In vivo pharmacodynamics of HMR 3270, a glucan synthase inhibitor, in a murine candidiasis model

Abstract

In vivo pharmacokinetic/pharmacodynamic characterization for numerous antibacterial compounds has had a significant impact upon optimal dosing regimen design and the development of in vivo susceptibility breakpoints. More recently, similar characterization has been undertaken for antifungal drug classes. Very little is known of these pharmacodynamic relationships for the new echinocandin class of compounds. We utilized a neutropenic murine model of disseminated candidiasis to describe the time course antifungal activity of HMR 3270, a new glucan synthase inhibitor. Single-dose in vivo time kill studies with four 16-fold escalating doses demonstrated concentration-dependent killing when drug levels in serum were more than four times the MIC. Postantifungal effects were dose dependent, ranging from 8 to 80 h duration. Multiple dosing regimen studies utilized six total doses, four dosing intervals, and a treatment duration of 6 days. Shortening the dosing interval from every 144 h (q144h) to q36h resulted in a fourfold rise in the dose necessary to achieve a net fungistatic effect. The peak/MIC ratio most strongly correlated with treatment outcomes (peak/MIC ratio, R(2) = 98%; ratio of the area under the concentration-time curve from 0 to 24 h to the MIC, R(2) = 79%, percentage of time above the MIC, R(2) = 61%). Studies were also conducted with five additional Candida albicans isolates to determine if a similar peak/MIC ratio was associated with efficacy. In vivo concentration-dependent killing was similarly observed in studies with each of the additional isolates. The peak/MIC ratio necessary to produce efficacy was relatively similar among the strains studied (P = 0.42). The peak/MIC ratio (mean +/- standard deviation) necessary to achieve a fungistatic effect was 3.72 +/- 1.84, and the ratio necessary to achieve maximal killing was near 10.

FIG. 1.

Serum HMR 3270 concentrations after administration of intraperitoneal doses of 4 and 16 mg/kg in neutropenic infected mice. Each symbol represents the geometric mean ± standard deviation (error bars) of the levels in the sera of four mice.

FIG. 2.

(Left panel) In vivo PAE following HMR 3270 doses of 0.25, 0.5, 1, and 4 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 horizontal bars represent the time that serum levels exceeded the MIC. (Right panel) In vivo time kill following HMR 3270 doses of 0.25, 0.5, 1, and 4 mg/kg against C. albicans K-1 in neutropenic infected mice. Each symbol represents the mean ± standard deviation (error bars) for two mice.

FIG. 2.

(Left panel) In vivo PAE following HMR 3270 doses of 0.25, 0.5, 1, and 4 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 horizontal bars represent the time that serum levels exceeded the MIC. (Right panel) In vivo time kill following HMR 3270 doses of 0.25, 0.5, 1, and 4 mg/kg against C. albicans K-1 in neutropenic infected mice. Each symbol represents the mean ± standard deviation (error bars) for two mice.

FIG. 3.

Relationship between the total dose and the change in log₁₀ CFU per kidney over the 6-day treatment period for HMR 3270 administered at different dosing intervals in a neutropenic murine model of disseminated candidiasis. Each total dose level was fractionated for each of the dosing intervals. Each symbol represents data for two mice. The dashed horizontal line represents the number of CFU at the start of therapy. SD, the static dose; 95% confidence intervals are given in parentheses.

FIG. 4.

Relationship between the time above the MIC, the AUC/MIC ratio, the peak/MIC ratio, and the change in log₁₀ CFU per kidney after 6 days of treatment. Each symbol represents data for two mice. The dashed horizontal line represents the number of CFU at the start of therapy.

FIG. 5.

Relationship between the peak/MIC ratio and the change in log₁₀ CFU per kidney after 6 days of treatment for HMR 3270 against six C. albicans organisms. Each symbol represents data for two mice. The dashed horizontal line represents the number of CFU at the start of therapy.