Central Nervous System Toxicity of Voriconazole: Risk Factors and Threshold – A Retrospective Cohort Study

PURPOSE: Voriconazole (VRC) is an antifungal agent which is used for treatment and prophylaxis of invasive fungal infections. The common clinical adverse reactions mainly include central nervous system (CNS) toxicity and abnormal liver function. These adverse reactions limit the clinical use of voriconazole to a certain extent. Therefore, the aim of this study was to analyze the risk factors of voriconazole neurotoxic side effects and to determine the plasma trough concentration (C(min)) threshold of voriconazole-induced CNS toxicity, so as to improve the safety of voriconazole treatment. PATIENTS AND METHODS: This study retrospectively collected the clinical data of 165 patients who received voriconazole and underwent therapeutic drug monitoring (TDM). CNS toxicity was defined using the National Cancer Institute (NCI) criteria, logistic regression was used to analyze the risk factors of CNS toxicity, classification and Regression tree (CART) model was used to determine the C(min) threshold for CNS toxicity. RESULTS: Voriconazole-related CNS toxicity occurred during treatment in 34 of 165 patients (20.6%) and the median time from administration to onset of CNS toxicity was 6 days (range, 2–19 days). The overall incidence of CNS toxicity was 20.6% (34/165), including visual disturbances in 4.8% (8/165) and nervous system disorders in 15.8% (26/165). C(min) significantly affects the occurrence of CNS toxicity and the threshold of C(min) for voriconazole CNS toxicity was determined to be 4.85 mg/L, when C(min) >4.85 mg/L and ≤4.85 mg/L, the incidence of CNS was 32.9% and 11.6%, respectively. CONCLUSION: Voriconazole trough concentration of C(min) is an independent risk factor for CNS toxicity, and the threshold of C(min) for CNS toxicity is 4.85mg/L. TDM should be routinely performed in patients with clinical use of voriconazole to reduce the occurrence of CNS toxicity of voriconazole.