Isavuconazole Pharmacodynamic Target Determination for Candida Species in an In Vivo Murine Disseminated Candidiasis Model

Pharmacodynamic (PD) studies with triazoles in the neutropenic murine disseminated candidiasis model have been performed extensively for Candida albicans. They have consistently shown that the pharmacodynamic index most closely correlated with efficacy is the ratio of the 24-h area under the concentration-time curve (AUC) to the MIC, and a target 24-h free-drug AUC/MIC ratio near 25 is associated with 50% of maximal microbiologic efficacy. We utilized this model to investigate the pharmacodynamics of isavuconazole. Isavuconazole pharmacokinetics were linear over the dose range studied. Oral-gastric doses of 640, 160, 40, and 10 mg of prodrug/kg of body weight produced peak levels of 0.51 to 25.4 mg/liter, an elimination half-life of 1 to 5 h, and an AUC from 0 h to infinity (AUC(0-infinity)) of 0.9 to 287 mg . h/liter. The AUC/MIC ratio was the pharmacodynamic index that correlated best with efficacy (R-2, 0.84). Pharmacodynamic target studies were performed using 4 C. albicans isolates with both a 24-h and a 96-h treatment duration. The strains were chosen to include previously characterized fluconazole-resistant strains. The mean 50% effective doses (ED50) (expressed in mg/kg of body weight/12 h) and associated 24-h free-drug AUC/MIC ratios were 89.3 +/- 46.7 and 67.7 +/- 35 for the 24-h treatment and 59.6 +/- 22 and 33.3 +/- 25.5 for the 96-h treatment. These differences were not statistically significant. Pharmacodynamic targets for two non-albicans Candida species were also explored. The mean ED50 (expressed in mg/kg/12 h) and associated 24-h free-drug AUC/MIC ratios were 31.2 and 6.2 for Candida tropicalis (n = 1) and 50.5 and 1.6 for Candida glabrata (n = 2). These PD targets were significantly different from C. albicans targets (P, 0.04). Isavuconazole PD targets for C. albicans are similar to those observed in this model with other triazoles. However, the PD targets for non-albicans Candida species were more than 10-fold lower than those for C. albicans (P, 0.04). This difference is similar to the species-specific PD relationships for the echinocandins. The lower PD targets for these species in this model will be important to consider in the analysis of clinical trial data and during the development of susceptibility breakpoints.