Pharmacological Basis of Cd101 Efficacy: Exposure Shape Matters

E. A. Lakota1, C. M. Rubino1, V. Ong2, K. Bartizal2, L. Miesel3, S. M. Bhavnani1, P. G. Ambrose1;

Author address: 

1ICPD, Latham, NY, 2Cidara Therapeutics, San Diego, CA, 3Europhins Panlabs, Ltd., St. Charles, MO

Abstract: 

Introduction: All commercially available echinocandin antifungal agents are administered once daily, with efficacy driven by AUC. CD101 is a novel echinocandin with a concentrationdependent pattern of fungicidal activity in vitro and a long half-life (up to 150 h in humans, approximately 70-80 h in mice). Given these distinct characteristics, it is likely that the shape of the CD101 AUC greatly influences efficacy. Methods: To test this hypothesis, we administered the same total AUC to groups (n=5) of neutropenic ICR mice infected with Candida albicans using 3 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/d over 7 days. The studies included a no-treatment control group. Animals were rendered neutropenic by 2 IP cyclophosphamide doses (150 mg/kg and 100 mg/kg, administered at -4 and -1 days) and inoculated with C. albicans R303 (1 x 103 CFU/mouse) 24 h prior to treatment. Animals were euthanized at 192 h post-inoculation. Paired kidneys were harvested, homogenized, serially diluted and plated for CFU determination. Results: As shown in the figure, fungi grew well in the no-treatment control group with variable activity in treatment groups. When the CD101 AUC0-168h was administered as a single dose, there was a >2 log10 CFU reduction from baseline at 192 h. When that same AUC was administered in 7 equal divided daily doses, there was an increase by >1 log10 CFU from baseline at 192 h. Conclusions: These data support the hypothesis that the shape of the CD101 AUC greatly influences efficacy. CD101 was significantly more effective when given once per week compared to the same dose divided into twice weekly or daily regimens.
2016

abstract No: 

SUNDAY-505

Full conference title: 

ASM Microbe 2016
    • ASM microbe 1st (2016)