Factors affecting voriconazole pharmacokinetic variability in critically ill patients: a systematic review

Background The efficacy and toxicity of voriconazole, a broad-spectrum antifungal agent, are correlated with its trough concentration (C _trough ). Patients hospitalised in the intensive care unit (ICU) frequently experience inadequate voriconazole exposure. We sought to identify factors associated with voriconazole variability in ICU patients and describe their impact on voriconazole C _trough . Methods We searched MEDLINE, Web of Science and Cochrane Library databases from inception through January 2023. Results Twenty-five studies evaluating nine factors of variability were included. Liver dysfunction, high body mass index, high SOFA score and high inflammation status were associated with voriconazole overexposure, whereas the oral route of administration and low body mass index were likely associated with voriconazole underexposure. The effects of extracorporeal membrane oxygenation, renal replacement therapy and hypoalbuminemia on voriconazole exposure were unclear. Conclusions A systematic dose adaptation is required for patients with liver dysfunction, and voriconazole dose calculation should not be based on total body weight, with a linear relationship in patients with extreme weights; using an adapted body weight may be an alternative. Intravenous administration should be favoured in patients without severe renal dysfunction. Further research to define the benefit of an individualised dosing approach for voriconazole in ICU patients that combines pharmacokinetic modelling and machine learning, is warranted. Meanwhile, close therapeutic drug monitoring is needed for ICU patients, especially patients with identified risk factors for under- or overexposure.