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Invasive pulmonary aspergillosis (IPA), most caused by Aspergillus fumigatus, is a serious life-threatening infection in immunocompromised patients. Voriconazole is used to prevent and treat IPA. However, little is known about the pharmacological characteristics of voriconazole in pulmonary epithelial cells, which are the target site for the prophylaxis and early treatment of IPA. The aim of the study was to evaluate the kinetics and activity of voriconazole against A. fumigatus in A549 cells. High-performance liquid chromatography/tandem mass spectrometry and time-kill method were used to study the cellular pharmacokinetic and pharmacodynamics of voriconazole. Voriconazole exerted a concentration-dependent toxic effect on A549 cells and could penetrate into cells, reaching plateau concentrations of 1.14 ± 0.64, 3.72 ± 1.38 and 6.36 ± 0.95 ng/mg protein after A549 cells were exposed to voriconazole at extracellular concentrations of 2, 8 and 16 mg/L for 2 h, respectively. The efflux of voriconazole was rapid, with a half-life of 10.2 min. Voriconazole can decrease the A. fumigatus conidia invade cells, and the number of viable A. fumigatus conidia in cells can be decreased 2.1- to 20.6-fold when A549 cells were cultured in medium containing voriconazole. After 24-h incubation, 75.6% and 80.5% of intracellular A. fumigatus were killed when extracellular voriconazole concentration was 8 and 16 mg/L, respectively. This study illustrated a new application for the prophylaxis and early treatment of IPA from the cellular pharmacokinetics and pharmacodynamics and emphasized the importance of monitoring concentrations of voriconazole in epithelial lining fluid in immunocompromised patients receiving voriconazole therapy. [ABSTRACT FROM AUTHOR]

Study Objectives To assess the pharmacokinetic and pharmacodynamic ( PK/ PD) properties of voriconazole and to investigate the relationship between PK/ PD parameters and the efficacy of a fixed-dose oral regimen in the treatment of invasive fungal infections ( IFIs). Design Prospective and observational PK/ PD study. Setting A university-affiliated medical center. Patients Fifteen hospitalized patients with proven IFIs who were treated with oral voriconazole for at least 2 weeks. Methods We investigated the PK/ PD properties of voriconazole using a noncompartmental analysis in 15 patients. Results Marked interpatient variation in voriconazole pharmacokinetic properties was noted including peak plasma concentrations (median 2.31 mg/L, range 1.06-4.01 mg/L), 12-hour area under the plasma concentration-time curve ( AUCτ) (median 21.18 hr mg/L, range 7.71-42.07 hr mg/L), ratio of the unbound drug AUC over 24 hours ( fAUC24) divided by the minimum inhibitory concentration ( fAUC24: MIC; median 62.61, range 6.48-415.30), and the free trough plasma concentration (Cmin) divided by the MIC ( fCmin: MIC; median 1.81, range 0.46-15.52). There was a good correlation between voriconazole Cmin and AUCτ ( R2 = 0.805). Voriconazole therapy was effective in 66.7% of patients (10/15). No significant difference was observed with regard to successful clinical response between the patients with a fAUC24: MIC and fCmin: MIC values higher than 25 and higher than 1 (10/12 vs 10/13, respectively; χ2 = 1.61, p=0.688). Conclusion There is substantial interpatient variability in the PK/ PD properties of voriconazole. fAUC24: MIC values higher than 25 and fCmin: MIC values higher than 1 may predict clinical response in patients with IFIs. Designing an optimal dosage regimen based on individual PK/ PD properties will improve the efficacy in patients with IFIs. [ABSTRACT FROM AUTHOR]

Background: Invasive pulmonary aspergillosis (IPA) is a life-threatening disease in immunosuppressed patients. Voriconazole is commonly used to prevent and treat IPA in the clinic, but the optimal prophylactic antifungal regimen is unknown. The objective of this study was to clarify the mechanism underlying how voriconazole prevents IPA based on a target cellular pharmacokinetics/pharmacodynamics model, with the aim of identifying a way to design an optimal prophylactic antifungal regimen.Methods: A nystatin assay was used to establish a target-cells model for A. fumigatus infection. An inhibitory effect sigmoid Emax model was developed to explore the cellular PK/PD breakpoint, and Monte Carlo simulation was used to design the prophylactic antifungal regimen.Results: The intracellular activity of voriconazole in the target cells varied with its concentration, with the minimum inhibitory concentration (MIC) being an important determinant. For A. fumigatus strains AF293 and AF26, voriconazole decreased the intracellular inoculum by 0.79 and 0.84 lg cfu, respectively. The inhibitory effect sigmoid Emax model showed that 84.01% of the intracellular inoculum was suppressed by voriconazole within 24 h, and that a PK/PD value of 35.53 for the extracellular voriconazole concentration divided by MIC was associated with a 50% suppression of intracellular A. fumigatus. The Monte Carlo simulation results showed that the oral administration of at least 200 mg of voriconazole twice daily was yielded estimated the cumulative fraction of response value of 91.48%. Concentration of voriconazole in the pulmonary epithelial lining fluid and the plasma of > 17.77 and > 1.55 mg/L, respectively, would ensure the PK/PD > 35.53 for voriconazole against most isolates of A. fumigatus and may will be benefit to prevent IPA in clinical applications.Conclusions: This study used a target cellular pharmacokinetics/pharmacodynamics model to reveal a potential mechanism underlying how voriconazole prevents IPA and has provided a method for designing voriconazole prophylactic antifungal regimen in immunosuppressed patients. [ABSTRACT FROM AUTHOR]