Voriconazole in the management of invasive pulmonary aspergillosis in patients with severe liver disease: balancing efficacy and hepatotoxicity

Abstract

Patients with severe liver disease (SLD) are prone to developing invasive pulmonary aspergillosis (IPA) due to immunodeficiency and microbial translocation, leading to high mortality rates. Although voriconazole is the first-line treatment for IPA, its use in patients with SLD is challenging due to the risk of hepatotoxicity. In this population, reduced hepatic blood flow and enzyme activity, compromised bile excretion, and increased intestinal permeability collectively affect voriconazole metabolism, resulting in a prolonged half-life, drug accumulation, and higher incidence of adverse events (AEs). Therapeutic drug monitoring (TDM) is essential to optimize voriconazole therapy, ensuring plasma concentrations within the therapeutic range (1.0-5.0 mg/L) while minimizing toxicity risks. This review highlights the risk factors for IPA in patients with SLD, the mechanisms of voriconazole-induced hepatotoxicity, its pharmacokinetics in this population, and current research on dose optimization. We emphasize the necessity of closely monitoring voriconazole plasma concentration, liver function, and inflammatory markers during treatment. For patients with SLD, we recommend a loading dose of 200 mg every 12 hours, with subsequent maintenance doses reduced to 1/4-1/3 of the standard dose, though the evidence remains limited. We call for large-scale clinical trials to define optimal dosing, efficacy, and safety of voriconazole for IPA in patients with SLD, providing clinicians with clearer treatment guidelines and improving patient outcomes.