Yun Juping, Bai Haihong, Wang Zihe, Ma Yingmin, Liu Wei
Department of Pharmacy, Beijing YouAn Hospital affiliated to Capital Medical University, Beijing, China.
Department of Respiratory and Critical Care Medicine, Beijing YouAn Hospital affiliated to Capital Medical University, Beijing, China.
Front Pharmacol. 2025 May 21;16:1543323. doi: 10.3389/fphar.2025.1543323. eCollection 2025.
Voriconazole (VRC) exhibits nonlinear pharmacokinetic (PK) characteristics and a narrow therapeutic window. Consequently, standardized dosage regimens are insufficient to achieve the targeted therapeutic exposure in patients with cirrhosis. While numerous population pharmacokinetic (PPK) studies on VRC have been conducted, data on the cirrhosis demographic remain limited.This study aimed to explore the PK characteristics of VRC and its covariates in a cirrhosis population, with the objective of recommending individualized dosing regimens.
Data collected from routine therapeutic drug monitoring (TDM) of patients with recorded VRC plasma concentrations during a period of therapy between September 2022 and August 2024 were included. A population pharmacokinetic (PPK) model was constructed using nonlinear mixed-effects modeling (NONMEM). Monte Carlo simulation was used to predict the target trough concentrations of VRC under steady-state conditions based on the final model parameters, thereby facilitating tailored dosage recommendations.
A total of 151 trough concentrations were obtained from 78 patients enrolled in the PPK study of VRC. A one-compartment model featuring first-order absorption and first-order elimination was optimal in describing the PK characteristics, additionally incorporating Child-Pugh grades and retinol-binding protein (RBP) as covariates affecting the central ventricular clearance rate (CL) of VRC. In the final model, the CL was determined as 6.96 L/h. For patients classified as Child-Pugh A and B with RBP ≥25 mg/L, the recommended dosages were 400 mg/d and 200 mg/d, respectively. At RBP levels <25 mg/L, the recommended dosages for Child-Pugh A and C patients were 200 mg/d and 100 mg/d, respectively, while for Child-Pugh B patients, both 200 mg/d and 100 mg/d were recommended.
Our results support the utility of RBP as a novel marker associated with VRC clearance. This biomarker may offer a practical option for VRC dosage optimization. The clinical dosage of VRC could be tailored according to the Child-Pugh grades and RBP levels of patients. While numerous unexplained factors potentially influence the pharmacokinetic properties of VRC, the application of PPK model-guided TDM is crucial for achieving precision in individualized medication regimens.
伏立康唑（VRC）呈现非线性药代动力学（PK）特征且治疗窗狭窄。因此，标准化给药方案不足以在肝硬化患者中实现目标治疗暴露。虽然已开展了众多关于VRC的群体药代动力学（PPK）研究，但肝硬化人群的数据仍然有限。本研究旨在探讨VRC在肝硬化人群中的PK特征及其协变量，目的是推荐个体化给药方案。
纳入2022年9月至2024年8月治疗期间记录有VRC血药浓度的患者常规治疗药物监测（TDM）收集的数据。使用非线性混合效应建模（NONMEM）构建群体药代动力学（PPK）模型。基于最终模型参数，采用蒙特卡洛模拟预测稳态条件下VRC的目标谷浓度，从而便于制定个性化给药建议。
VRC的PPK研究纳入的78例患者共获得151个谷浓度。具有一级吸收和一级消除的单室模型最能描述PK特征，另外纳入Child-Pugh分级和视黄醇结合蛋白（RBP）作为影响VRC中央室清除率（CL）的协变量。在最终模型中，CL确定为6.96 L/h。对于Child-Pugh A级和RBP≥25 mg/L的B级患者，推荐剂量分别为400 mg/d和200 mg/d。在RBP水平<25 mg/L时，Child-Pugh A级和C级患者的推荐剂量分别为200 mg/d和100 mg/d，而对于Child-Pugh B级患者，推荐200 mg/d和100 mg/d。
我们的结果支持RBP作为与VRC清除相关的新型标志物的效用。该生物标志物可为VRC剂量优化提供实用选择。VRC的临床剂量可根据患者的Child-Pugh分级和RBP水平进行调整。虽然众多无法解释的因素可能影响VRC的药代动力学特性，但PPK模型指导的TDM应用对于实现个体化用药方案的精准性至关重要。
