Pharmacodynamics of the Long Acting Echinocandin, CD101, in the Neutropenic Invasive Candidiasis Murine Model Using an Extended Interval Dosing Design [PublishAheadOfPrint]

Echinocandins are important in the prevention and treatment of invasive candidiasis but limited by current dosing regimens that include daily intravenous administration. The novel echinocandin CD101 has a prolonged half-life of approximately 130 h in humans making it possible to design once-weekly dosing strategies. The current study examined the pharmacodynamic activity of CD101 using the neutropenic invasive candidiasis mouse model against select C. albicans (n=4), C. glabrata (n=3), and C. parapsilosis (n=3) strains. The CD101 MIC ranged from 0.03 -- 1 mg/L. Plasma pharmacokinetic measurements were performed from uninfected mice after intraperitoneal administration of 1, 4, 16, and 64 mg/kg. The elimination half-life was prolonged at 28 -- 41 h. Neutropenic mice were infected with each strain by lateral tail vein injection, treated with a single dose of CD101, and monitored for 7 days at which time organism burden was enumerated from the kidneys. Dose-dependent activity was observed for each organism. The PK/PD index AUC/MIC correlated well with efficacy (R² 0.74 -- 0.93). The median stasis 24-h free drug AUC/MIC targets were: C. albicans 2.92, C. glabrata 0.07, and C. parapsilosis 2.61. The PK/PD targets for 1-log₁₀ kill endpoint were 2-4--fold higher. Interestingly, the aforementioned PK/PD targets were numerically lower for all three species compared to other echinocandins. In summary, CD101 is a promising, novel echinocandin with advantageous pharmacokinetic properties and potent in vivo pharmacodynamic activity.

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