Using Child‐Pugh Class to Optimize Voriconazole Dosage Regimens and Improve Safety in Patients with Liver Cirrhosis: Insights from a Population Pharmacokinetic Model‐based Analysis

作者：Taotao Wang, Miao Yan, Dan Tang, Yuzhu Dong, Yuzhu Dong, Li Zhu, Qian Du, Dan Sun, Jianfeng Xing, Yalin Dong, Yalin Dong · 发表于：Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · 年份：2020 · DOI：10.1002/phar.2474 · 被引用次数：21 · 研究领域：Antifungal resistance and susceptibility、Ocular Infections and Treatments、Fungal Infections and Studies

Background Cirrhotic patients are at a high risk of fungal infections. Voriconazole is widely used as prophylaxis and in the treatment of invasive fungal disease. However, the safety, pharmacokinetics, and optimal regimens of voriconazole are currently not well defined in cirrhotic patients. Design Retrospective pharmacokinetics study. Setting Two large, academic, tertiary‐care medical center. Patients Two hundred nineteen plasma trough concentrations ( C min ) from 120 cirrhotic patients and 83 plasma concentrations from 11 non‐cirrhotic patients were included. Methods Data pertaining to voriconazole were collected retrospectively. A population pharmacokinetics analysis was performed and model‐based simulation was used to optimize voriconazole dosage regimens. Results Voriconazole‐related adverse events (AEs) developed in 29 cirrhotic patients, and the threshold C min for AE was 5.12 mg/L. A two‐compartment model with first‐order elimination adequately described the data. The Child‐Pugh class and body weight were the significant covariates in the final model. Voriconazole clearance in non‐cirrhotic, Child‐Pugh class A and B cirrhotic (CP‐A/B) and Child‐Pugh class C cirrhotic (CP‐C) patients was 7.59, 1.86, and 0.93 L/hour, respectively. The central distribution volume and peripheral distribution volume was 100.8 and 55.2 L, respectively. The oral bioavailability was 91.6%. Model‐based simulations showed that a loading dose regimen of 200 mg/12 hours intravenously or orally l...