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

项目总结/文摘

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.