In VitroPharmacokinetic/Pharmacodynamic Modeling of Voriconazole Activity against Aspergillus Species in a NewIn VitroDynamic Model

Abstract

ABSTRACTThe pharmacodynamics (PD) of voriconazole activity againstAspergillusspp. were studied using a newin vitrodynamic model simulating voriconazole human pharmacokinetics (PK), and the PK-PD data were bridged with human drug exposure to assess the percent target (near-maximum activity) attainment of different voriconazole dosages. ThreeAspergillusclinical isolates (1A. fumigatus, 1A. flavus, and 1A. terreusisolate) with CLSI MICs of 0.5 mg/liter were tested in anin vitromodel simulating voriconazole PK in human plasma withCmaxvalues of 7, 3.5, and 1.75 mg/liter and at1/2of 6 h. The area under the galactomannan index-time curve (AUCGI) was used as the PD parameter.In vitroPK-PD data were bridged with population human PK of voriconazole exposure, and the percent target attainment was calculated. Thein vitroPK-PD relationship offAUC0-24-AUCGIfollowed a sigmoid pattern (globalR2= 0.97), with near-maximum activities (10% fungal growth) observed at anfAUC0-24(95% confidence interval [CI]) of 18.9 (14.4 to 23.1) mg · h/liter againstA. fumigatus, 26.6 (21.1 to 32.9) mg · h/liter againstA. flavus, and 36.2 (27.8 to 45.7) mg · h/liter againstA. terreus(F test;P< 0.0001). Target attainment for 3, 4, and 5 mg/kg-of-body-weight voriconazole dosages was 24% (11 to 45%), 80% (32 to 97%), and 93% (86 to 97%) forA. fumigatus, 12% (5 to 26%), 63% (17 to 93%), and 86% (73 to 94%) forA. flavus, and 4% (2 to 11%), 36% (6 to 83%), and 68% (47 to 83%) forA. terreus. Based on thein vitroexposure-effect relationships, a standard dosage of voriconazole may be adequate for most patients withA. fumigatusbut notA. flavusandA. terreusinfections, for which a higher drug exposure may be required. This could be achieved using a higher voriconazole dosage, thus highlighting the usefulness of therapeutic drug monitoring in patients receiving a standard dosage.