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

项目摘要/摘要 肺移植可以挽救晚期肺部疾病患者的生命，但结果远远落后。 其他主要实体器官移植的部分原因是急性细胞排斥反应(ACR)等并发症， 急性肾脏损伤(AKI)和慢性肾脏疾病(CKD)。肺移植受者面临的风险尤其大 在移植后早期的侮辱，以危重疾病和并发症为特征 显著影响长期移植成功。肾毒性免疫抑制剂的围手术期剂量 90%的肺移植受者使用他克莫司(Tac)预防同种异体移植排斥反应，他克莫司可能是治疗排斥反应的靶点。 提高并发症发生率和远期疗效。我们在一项关于肺移植的国际调查中展示了 临床医生认为，移植后早期的TAC剂量、启动时间和靶浓度， 没有共识的指导方针，在不同的中心差别很大。调查对象也表达了广泛的担忧 AKI和ACR风险与围手术期TAC水平有关。可以为早期给药实践提供信息的数据 为了平衡对同种异体移植的风险，肾脏是有限的。我们的小型单中心研究表明，AKI的风险随着 早期TAC水平较高，但ACR结果尚不确定。我们发现，均匀的初始TAC剂量与槽 监测(78%的受访者使用的方法)导致73%的天数超出范围1- 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，将风险降至最低的目标水平仍然不明确，目前的做法未能实现目标。稳健的研究 为了量化风险和改善tac浓度：剂量预测可能会影响肺移植的临床实践。 我们建议进行研究，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)，一个由美国国立卫生研究院资助的多中心前瞻性队列，旨在研究急性和长期 终末期肺移植并发症。这项提案中的6个LTOG中心已经招募了1400名患者 2014年，特别适合于严格研究早期TAC暴露，以提供短期和短期之间的平衡 长期肾毒性和同种异体移植排斥反应。我们假设在前两周暴露在TAC中 与移植的短期和长期并发症有关，而且遗传和临床变量可能 通知个性化的早期TAC剂量算法，以最大限度地减少最佳目标范围周围的变异性。添加 进一步的临床数据、基因分型和预期人群药代动力学(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 肺移植后前2周的暴露，以及2)建立和验证TAC的PopPK模型 在移植早期暴露，以提供个性化的、临床可用的剂量算法。 这些目标的完成将澄清与高度脆弱的肺的围手术期TAC剂量相关的风险 并提供了一种有用的临床工具，以准确地个体化给药，这两种方法相结合 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。

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.