Pharmacological Basis of CD101 Efficacy: Exposure Shape Matters [PublishAheadOfPrint]

CD101 is a novel echinocandin with concentration-dependent fungicidal activity in vitro and a long half-life (~133 hours in humans, ~70-80 hours 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, the same total area under the concentration-time curve (AUC) was 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 IV dose or in equal divided doses of either 1 mg/kg twice weekly or 0.29 mg/kg/day over seven days. The studies were performed using a murine disseminated candidiasis model. Animals were euthanized at 168 hours following the start of treatment. Fungi grew well in the no-treatment control group with variable activity in treatment groups. When the CD101 AUC_0-168 was administered as a single dose, a >2-log₁₀ CFU reduction from baseline at 168 hours was observed. When twice weekly and daily regimens with similar AUC values were administered, net fungal stasis and a >1-log₁₀ CFU increase from baseline were observed, respectively. These data support the hypothesis that the shape of the CD101 AUC influences efficacy. Thus, CD101 demonstrated a greater degree of fungal killing when administered once per week relative to when the same dose was divided into twice weekly or daily regimens.

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