title: In vitro pharmacokinetic/pharmacodynamic modeling of voriconazole activity against Aspergillus species in a new in vitro dynamic model.
abstract: The pharmacodynamics (PD) of voriconazole activity against Aspergillus spp. were studied using a new in vitro dynamic 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. Three Aspergillus clinical isolates (1 A. fumigatus, 1 A. flavus, and 1 A. terreus isolate) with CLSI MICs of 0.5 mg/liter were tested in an in vitro model simulating voriconazole PK in human plasma with C(max) values of 7, 3.5, and 1.75 mg/liter and a t(1/2) of 6 h. The area under the galactomannan index-time curve (AUC(GI)) was used as the PD parameter. In vitro PK-PD data were bridged with population human PK of voriconazole exposure, and the percent target attainment was calculated. The in vitro PK-PD relationship of fAUC(0-24)-AUC(GI) followed a sigmoid pattern (global R(2) = 0.97), with near-maximum activities (10% fungal growth) observed at an fAUC(0-24) (95% confidence interval [CI]) of 18.9 (14.4 to 23.1) mg · h/liter against A. fumigatus, 26.6 (21.1 to 32.9) mg · h/liter against A. flavus, and 36.2 (27.8 to 45.7) mg · h/liter against A. 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%) for A. fumigatus, 12% (5 to 26%), 63% (17 to 93%), and 86% (73 to 94%) for A. flavus, and 4% (2 to 11%), 36% (6 to 83%), and 68% (47 to 83%) for A. terreus. Based on the in vitro exposure-effect relationships, a standard dosage of voriconazole may be adequate for most patients with A. fumigatus but not A. flavus and A. terreus infections, 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.
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, Greece.
authors.forename: R
authors.initials: R
authors.lastname: Al-Saigh
authors.forename: A
authors.initials: A
authors.lastname: Elefanti
authors.forename: A
authors.initials: A
authors.lastname: Velegraki
authors.forename: L
authors.initials: L
authors.lastname: Zerva
authors.forename: J
authors.initials: J
authors.lastname: Meletiadis
mesh_terms: D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001230:Aspergillus / Q000187:drug effects*; D001232:Aspergillus fumigatus / Q000187:drug effects; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014230:Triazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole