PK/PD modeling and simulation of the in vitro activity of the combinations of isavuconazole with echinocandins against Candida auris

by Selleckchem | Apr 24 2023

In vitro combination of echinocandins and isavuconazole against the emerging species Candida auris is mainly synergistic. However, this combination has not been evaluated in clinical settings. A pharmacokinetic/pharmacodynamic modeling and simulation approach based on in vitro data may be helpful to further study the therapeutic potential of these combinations. Therefore, the aims of this study were to characterize the time course of growth and killing of C. auris in response to the combination of the three approved echinocandins and isavuconazole using a semimechanistic model and to perform model-based simulations in order to predict the in vivo response to combination therapy. In vitro static time-kill curve data for isavuconazole and echinocandins combinations against six blood isolates of C. auris were best modeled considering the total killing of the fungal population as dependent on the additive effects of both drugs. Once assessed, the predictive performance of the model using simulations of different dosing and fungal susceptibility scenarios were conducted. Model-based simulations revealed that none of the combinations at standard or higher dosages would be effective against the studied isolates of C. auris and it was predicted that the combinations of isavuconazole with anidulafungin or caspofungin would be effective for minimum inhibitory concentrations up to 0.03 and 0.06 mg/L respectively, whereas the combination with micafungin would lead to treatment failure. The current approach highlights the importance of bridging the in vitro results to the clinic.

Comments：

The study aims to evaluate the therapeutic potential of combining the three approved echinocandins and isavuconazole against Candida auris, an emerging species of fungal infection. The researchers used a pharmacokinetic/pharmacodynamic modeling and simulation approach based on in vitro data to predict the in vivo response to combination therapy.

The in vitro static time-kill curve data for isavuconazole and echinocandins combinations against six blood isolates of C. auris were best modeled considering the total killing of the fungal population as dependent on the additive effects of both drugs. Model-based simulations were conducted to predict the efficacy of different dosing and fungal susceptibility scenarios.

The results of the simulations revealed that none of the combinations at standard or higher dosages would be effective against the studied isolates of C. auris. However, the combination of isavuconazole with anidulafungin or caspofungin would be effective for minimum inhibitory concentrations up to 0.03 and 0.06 mg/L, respectively, while the combination with micafungin would lead to treatment failure.

Overall, this study highlights the importance of bridging in vitro results to the clinic and provides insights into the potential therapeutic options for treating C. auris infections. However, further clinical studies are needed to validate these predictions and determine the optimal dosing regimens for these drug combinations.