Pharmacokinetic/pharmacodynamic modelling and in vitro simulation of dynamic voriconazole-Candida interactions

Using dynamic time-kill experiments with changing voriconazole concentrations, it was demonstrated that Candida albicans ATCC 90029 as well as Candida glabrata and Candida parapsilosis clinical isolates (two each) were significantly inhibited by starting concentrations of 4x and 16x the minimum inhibitory concentration (MIC) but not 1x MIC. Time-kill data were accurately fitted using a sigmoidal E(max) model. Pharmacokinetic (PK) parameters from human data sets were used in the model to simulate kill curves for typical treatment regimens. Simulated curves predicted that voriconazole would exert prolonged fungistatic activity against all five isolates. For three isolates, reductions from starting inocula over 60 h were predicted to exceed 2 log. Combining in vitro time-kill data with existing in vivo PK data might serve as an alternative to animal studies in defining optimal antifungal regimens.