A strategy for designing voriconazole dosage regimens to prevent invasive pulmonary aspergillosis based on a cellular pharmacokinetics/pharmacodynamics model

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 0.84lg cfu, respectively. The inhibitory effect sigmoid E _max model showed that 84.01% of the intracellular inoculum was suppressed by voriconazole within 24h, 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 200mg 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 >1.55mg/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.