Du Wenwen, Chen Wenqian, Zhang Dan, Li Shu, Li Bo, Zuo Xianbo, Li Pengmei, Wang Xiaoxing
Department of Pharmacy, China-Japan Friendship Hospital, Chaoyang District, Beijing, China.
Department of Dermatology, Department of Pharmacy, China-Japan Friendship Hospital, Chaoyang District, Beijing, China.
Int J Clin Pharm. 2025 Jul 16. doi: 10.1007/s11096-025-01946-8.
Voriconazole serves as a cornerstone antifungal therapy for lung transplant (LTx) patients; however, its use is associated with a notable risk of hepatotoxicity.
This study aimed to identify potential prognostic factors and develop a robust prediction nomogram for voriconazole-associated liver injury (VALI) in this population.
This retrospective observational study included 97 LTx patients treated with voriconazole between 2017 and 2024. Patients were randomly divided into a training cohort and a validation cohort, with a ratio of 75:25. Voriconazole blood concentrations were measured, and genetic polymorphisms related to voriconazole metabolism were analyzed. Potential prognostic factors associated with VALI were identified by using univariate and multivariate Cox proportional hazard models. The nomogram was evaluated by C-index, calibration curve and clinical utility.
The overall incidence of VALI was 30.9%. In the multivariate analysis, voriconazole concentration (HR 1.318, 95% CI 1.052-1.650, p = 0.016), voriconazole dose (HR 1.005, 95% CI 1.001-1.008, p = 0.006), concomitant mycophenolate mofetil (MMF) use (HR 0.320, 95% CI 0.116-0.885, p = 0.028), and rs4244285 polymorphism (HR 2.466, 95% CI 0.936-6.498, p = 0.068) were identified as independent predictive factors for VALI. The C-indexes of the nomogram were 0.807 (95% CI 0.725-0.889) for the training cohort and 0.82 (95% CI 0.681-0.959) for the validation cohort. Furthermore, the nomogram demonstrated excellent calibration and clinical applicability. Receiver operating characteristic (ROC) curve analysis determined the voriconazole cut-off trough concentration for hepatotoxicity stratified by MMF use. Stratified analysis indicated that the optimal voriconazole trough thresholds for minimizing VALI risk were 2.8 ng/mL in MMF users (AUC 0.769, p < 0.001) and 2.6 ng/mL in non-users (AUC 0.795, p = 0.011).
This study highlights the significance of therapeutic drug monitoring for voriconazole in stratifying the risk probability of VALI among LTx patients. Additionally, we have established a predictive nomogram to aid clinicians and pharmacists in assessing the likelihood of VALI following voriconazole administration in this patient population. However, before clinical implementation, external validation in independent cohorts and prospective utility studies are imperative to confirm the generalizability and clinical efficacy of this model.
伏立康唑是肺移植（LTx）患者抗真菌治疗的基石；然而，其使用与显著的肝毒性风险相关。
本研究旨在确定潜在的预后因素，并为该人群中伏立康唑相关肝损伤（VALI）制定一个可靠的预测列线图。
这项回顾性观察研究纳入了2017年至2024年间接受伏立康唑治疗的97例LTx患者。患者被随机分为训练队列和验证队列，比例为75:25。测量伏立康唑血药浓度，并分析与伏立康唑代谢相关的基因多态性。通过单因素和多因素Cox比例风险模型确定与VALI相关的潜在预后因素。通过C指数、校准曲线和临床实用性对列线图进行评估。
VALI的总体发生率为30.9%。在多因素分析中，伏立康唑浓度（HR 1.318，95%CI 1.052 - 1.650，p = 0.016）、伏立康唑剂量（HR 1.005，95%CI 1.001 - 1.008，p = 0.006）、同时使用霉酚酸酯（MMF）（HR 0.320，95%CI 0.116 - 0.885，p = 0.028）和rs4244285多态性（HR 2.466，95%CI 0.936 - 6.498，p = 0.068）被确定为VALI的独立预测因素。训练队列列线图的C指数为0.8（95%CI ），验证队列列线图的C指数为0.82（95%CI 0.681 - 0.959）。此外，列线图显示出良好的校准和临床适用性情况。受试者工作特征（ROC）曲线分析确定了按MMF使用情况分层的伏立康唑肝毒性临界谷浓度。分层分析表明，将VALI风险降至最低的最佳伏立康唑谷阈值在MMF使用者中为2.8 ng/mL（AUC 0.769，p < 0.001），在非使用者中为2.6 ng/mL（AUC 0.795，p = 0.011）。
本研究强调了伏立康唑治疗药物监测在分层LTx患者中VALI风险概率方面的重要性。此外，我们建立了一个预测列线图，以帮助临床医生和药剂师评估该患者群体中伏立康唑给药后发生VALI的可能性。然而，在临床实施之前，独立队列中的外部验证和前瞻性实用性研究对于确认该模型的普遍性和临床疗效至关重要。
