Pharmacodynamics of a new triazole, posaconazole, in a murine model of disseminated candidiasis

Abstract

Previous in vivo studies have characterized the pharmacodynamic characteristics of two triazole compounds, fluconazole and ravuconazole. These investigations demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio is the critical pharmacokinetic-pharmacodynamic (PK-PD) parameter associated with treatment efficacy. Further analysis demonstrated that a free-drug triazole 24-h AUC/MIC ratio of 20 to 25 was predictive of treatment success in both experimental models and clinical trials. We used a neutropenic murine model of disseminated Candida albicans infection to similarly characterize the time course activity of the new triazole, posaconazole. The PK-PD parameters (percent time above MIC, AUC/MIC ratio, and peak serum drug level/MIC ratio) were correlated with in vivo efficacy, as measured by organism number in kidney cultures after 48 h of therapy. Kinetics and protein binding following oral posaconazole dosing were performed in neutropenic infected mice. Peak levels and AUC from 0 h to infinity values were nonlinear over the 16-fold dose range studied. Serum drug elimination half-life ranged from 12.0 to 17.7 h. Protein binding was 99%. Single dose postantifungal effect studies demonstrated prolonged suppression of organism regrowth after serum posaconazole levels had fallen below the MIC. Treatment efficacy with the four dosing intervals studied was similar, supporting the AUC/MIC ratio as the PK-PD parameter predictive of efficacy. Nonlinear regression analysis also suggested that the AUC/MIC ratio was strongly predictive of treatment outcomes (AUC/MIC ratio R(2) = 83%; peak serum drug/MIC ratio R(2) = 85%; time that serum levels of posaconazole remained above the MIC R(2) = 65%). Similar studies were conducted with 11 additional C. albicans isolates with various posaconazole susceptibilities (MIC, 0.015 to 0.12 micro g/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The posaconazole free-drug AUC/MIC ratios were similar for all of the organisms studied (6.12 to 26.7, mean +/- SD = 16.9 +/- 7.8, P value, 0.42). These free-drug AUC/MIC ratios are similar to those observed for other triazoles in this model.

FIG. 1.

Serum posaconazole concentrations after administration of oral doses of 20, 80, and 320 mg/kg in neutropenic infected mice. Each symbol represents the geometric mean ± SD of the levels in the sera of three mice.

FIG. 2.

In vivo PAFE following posaconazole doses of 10, 5, and 2.5 mg/kg against C. albicans K-1 in neutropenic infected mice. Each symbol represents the mean ± SD for two mice. The width of a horizontal bar represents the time that serum free drug levels exceeded the MIC.

FIG. 3.

Relationship between the 24-h total dose and the change in log₁₀ CFU per kidney over the treatment period for posaconazole administered at different dosing intervals in a neutropenic murine model of disseminated candidiasis. Each symbol represents data for two mice.

FIG. 4.

Relationship between free-drug T>MIC, AUC/MIC, peak/MIC, and the change in log₁₀ CFU per kidney. Each symbol represents data for two mice. R² is the coefficient of determination.

FIG. 5.

Relationship between the free-drug 24-h AUC/MIC ratio and the log₁₀ CFU per kidney after 2 days of treatment for posaconazole against 12 C. albicans organisms. Each symbol represents data for two mice. R² is the coefficient of determination.