In vivo pharmacodynamics of a new triazole, ravuconazole, in a murine candidiasis model

Abstract

In vivo studies have characterized the pharmacodynamic characteristics of the triazole fluconazole. These investigations demonstrated that the ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (24-h AUC/MIC ratio) is the critical pharmacokinetic/pharmacodynamic (PK/PD) parameter associated with treatment efficacy. Further analysis demonstrated that a fluconazole 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 ravuconazole. The PK/PD parameters (percent time above the MIC, AUC/MIC ratio, and peak level in serum/MIC ratio) were correlated with in vivo efficacy, as measured by organism number in kidney cultures after 24 and 72 h of therapy. Ravuconazole kinetics and protein binding were performed in neutropenic infected mice. Peak/dose and AUC/dose values ranged from 0.03 to 0.04 and 0.30 to 0.34, respectively. Serum elimination half-life ranged from 3.9 to 4.8 h. Protein binding was 95.8%. Single-dose postantifungal effect studies demonstrated prolonged suppression of organism regrowth after serum ravuconazole levels had fallen below the MIC. Treatment efficacies with the five dosing intervals studied were similar, supporting the argument for 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) = 91%; peak/MIC ratio, R(2) = 85%; percent time above the MIC, R(2) = 47 to 65%). Similar studies were conducted with seven additional C. albicans isolates with various ravuconazole susceptibilities (MIC, 0.016 to 0.12 micro g/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The ravuconazole free-drug AUC/MIC ratios were similar for all of the organisms studied (10 to 36; mean +/- SD = 20.3 +/- 8.2; P = 0.43). These free-drug AUC/MIC ratios are similar to those observed for fluconazole in this model.

FIG. 1.

Serum ravuconazole concentrations after administration of oral doses of 10, 40, and 160 mg/kg in neutropenic infected mice. Each symbol represents the geometric mean ± standard deviation (error bars) of the levels in the sera of three mice.

FIG. 2.

In vivo PAE following ravuconazole doses of 10 and 40 mg/kg against C. albicans K-1 in neutropenic infected mice. Each symbol represents the mean ± standard deviation (error bars) for two mice. The widths of the hollow horizontal bars represents the time that total serum drug levels exceeded the MIC. The widths of the solid horizontal bars represents the time that free serum drug levels exceeded the MIC.

FIG. 3.

Relationship between the 24-h total dose and the change in log₁₀ CFU per kidney using C. albicans K-1 over the treatment period for ravuconazole administered at different dosing intervals in a neutropenic murine model of disseminated candidiasis. Each symbol represents the mean ± standard deviation (error bars) for two mice. The hollow symbols represent the 24-h treatment durations. The solid symbols represent the 72-h treatment duration. The dashed horizontal line represents the number of CFU at the start of therapy.

FIG. 4.

Relationship between total drug time above the MIC (T>MIC), AUC/MIC ratio, peak/MIC ratio, and the change in log₁₀ CFU per kidney. Each symbol represents data for two mice. The dashed horizontal line represents the number of CFU at the start of therapy. R² is the coefficient of determination.

FIG. 5.

(A) Relationship between total drug 24-h AUC/MIC ratio and the change in log₁₀ CFU per kidney after 3 days of treatment for ravuconazole against eight C. albicans organisms. Each hollow symbol represents data for two ravuconazole-treated mice. Each solid symbol represents data for two fluconazole-treated mice (from reference 1). (B) Relationship between the free-drug 24-h AUC/MIC ratio and the change in log₁₀ CFU per kidney after 3 days of treatment for ravuconazole against eight C. albicans organisms. Each hollow symbol represents data for two ravuconazole-treated mice. Each solid symbol represents data for two fluconazole-treated mice. (Reprinted from reference 1.)

FIG. 5.

(A) Relationship between total drug 24-h AUC/MIC ratio and the change in log₁₀ CFU per kidney after 3 days of treatment for ravuconazole against eight C. albicans organisms. Each hollow symbol represents data for two ravuconazole-treated mice. Each solid symbol represents data for two fluconazole-treated mice (from reference 1). (B) Relationship between the free-drug 24-h AUC/MIC ratio and the change in log₁₀ CFU per kidney after 3 days of treatment for ravuconazole against eight C. albicans organisms. Each hollow symbol represents data for two ravuconazole-treated mice. Each solid symbol represents data for two fluconazole-treated mice. (Reprinted from reference 1.)