Voriconazole Dosing and Therapeutic Drug Monitoring in Patients Before and After Liver Transplantation

BACKGROUND: Voriconazole is a triazole antifungal, primarily metabolized by the liver, and poses a dosing challenge in patients with liver impairment. Although the manufacturer recommends a maintenance dose reduction for mild-to-moderate hepatic dysfunction, no standardized recommendations exist for severe liver impairment. Prior evidence suggests a need for significant dose reduction in the setting of severe liver failure; however, there is limited data on empirical dosing in patients undergoing orthotopic liver transplant (OLT) evaluation and surgery. METHODS: This is a single-center, retrospective cohort study assessing voriconazole dosing and therapeutic drug monitoring (TDM) in patients with advanced cirrhosis who received voriconazole during urgent OLT evaluation and/or surgery. Patients were included if voriconazole trough concentrations were collected at least 7 days after therapy initiation pre-OLT or at least 5 days post-OLT. The target therapeutic range was defined as 1-4 mcg/mL. The primary outcome was the distribution of voriconazole trough concentrations in the pre- and post-transplant cohorts. RESULTS: The pre-OLT cohort comprised 76 patients with 124 concentrations, and the post-OLT cohort comprised 36 patients with 71 concentrations. As anticipated, the pre-OLT group exhibited more abnormal liver enzymes and a high median Model for End-Stage Liver Disease (MELD) score of 35 (Interquartile Range (IQR) 29.5-40). In the pre-OLT setting, doses less than 2 mg/kg/dose were more likely associated with therapeutic voriconazole concentrations. Supratherapeutic concentrations were observed in 41 patients (average dose of 2.4 mg/kg/dose), of which five patients required therapy interruption. In the post-OLT group, only 23 of 71 concentrations fell within the therapeutic range, with an average dose of 2.8 mg/kg/dose. CONCLUSION: We found that empiric voriconazole dosing in patients with advanced cirrhosis undergoing OLT evaluation should not exceed 2 mg/kg/dose initially to mitigate the risk of drug accumulation and potential toxicity. In post-OLT patients, it is reasonable to consider reverting to standard manufacturer-recommended dosing. Given the pharmacokinetic variability observed, TDM is essential for effective and safe management in this high-risk patient population.