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 肺移植可以挽救晚期肺病患者的生命，但结果远远落后 其他主要实体器官移植的部分原因是并发症，如急性细胞排斥反应（ACR）， 急性肾损伤（阿基）和慢性肾病（CKD）。肺移植受者的风险尤其高 对于移植后早期的损伤，其特征是危重病和并发症， 对长期移植成功率有很大影响。肾毒性免疫抑制剂的围手术期剂量 他克莫司（tacrolimus，tac）用于90%的肺移植受者以预防同种异体移植排斥反应， 改善并发症发生率和长期结果。我们在一项国际肺移植调查中发现 临床医生认为，移植后早期tac给药，启动时间和目标浓度， 没有共识指南，各中心差异很大。调查受访者还表示了广泛的担忧 阿基和ACR风险与围手术期tac水平有关。可以告知早期给药实践的数据 以平衡同种异体移植物和肾脏的风险。我们的小型单中心研究表明，阿基风险随着 早期tac水平较高，但ACR结果不确定。我们发现初始tac剂量与谷浓度一致 监测（78%的调查受访者使用的方法）导致73%的第1天超出范围水平- 遗传和临床因素可以预测42%的tac浓度：剂量变异性。 因此，尽量减少风险的目标水平仍然不明确，目前的做法未能实现目标。稳健性研究 量化风险并提高tac浓度：剂量预测可能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这一关键的知识差距 结果组（LTOG），一个由NIH资助的多中心前瞻性队列，旨在研究急性和长期的 长期肺移植并发症自2011年以来，本提案中的6家LTOG中心已招募了>1400例患者。 2014年，是唯一适合严格研究早期的tac暴露，以告知短期和短期之间的平衡， 长期肾毒性和同种异体移植排斥。我们假设前两周接触tac 与短期和长期移植并发症有关，遗传和临床变量可以 通知个性化早期TAC给药算法以最小化最佳目标范围周围的可变性。添加 进一步的临床数据、基因分型和前瞻性群体药代动力学（popPK）建模研究， LTOG的现有资源，我们的目标是：1）确定与tac相关的阿基，CKD和ACR的风险 肺移植后前2周内的暴露，以及2）推导并验证tac的popPK模型 在早期移植期间的暴露，以告知个性化的，临床上可用的给药算法。 这些目标的完成将阐明与高度脆弱肺围手术期tac给药相关的风险 移植人群，并提供了一个可用的临床工具，以准确地个性化给药， 将有可能减少同种异体移植和肾脏并发症，并最大限度地提高长期移植成功率。