Defining optimal tacrolimus dosing and concentrations in the early post-lung transplant period based on short- and long-term clinical impacts

根据短期和长期临床影响确定肺移植后早期最佳他克莫司剂量和浓度

• 批准号: 10687432
• 负责人: Michael G. S. Shashaty
• 金额: $ 75.65万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687432
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Algorithms; Allografting; Chronic Kidney Failure; Clinical; Clinical Data; Complication; Consensus; Critical Illness; Cystic Fibrosis; Data; Disease Outcome; Dose; Enrollment; Equilibrium; Exposure to; Frequencies; Funding; Genetic; Genotype; Graft Rejection; Guidelines; Immunosuppressive Agents; International; Kidney; Kidney Transplantation; Knowledge; Lung Transplantation; Lung diseases; Modeling; Monitor; Organ Transplantation; Outcome; Patients; Perioperative; Persons; Pharmaceutical Preparations; Population; Prospective cohort; Pulmonary Emphysema; Pulmonary Fibrosis; Research; Resources; Respondent; Risk; Solid; Study models; Surveys; Tacrolimus; Time; Toxic effect; Transplant Recipients; Transplantation; Transplanted Lung Complication; United States National Institutes of Health; allograft rejection; base; clinical practice; clinical predictors; cohort; design; dose individualization; effective therapy; genetic predictors; high risk; improved; nephrotoxicity; organ transplant rejection; pharmacokinetic model; post-transplant; prevent; prospective; risk minimization; success; tool

PROJECT SUMMARY/ABSTRACT Lung transplantation can be lifesaving for patients with advanced lung disease, but outcomes lag far behind those of other major solid organ transplants in part due to complications such as acute cellular rejection (ACR), acute kidney injury (AKI), and chronic kidney disease (CKD). Lung transplant recipients are particularly at risk for insults in the early post-transplant period, characterized by critical illness and complications that may significantly impact long-term transplant success. Perioperative dosing of the nephrotoxic immunosuppressant tacrolimus (tac), used in 90% of lung transplant recipients to prevent allograft rejection, may be a target to improve complication rates and long-term outcomes. We showed in an international survey of lung transplant clinicians that early post-transplant tac dosing, timing of initiation, and target concentrations, for which there are no consensus guidelines, vary widely across centers. Survey respondents also expressed broad concern about both AKI and ACR risk related to perioperative tac levels. Data that could inform early dosing practices to balance risk to allograft and kidneys are limited. Our small single-center study showed that AKI risk rose with high early tac levels, but ACR findings were inconclusive. We found that uniform initial tac dosing with trough monitoring (an approach used by 78% of our survey respondents) led to out-of-range levels on 73% of days 1- 14 post-transplant, and that genetic and clinical factors could predict 42% of tac concentration:dose variability. Thus, target levels to minimize risk remain unclear and current practices fail to achieve targets. Robust studies to quantify risk and improve tac concentration:dose prediction could impact lung transplant clinical practice. We propose studies to bridge this crucial knowledge gap by leveraging the resources of the Lung Transplant Outcomes Group (LTOG), an NIH-funded multicenter prospective cohort designed to study acute and long- term lung transplant complications. The 6 LTOG centers in this proposal have enrolled >1400 patients since 2014 and are uniquely suited to rigorously study early tac exposure to inform the balance between short- and long-term nephrotoxicity and allograft rejection. We hypothesize that tac exposure during the first 2 weeks is associated with both short- and long-term transplant complications, and that genetic and clinical variables can inform a personalized early tac dosing algorithm to minimize variability around an optimal target range. Adding further clinical data, genotyping, and prospective population pharmacokinetic (popPK) modeling studies to the existing resources of the LTOG, we aim to: 1) Determine risk of AKI, CKD, and ACR associated with tac exposure during the first 2 weeks after lung transplantation, and 2) Derive and validate a popPK model of tac exposure during the early transplant period to inform a personalized, clinically usable dosing algorithm. Completion of these aims will clarify risks associated with perioperative tac dosing in the highly vulnerable lung transplant population and provide a usable clinical tool to accurately individualize dosing, which in combination will have the potential to reduce allograft and kidney complications and maximize long-term transplant success.

项目摘要/摘要 对于患有晚期肺部疾病的患者，肺移植可能是救生的，但结果远远落后于 其他主要固体器官移植的部分部分是由于并发症，例如急性细胞排斥（ACR）， 急性肾脏损伤（AKI）和慢性肾脏病（CKD）。肺移植接受者特别有风险 在移植后早期的侮辱中，其特征是危害疾病和可能的并发症 显着影响长期移植成功。肌活动剂量的肾毒性免疫抑制剂 克莫司（TAC），在90％ 提高并发症率和长期结局。我们在一项国际肺移植调查中展示了 移植后TAC剂量的早期临床医生，启动时间和目标浓度 不是共识准则，在各个中心之间差异很大。调查受访者还表示广泛关注 关于与围手术期TAC水平有关的AKI和ACR风险。可以告知早期给药实践的数据 平衡同种异体移植和肾脏的风险是有限的。我们的小单中心研究表明，Aki风险与 早期的TAC水平很高，但ACR发现尚无定论。我们发现均匀的初始TAC剂量与槽 监测（我们78％的调查受访者使用的一种方法）导致了73％的1-天的范围水平。 14移植后，遗传和临床因素可以预测42％的TAC浓度：剂量变异性。 因此，降低风险的目标水平仍然不清楚，并且当前的做法无法实现目标。强大的研究 为了量化风险并提高TAC浓度：剂量预测可能会影响肺移植临床实践。 我们建议通过利用肺移植的资源来弥合关键知识差距的研究 成果组（LTOG）是NIH资助的多中心前瞻性队列，旨在研究急性和长期 术语肺移植并发症。此提案中的6个LTOG中心已招募了> 1400名患者 2014年，非常适合严格研究早期TAC的暴露，以告知短期和 长期肾毒性和同种异体移植排斥。我们假设最初2周的TAC暴露是 与短期和长期移植并发症都相关，遗传和临床变量可以 告知个性化的早期TAC剂量算法，以最大程度地减少最佳目标范围内的可变性。添加 进一步的临床数据，基因分型和前瞻性人群药代动力学（POPPK）建模研究 LTOG的现有资源，我们的目标是：1）确定与TAC相关的AKI，CKD和ACR的风险 肺移植后的前2周内暴露，2）得出并验证TAC的POPPK模型 在早期移植期间的暴露，以告知个性化的临床用剂量算法。 这些目标的完成将阐明与高度脆弱的肺部围手术期TAC相关的风险 移植人群并提供可用的临床工具，以准确个性化给药，该工具结合起来 有可能减少同种异体移植和肾脏并发症并最大程度地提高长期移植成功。