Kapnadak Siddhartha G, Ramos Kathleen J
Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
Curr Opin Pulm Med. 2024 Nov 1;30(6):660-666. doi: 10.1097/MCP.0000000000001110. Epub 2024 Jul 31.
In 2019, the United States Food and Drug Administration approved a breakthrough therapeutic for cystic fibrosis, elexacaftor-tezacaftor-ivacaftor (ETI), because of its profound effect on lung function in large phase III clinical trials. ETI acts directly on the dysfunctional protein that causes the systemic manifestations of cystic fibrosis and also leads to improvement in nonpulmonary symptoms of cystic fibrosis. Transplant recipients were excluded from the pivotal clinical trials of ETI but may stand to benefit from correction of the underlying protein defect. Drug interactions between the three drugs in ETI and immunosuppression medications are one of the primary concerns about using ETI after transplant. No rigorous studies exist to assess the safety of ETI in transplant recipients.
Multiple recent publications describe the use of ETI after solid organ transplantation, including lung and nonlung transplants, and the real-world evidence for drug interactions between ETI and immunosuppression medications. In nonlung transplant recipients, the pulmonary benefits of ETI have been confirmed, but adverse events occur and may have implications for their transplanted organ (e.g. liver biopsy in the setting of elevated transaminases). Lung transplant recipients may have higher rates of ETI discontinuation than nontransplant recipients given a lack of direct pulmonary benefit and frequency of side effects. Drug interactions have not been difficult to manage, with most studies reporting variable rates of mild to moderate increased tacrolimus levels after initiation of ETI.
Limited data exist to support the use of ETI after solid organ transplantation and further research is warranted. Given the unknown risks and benefits, case by case consideration of ETI use is indicated when extra-pulmonary manifestations are present in lung transplant recipients with cystic fibrosis. Given the proven benefit in cystic fibrosis lung disease, benefits likely outweigh the risks of ETI for nonlung solid organ transplant recipients.
2019年，美国食品药品监督管理局批准了一种用于治疗囊性纤维化的突破性疗法——依列卡福-替扎卡福-依伐卡福（ETI），因为它在大型III期临床试验中对肺功能有显著影响。ETI直接作用于导致囊性纤维化全身表现的功能失调蛋白，还能改善囊性纤维化的非肺部症状。移植受者被排除在ETI的关键临床试验之外，但可能会从潜在蛋白缺陷的纠正中获益。ETI中的三种药物与免疫抑制药物之间的药物相互作用是移植后使用ETI的主要担忧之一。目前尚无严格的研究来评估ETI在移植受者中的安全性。
最近的多篇文献描述了ETI在实体器官移植后的应用，包括肺移植和非肺移植，以及ETI与免疫抑制药物之间药物相互作用的真实世界证据。在非肺移植受者中，ETI的肺部益处已得到证实，但会出现不良事件，可能对其移植器官有影响（例如转氨酶升高时进行肝活检）。由于缺乏直接的肺部益处和副作用的发生率，肺移植受者停用ETI的比例可能高于非移植受者。药物相互作用并不难处理，大多数研究报告称，开始使用ETI后，他克莫司水平轻度至中度升高的发生率各不相同。
支持实体器官移植后使用ETI的数据有限，有必要进行进一步研究。鉴于风险和益处未知，对于患有囊性纤维化的肺移植受者出现肺外表现时，应逐案考虑使用ETI。鉴于ETI在囊性纤维化肺病中已被证实的益处，对于非肺实体器官移植受者，其益处可能超过风险。
