In Vivo Pharmacodynamic Characterization of Anidulafungin in a Neutropenic Murine Candidiasis Model

Abstract

Multiple in vivo studies have characterized the pharmacodynamics of drugs from the triazole and polyene antifungal drug classes. Fewer studies have investigated these pharmacodynamic relationships for the echinocandin drug class. We used a neutropenic murine model of disseminated Candida albicans, Candida tropicalis, and Candida glabrata infection to characterize the time course of activity of the new echinocandin anidulafungin. The pharmacokinetic-pharmacodynamic (PK-PD) indices (the percentage of time that the drug concentration was above the MIC, the ratio of the area under the concentration-time curve from 0 to 24 h [AUC 0-24 ] to the MIC, and the ratio of the maximum serum drug concentration [C max ] to the MIC) were correlated with in vivo efficacy, as measured by organism numbers in kidney cultures after 96 h of therapy. The kinetics following intraperitoneal anidulafungin dosing in neutropenic infected mice were monitored. Peak levels and AUCs were linear over the 16-fold dose range studied. The drug elimination half-life in serum ranged from 14 to 24 h. Single-dose postantifungal-effect studies demonstrated prolonged suppression of organism regrowth after serum anidulafungin levels had fallen below the MIC. Of the four dosing intervals studied, treatment with the more widely spaced dosing regimens was most efficacious, suggesting the C max /MIC ratio as the PK-PD index most predictive of efficacy. Nonlinear regression analysis suggested that both the C max /MIC and AUC/ MIC ratios were strongly predictive of treatment success. Studies were then conducted with 13 additional C. albicans, C. tropicalis, and C. glabrata isolates with various anidulafungin susceptibilities (MICs of anidulafungin for these strains, 0.015 to 2.0 g/ml) to determine if similar C max /MIC and AUC 0-24 /MIC ratios for these isolates were associated with efficacy. The anidulafungin exposures associated with efficacy were similar among Candida species.The incidence of invasive fungal infections continues to rise (36,42). Despite advances in antifungal therapy, morbidity and mortality associated with these infections remain high. The echinocandins constitute the most recently Food and Drug Administration-approved antifungal drug class (10, 14, 50). The three available drugs from this class include anidulafungin, caspofungin, and micafungin. These compounds exhibit broad-spectrum activity against Candida and Aspergillus species, including emerging non-albicans Candida species (10,14,20,40,41,54). The present studies were designed to determine the in vivo pharmacodynamic (PD) characteristics of a new compound against Candida albicans, C. tropicalis, and C. glabrata. We first examined the impact of the anidulafungin concentration on in vivo antimicrobial killing activity over time. Studies were then performed to determine (i) which pharmacokinetic (PK) index (the maximum concentration of the drug in serum [C max ], the area under the concentration-time curve [AUC], or the duration of time that levels in serum exceed the MIC [TϾMIC]) bes...

Correlation of MIC with Outcome for Candida Species Tested against Caspofungin, Anidulafungin, and Micafungin: Analysis and Proposal for Interpretive MIC Breakpoints

“…The PD indices associated with treatment efficacy for the echinocandins include the area under the concentration-time curve (AUC)/MIC and time to maximum concentration of drug in serum (C max )/MIC ratios. The PD target associated with a stasis endpoint for echinocandins is equivalent to AUC/MIC and C max /MIC ratios near 10 and 1, respectively (2,3,20,24,32,64). Free (not bound to protein) echinocandin concentrations are considered in these estimates.…”

“…A stasis endpoint in an in vivo model of invasive C. albicans and C. glabrata infection for both anidulafungin and micafungin was achieved at an AUC/MIC ratio of 10 to 20 when free-drug concentrations were considered. The PK of these compounds in patients would be expected to meet and exceed this target for these species (2,3). This target would not be achieved for the MIC distribution commonly observed with C. parapsilosis (Table 1).…”

“…More-extensive animal model PD target investigation has been undertaken with these echinocandins (2,3). Similar to caspofungin, the PD indices associated with efficacy for these agents were the AUC/MIC and C max /MIC ratios (2,3,23,24,32). A stasis endpoint in an in vivo model of invasive C. albicans and C. glabrata infection for both anidulafungin and micafungin was achieved at an AUC/MIC ratio of 10 to 20 when free-drug concentrations were considered.…”

“…The AUC (total drug concentration) for anidulafungin (200-mg loading dose and 100-mg maintenance dose) is 112 mg ⅐ h/liter, and that for micafungin (100-mg daily dose) is 126 mg ⅐ h/liter (8,16). More-extensive animal model PD target investigation has been undertaken with these echinocandins (2,3). Similar to caspofungin, the PD indices associated with efficacy for these agents were the AUC/MIC and C max /MIC ratios (2,3,23,24,32).…”

In Vitro Activity of Anidulafungin and Other Agents against Esophageal Candidiasis-Associated Isolates from a Phase 3 Clinical Trial

“…Anidulafungin is an echinocandin antifungal agent with broad-spectrum activity against Candida species (2,12,13,17,19,20), including fluconazole-resistant strains (10,16); concentration-dependent fungicidal activity; and a long postantifungal effect in vitro and in animal infection models (1,6,7,10,16,18). It is available in the United States for intravenous treatment of esophageal candidiasis, a debilitating opportunistic infection among persons with HIV infection (9) for which cross-resistance among azoles may limit treatment options (4,14).…”