research; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacology; Pharmacotherapy; Population; Population Control; Process; Publications; Research; Research Proposals; Safety; Sampling; Tacrolimus; Techniques; Testing; Therapeutic Effect; Therapeutic immunosuppression; Time; Training; Transplant Recipients; Transplantation; Treatment-related toxicity; absorption; antibody-mediated rejection; career; congenital heart disorder; genetic variant; improved; improved outcome; innovation; metabolomics; organ transplant rejection; patient population; pharmacodynamic biomarker; pharmacodynamic model; pharmacokinetic model; post-transplant; precision medicine; prevent; prospective; skill acquisition; skills; success; survival outcome; targeted biomarker; tool

ABSTRACT Of the more than 400 children annually receiving a heart transplant, the likelihood that the child dies within five years (25%) is equivalent to the potential that the child lives >20 years post-transplant. The success of the transplant, and thus long-term survival of the child, is well known to correlate with achieving adequate immunosuppression to prevent rejection, especially in the period immediately following transplant. Attaining adequate immunosuppression is complicated by several factors, many of which impact the pharmacokinetics (PK) of the immunosuppressive agent. These factors include age of the patient, renal and hepatic function, concomitant medications, patient genetics, and the time post-transplant. Frequent, invasive drug monitoring is used clinically to assess how these factors impact an individual child’s PK, and in turn the dose required to achieve and maintain adequate immunosuppression. However, this empirical “guess and check” approach often results in the child spending substantial time receiving immunosuppressive therapy that is either ineffective or unsafe, decreasing the longevity of the transplant organ and thus, long-term patient survival. A more desirable approach would be to guide dosing using a precision medicine approach, wherein patient specific factors are used a priori to predict the dose most likely to achieve adequate immunosuppression. Developing a precision medicine platform for immunosuppression following pediatric heart transplant has the potential to not only improve outcomes in heart transplant recipients, but across all transplant types. This proposal aims to: 1) determine the impact of CYP3A5 genetic variation on tacrolimus concentrations in children, 2) prospectively validate the clinical utility of a PK-guided precision medicine platform in pediatric heart transplant patients receiving tacrolimus-based immunosuppression; and 3) identify and correlate biomarkers of transplant outcomes and tacrolimus safety/effect with the PK of tacrolimus, in order to establish the tacrolimus concentrations required for safe and effective immunosuppression in pediatric heart transplant recipients. The overall objective of this study is to improve the long-term survival of children with heart transplant via optimization of the child’s immunosuppressive therapy. Importantly, the interdisciplinary nature of this mentored research proposal will facilitate my progress towards an independent career developing precision medicine tools to improve health outcomes in children.

摘要 在每年接受心脏移植的400多名儿童中， 年（25%）相当于移植后儿童存活>20年的潜力。的成功 众所周知，移植，从而儿童的长期存活，与实现足够的 免疫抑制，以防止排斥反应，特别是在移植后立即。实现 充分的免疫抑制是复杂的几个因素，其中许多影响药代动力学 (PK)免疫抑制剂。这些因素包括患者的年龄、肾功能和肝功能， 合并用药、患者遗传学和移植后时间。频繁的侵入性药物监测 临床上用于评估这些因素如何影响个体儿童的PK，进而评估 达到并维持足够的免疫抑制。然而，这种经验性的“猜测和检查”方法往往 导致儿童花费大量时间接受无效的免疫抑制治疗， 不安全，降低移植器官的寿命，从而降低患者的长期存活率。更期望的 方法将是使用精确医学方法指导给药，其中患者特异性因素是 用于先验预测最有可能实现充分免疫抑制的剂量。开发一个精确的 儿科心脏移植后免疫抑制的药物平台不仅有可能 改善心脏移植受者的预后，但适用于所有移植类型。本建议旨在：1） 确定CYP 3A 5遗传变异对儿童他克莫司浓度的影响，2）前瞻性 验证PK引导的精准医疗平台在儿科心脏移植患者中的临床效用 接受基于他克莫司的免疫抑制;以及3）鉴定移植结果的生物标志物并使其相关 以及他克莫司的安全性/效应与他克莫司的PK，以确定所需的他克莫司浓度 用于儿科心脏移植受者的安全有效的免疫抑制。本报告的总体目标 这项研究旨在通过优化儿童心脏移植的长期存活率， 免疫抑制治疗重要的是，这一指导研究提案的跨学科性质将 促进我走向独立的职业发展，开发精确的医学工具，以改善健康 儿童的成果。