Guimbellot J S, Chalamalla Ashritha, Baker Elizabeth, Ryan K J, Dowell A, Abouelenein Saly, Bartlett L E, Bergeron J, Turner G, Acosta E P, Ramos K J
Department of Pediatrics, Section of Pulmonary and Sleep Medicine, University of Arkansas for Medical Sciences, 1 Children's Way, Little Rock, AR, USA.
Department of Pediatrics, Section of Pulmonary and Sleep Medicine, University of Arkansas for Medical Sciences, 1 Children's Way, Little Rock, AR, USA; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
J Cyst Fibros. 2025 May;24(3):534-541. doi: 10.1016/j.jcf.2025.03.010. Epub 2025 Mar 21.
CFTR modulators in post-transplant people with cystic fibrosis (pwCF) are less frequently used due to uncertainty regarding effectiveness and interactions with immunosuppressive agents. Elexacaftor/tezacaftor/ivacaftor (ETI) is a triple combination cystic fibrosis (CF) therapeutic with benefits in multiple organ systems where complications can impact lung transplant (LTx) outcomes, including malnutrition, diabetes, and sinus disease. ETI use in LTx recipients is variable.
We conducted a pharmacokinetics (PK) study of concentrations of ETI parent compounds and the four major metabolites (M23-ELX, M1-TEZ, M1-IVA, M6-IVA) in a prospective non-randomized observational study, with all transplant participants concomitantly taking tacrolimus for LTx immunosuppression and excluded if taking any other medication with known interactions (e.g., azole antifungals) and compared to a non-transplant group of pwCF. We completed non-compartmental analysis (NCA) for both groups and compared the transplant to non-transplant PK parameters, as well as to published data from the manufacturer for non-transplant pwCF. Area under the curve (AUC), average concentrations (C), minimum and maximum concentrations, clearance, and other parameters were determined.
Twelve transplant and fourteen non-transplant participants with CF completed the study. There were no significant differences between the mean values for any PK parameters for the transplant and non-transplant groups and no substantial differences in frequency of concentrations outside the therapeutic ranges in the two groups.
Our data suggest there are not significant differences in concentrations of ELX, TEZ, IVA, or their major human metabolites in LTx recipients compared to non-transplant pwCF.
由于疗效的不确定性以及与免疫抑制剂的相互作用，囊性纤维化（CF）移植后患者较少使用CFTR调节剂。依列卡福/替扎卡福/依伐卡福（ETI）是一种三联组合的囊性纤维化（CF）治疗药物，对多个器官系统有益，这些器官系统中的并发症会影响肺移植（LTx）的结果，包括营养不良、糖尿病和鼻窦疾病。LTx受者中ETI的使用情况各不相同。
我们在一项前瞻性非随机观察性研究中，对ETI母体化合物和四种主要代谢物（M23-ELX、M1-TEZ、M1-IVA、M6-IVA）的浓度进行了药代动力学（PK）研究，所有移植参与者均同时服用他克莫司进行LTx免疫抑制，若服用任何其他有已知相互作用的药物（如唑类抗真菌药）则被排除，并与非移植CF患者组进行比较。我们对两组都完成了非房室分析（NCA），并比较了移植组与非移植组的PK参数，以及与制造商公布的非移植CF患者的数据。测定了曲线下面积（AUC）、平均浓度（C）、最低和最高浓度、清除率及其他参数。
12名移植CF患者和14名非移植CF患者完成了该研究。移植组和非移植组任何PK参数的平均值之间均无显著差异，两组治疗范围外浓度的频率也无实质性差异。
我们的数据表明，与非移植CF患者相比，LTx受者中ELX、TEZ、IVA或其主要人体代谢物的浓度没有显著差异。
