Pharmacodynamics of a Long-Acting Echinocandin, CD101, in a Neutropenic Invasive-Candidiasis Murine Model Using an Extended-Interval Dosing Design
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...
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Published in | Antimicrobial agents and chemotherapy Vol. 62; no. 2 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Microbiology
01.02.2018
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Subjects | |
Online Access | Get full text |
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Summary: | 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 present study examined the pharmacodynamic activity of CD101 using the neutropenic invasive candidiasis mouse model against select
(
= 4),
(
= 3), and
(
= 3) strains. The CD101 MIC ranged from 0.03 to 1 mg/liter. Plasma pharmacokinetic measurements were performed using uninfected mice after intraperitoneal administration of 1, 4, 16, and 64 mg/kg. The elimination half-life was prolonged at 28 to 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 the organism burden was enumerated from the kidneys. Dose-dependent activity was observed for each organism. The pharmacokinetic/pharmacodynamic (PK/PD) index of the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC index) correlated well with efficacy (
, 0.74 to 0.93). The median stasis 24-h free-drug AUC/MIC targets were as follows: for
, 2.92; for
, 0.07; and for
, 2.61. The PK/PD targets for 1-log
kill endpoint were 2- to 4-fold higher. Interestingly, the aforementioned PK/PD targets of CD101 were numerically lower for all three species than those of other echinocandins. In summary, CD101 is a promising, novel echinocandin with advantageous pharmacokinetic properties and potent
pharmacodynamic activity. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Citation Lepak AJ, Zhao M, VanScoy B, Ambrose PG, Andes DR. 2018. Pharmacodynamics of a long-acting echinocandin, CD101, in a neutropenic invasive-candidiasis murine model using an extended-interval dosing design. Antimicrob Agents Chemother 62:e02154-17. https://doi.org/10.1128/AAC.02154-17. |
ISSN: | 0066-4804 1098-6596 |
DOI: | 10.1128/AAC.02154-17 |