Abstract
BackgroundInvasive 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.MethodsA 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.ResultsThe 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.ConclusionsThis 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.
Highlights
Invasive pulmonary aspergillosis (IPA) is a life-threatening disease in immunosuppressed patients
Biomarker We examined the viability of infected Human pulmonary epithelial cells (A549) cells for Ce values ranging from 0.0155 to 64 mg/L by measuring the lactate dehydrogenase (LDH) released into the medium
We found that the kinetics profile of galactomannan was correlated with Static concentration (Cs) e and that voriconazole induced a Cellular pharmacodynamics of voriconazole against AF293 and AF26 The initial intracellular inoculum was 1–2 × 105 cfu/mL per plate for the two strains investigated in this study
Summary
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. Invasive pulmonary aspergillosis (IPA) is mainly caused by A. fumigatus and has a high morbidity and mortality in high-risk immunosuppressed patients [1]. Pulmonary epithelial cells are the first cells encountered by the inhaled spores, which germinate and grow in these cells, followed by the development of serious IPA disease in immunosuppressed patients [8]. Pulmonary epithelial cells can be viewed as the target of prophylaxis in IPA
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