Abstract
ABSTRACTCD101 is a novel echinocandin with concentration-dependent fungicidal activity in vitro and a long half-life (∼133 h in humans, ∼70 to 80 h in mice). Given these characteristics, it is likely that the shape of the CD101 exposure (i.e., the time course of CD101 concentrations) influences efficacy. To test this hypothesis, doses which produce the same total area under the concentration-time curve (AUC) were administered to groups of neutropenic ICR mice infected with Candida albicans R303 using three different schedules. A total CD101 dose of 2 mg/kg was administered as a single intravenous (i.v.) dose or in equal divided doses of either 1 mg/kg twice weekly or 0.29 mg/kg/day over 7 days. The studies were performed using a murine disseminated candidiasis model. Animals were euthanized at 168 h following the start of treatment. Fungi grew well in the no-treatment control group and showed variable changes in fungal density in the treatment groups. When the CD101 AUC from 0 to 168 h (AUC0–168) was administered as a single dose, a >2 log10 CFU reduction from the baseline at 168 h was observed. When twice-weekly and daily regimens with similar AUC values were administered, net fungal stasis and a >1 log10 CFU increase from the baseline were observed, respectively. These data support the hypothesis that the shape of the CD101 AUC influences efficacy. Thus, CD101 administered once per week demonstrated a greater degree of fungal killing than the same dose divided into twice-weekly or daily regimens.
Highlights
CD101 is a novel echinocandin with concentration-dependent fungicidal activity in vitro and a long half-life (ϳ133 h in humans, ϳ70 to 80 h in mice)
No overt signs of toxicities were observed in any of the mice evaluated. The goal of these studies was to examine the impact of the shape of the drug exposure, as measured by area under the concentration-time curve (AUC), on the fungicidal activity of CD101
Using a frontloading experiment design, in which similar AUC values were achieved through single, twice weekly, or daily dosing, we successfully demonstrated that the shape of the CD101 exposure greatly influenced fungicidal activity
Summary
CD101 is a novel echinocandin with concentration-dependent fungicidal activity in vitro and a long half-life (ϳ133 h in humans, ϳ70 to 80 h in mice) Given these characteristics, it is likely that the shape of the CD101 exposure (i.e., the time course of CD101 concentrations) influences efficacy. When twice-weekly and daily regimens with similar AUC values were administered, net fungal stasis and a Ͼ1 log CFU increase from the baseline were observed, respectively These data support the hypothesis that the shape of the CD101 AUC influences efficacy. CD101 demonstrates a concentration-dependent pattern of fungal killing [9], as previously observed with anidulafungin, caspofungin, and micafungin [10] This property, in conjunction with CD101’s long half-life in humans, led to the hypothesis that a front-loaded CD101 dosing regimen would provide fungal killing superior to that of November 2017 Volume 61 Issue 11 e00758-17. Our objective was to evaluate a single-dose regimen fractionated to yield multiple dosing regimens with equivalent areas under the concentration-time curve (AUC) for CD101 and to assess their corresponding changes in log CFU counts at 168 h to determine if exposure shape impacts antifungal activity
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