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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 E max 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 E max 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.

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., (© 2016 Société Française de Pharmacologie et de Thérapeutique.)

Invasive fungal disease (IFD) is a significant cause of morbidity and mortality in hospitalized patients. To maximize the efficacy of voriconazole treatment, the study established the relationship between voriconazole pharmacokinetic/pharmacodynamic (PK/PD) and probability of response and optimized voriconazole dosage regimen in patients with IFD based on Monte Carlo simulation. Forty-four patients proven with IFD were involved in this study. Among them, the overall cure rate was 75% (33/44) and there was a significant difference between Cmin /MIC values in patients with lack of response (n = 11) and those with successful response (n = 33) (mean value: 1.91 vs. 11.33; P < 0.05). Logistic regression model showed a high correlation between voriconazole Cmin /MIC ratio and clinical response (P = 0.044, OR = 1.349). According to Monte Carlo simulation results under different voriconazole dosing regimens, we could draw a conclusion that 200 mg voriconazole administered intravenously or orally twice daily for Candida infections and 300 mg administered orally or with 200 mg administered intravenously twice daily for Aspergillus infections were rational, which could achieve a value of the cumulative fraction of response >90%. This study built the relationship between voriconazole PK/PD and clinical response and obtained the reasonable empirical dosage regimen, which can be used to customize individual dosage regimen and improve the efficacy of voriconazole treatment., (© 2016 Société Française de Pharmacologie et de Thérapeutique.)

Study Objectives: To determine the incidence of hepatotoxicity in critically ill patients who were treated with voriconazole and to identify potential risk factors for voriconazole-associated hepatotoxicity in these patients., Design: Single-center prospective observational study., Setting: Intensive care unit (ICU) in a university-affiliated hospital in Xi'an, China., Patients: Sixty-three adults, admitted to the ICU between January 2010 and July 2015, who had an ICU length of stay longer than 3 days, had received voriconazole treatment for at least 3 days, and had at least one trough voriconazole plasma concentration (VPC) measurement., Intervention: All patients received CYP2C19 genotyping and were evaluated for the development of hepatotoxicity by assessing liver function tests performed before, during, and after voriconazole therapy., Measurements and Main Results: Hepatotoxicity was classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade scores and was defined as a CTCAE grade score that had increased by at least 2 grade scores over the baseline score. Hepatotoxicity occurred in 12 (19%) of the 63 patients. Characteristics of the patients who developed hepatotoxicity were compared with those of the patients who did not develop hepatotoxicity by univariate and multivariate Cox regression analyses. In the univariate analysis, Acute Physiology and Chronic Health Evaluation II score, invasive fungal infection classification, CYP2C19 genotype, and trough VPC were identified as the variables, and they were subsequently combined in the multivariate regression analysis. Multivariate Cox regression analysis revealed that hepatotoxicity was independently associated with trough VPC (hazard ratio 1.76, p<0.001). The relationships between trough VPCs and probability of hepatotoxicity were explored by using logistic regression analysis, and a target VPC upper limit of 4 mg/L was identified. The Kaplan-Meier method for the cumulative incidence of hepatotoxicity showed a significant difference between patients with trough VPCs of 4 mg/L or higher and those with VPCs lower than 4 mg/L (p<0.001)., Conclusion: Trough VPC was an independent risk factor associated with a greater risk of developing hepatotoxicity in critically ill patients, with a potentially toxic target trough concentration threshold of 4 mg/L identified for this complex population., (© 2016 Pharmacotherapy Publications, Inc.)

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 (R(2)  = 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; χ(2)  = 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., (© 2015 Pharmacotherapy Publications, Inc.)

• Etest method is useful for in vitro testing of combination antifungal therapy. • A combination of caspofungin and triazoles was effective for Candida infections. • Caspofungin and triazole combination was effective for Candida. glabrata with FKS mutation. Increased resistance of Candida species, especially Candida. glabrata is problematic. Combination antifungal therapies were studied to solve the problem. In this study, combinations of caspofungin with fluconazole and voriconazole were evaluated in 28 Candida species (including 15 C. glabrata and 12 with FKS mutation) at 24 and 48 hours using two Etest methods (direct cover method and MIC/MIC method). For Candida isolates, direct cover method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 12/28 (43%) isolates at 24 hours, and against 16/28 (57%) isolates at 48 hours. The MIC/MIC method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 11/28 (39%) and 12/28 (43%) isolates at 24 hours, and against 16/28 (57%) and 17/28 (61%) isolates at 48 hours, respectively. For C. glabrata , direct cover method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 11/15 (73%) and 10/15 (67%) isolates at 24 hours, and 11/15 (73%) and 13/15 (87%) isolates at 48 hours, respectively. The MIC/MIC method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against both 11/15 (73%) isolates at 24 hours, and 10/15 (67%) and 14/15 (93%) isolates at 48 hours, respectively. A combination of caspofungin and fluconazole or voriconazole might be effective against infections caused by Candida species, especially C. glabrata with FKS mutation. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether combinations of antifungal drugs are effective and safe for patients in intensive-care units. Methods: This study compared the efficacy and safety of caspofungin (CAS), voriconazole (VOR), amphotericin B liposome (L-AmB), CAS+VOR, and CAS+L-AmB as empirical, preemptive, and targeted therapies for invasive fungal infection (IFI). Results: Comparing the CAS, VOR, and CAS+VOR groups revealed that there were no differences in response rates between all therapy types, IFI-associated death within 90 days was less common in the CAS+VOR group (1.8%) than the VOR group (14.3%), and there were more adverse events in the VOR group than in the CAS group (P < 0.05). For empirical or preemptive therapy, the CAS group had a better response rate (80.0%) than the CAS+VOR group (47.1%), and there were more adverse events in the VOR group than in the CAS group (P < 0.05). For targeted therapy, no differences were found for efficacy and safety. There were no differences among the CAS, L-AmB, and CAS+L-AmB groups in efficacy and safety. Conclusion: Patients who received CAS monotherapy as an empirical or preemptive therapy could achieve good outcomes. Patients who received CAS+VOR or CAS+L-AmB achieved almost the same outcomes when compared with those who received CAS, VOR, and L-AmB monotherapy as targeted therapies, but those who received CAS+VOR had a lower IFI mortality rate than did those who received VOR monotherapy. [ABSTRACT FROM AUTHOR]

Voriconazole is used to prevent invasive pulmonary aspergillosis. However, little is known about the concentrations of voriconazole in human lung epithelial cells (A549), which is the target for preventing invasive pulmonary aspergillosis. The goal of this study was to develop a high-performance liquid chromatography–tandem mass spectrometry method to quantify voriconazole in A549 cells. A triple-quadrupole mass spectrometer in selected reaction monitoring mode was used with positive electrospray ionization. The total duration of each run was 5 min. The calibration curves fit a least squares model for the voriconazole concentration ranging from 0.625 to 160 ng/mL. Intraday and interday coefficients of variation were less than 10%. Recoveries at the concentrations of the quality control samples where greater than 85%, and the matrix effects showed that the ratios of the peak response exhibited a 15% suppression of the signal in the matrix compared to water. Voriconazole may penetrate A549 cells. However, the voriconazole uptake was slow in A549 cells, reaching a plateau at 2 h, where the dose-dependent intracellular voriconazole concentrations were 1.98 ± 0.38, 4.43 ± 0.54, and 8.14 ± 0.52 ng/mg protein for extracellular voriconazole concentrations of 5, 10, and 20 µg/mL, respectively. The uptake of voriconazole by A549 cells was linear at extracellular concentrations from 0 to 20 µg/mL. This study established a rapid and sensitive method suitable for determining voriconazole in A549 cells and described the kinetic properties of the absorption of voriconazole by A549 cells. [ABSTRACT FROM PUBLISHER]