Population pharmacokinetic model‐guided optimization of intravenous voriconazole dosing regimens in critically ill patients with liver dysfunction

作者：Xiaobin Lin, Ka Yin Lui, Penghao Guo, Xiaoman Liu, Tao Liang, Xiaoguang Hu, Tong Li, Jingjing Wu, Yan‐zhe Xia, Pan Chen, Guo‐ping Zhong, Xiao Chen, Changjie Cai · 发表于：Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · 年份：2021 · DOI：10.1002/phar.2634 · 被引用次数：21 · 研究领域：Antifungal resistance and susceptibility、Ocular Infections and Treatments、Neutropenia and Cancer Infections

Abstract Study Objectives This study aimed to establish a population pharmacokinetic (PPK) model of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction and to explore the optimal dosing strategies in specific clinical scenarios for invasive fungal infections (IFIs) caused by common Aspergillus and Candida species. Design Prospective pharmacokinetics study. Setting The intensive care unit in a tertiary‐care medical center. Patients A total of 297 plasma VRC concentrations from 26 critically ill patients with liver dysfunction were included in the PPK analysis. Methods Model‐based simulations with therapeutic range of 2–6 mg/L as the plasma trough concentration ( C min ) target and the free area under the concentration‐time curve from 0 to 24 h (ƒAUC 24 ) divided by the minimum inhibitory concentration (MIC) (ie, ƒAUC 24 /MIC) ≥25 as the effective target were performed to optimize VRC dosing regimens for Child‐Pugh class A and B (CP‐A/B) and Child‐Pugh class C (CP‐C) patients. Results A two‐compartment model with first‐order elimination adequately described the data. Significant covariates in the final model were body weight on both central and peripheral distribution volume and Child‐Pugh class on clearance. Intravenous VRC loading dose of 5 mg/kg every 12 h (q12h) for the first day was adequate for CP‐A/B and CP‐C patients to attain the C min target at 24 h. The maintenance dose regimens of 100 mg q12h or 200 mg q24h for CP‐A/B patients and 50 mg ...