Population Pharmacodynamics of Amphotericin B Deoxycholate for Disseminated Infection Caused by Talaromyces marneffei.
Abstract
Amphotericin B deoxycholate (DAmB) is a first-line agent for the initial treatment
of talaromycosis. However, little is known about the population pharmacokinetics and
pharmacodynamics of DAmB for talaromycosis. Pharmacokinetic data were obtained from
78 patients; among them, 55 patients had serial fungal CFU counts in blood also available
for analysis. A population pharmacokinetic-pharmacodynamic model was fitted to the
data. The relationships between the area under the concentration-time curve (AUC)/MIC
and the time to blood culture sterilization and the time to death were investigated.
There was only modest pharmacokinetic variability in the average AUC, with a mean
± standard deviation of 11.51 ± 3.39 mg·h/liter. The maximal rate of drug-induced
kill was 0.133 log10 CFU/ml/h, and the plasma concentration of the DAmB that induced
the half-maximal rate of kill was 0.02 mg/liter. Fifty percent of patients sterilized
their bloodstreams by 83.16 h (range, 13 to 264 h). A higher initial fungal burden
was associated with a longer time to sterilization (hazard ratio [HR], 0.51; 95% confidence
interval [CI], 0.36 to 0.70; P < 0.001). There was a weak relationship between AUC/MIC
and the time to sterilization, although this did not reach statistical significance
(HR, 1.03; 95% CI, 1.00 to 1.06, P = 0.091). Furthermore, there was no relationship
between the AUC/MIC and time to death (HR, 0.97; 95% CI, 0.88 to 1.08; P = 0.607)
or early fungicidal activity {slope = log[(0.500 - 0.003·(AUC/MIC)]; P = 0.319} adjusted
for the initial fungal burden. The population pharmacokinetics of DAmB are surprisingly
consistent. The time to sterilization of the bloodstream may be a useful pharmacodynamic
endpoint for future studies. (This study has been registered at the ISRCTN registry
under no. ISRCTN59144167.).
Type
Journal articleSubject
PK-PDPenicillium
Talaromyces
amphotericin
antifungal
pharmacodynamics
population pharmacokinetics
talaromycosis
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https://hdl.handle.net/10161/18492Published Version (Please cite this version)
10.1128/AAC.01739-18Publication Info
Le, Thuy; Ly, Vo Trieu; Thu, Nguyen Thi Mai; Nguyen, Ashley; Thanh, Nguyen Tat; Chau,
Nguyen Van Vinh; ... Hope, William (2019). Population Pharmacodynamics of Amphotericin B Deoxycholate for Disseminated Infection
Caused by Talaromyces marneffei. Antimicrobial Agents and Chemotherapy, 63(2). pp. e01739-18. 10.1128/AAC.01739-18. Retrieved from https://hdl.handle.net/10161/18492.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Thuy Le
Associate Professor of Medicine
John Robert Perfect
James B. Duke Distinguished Professor of Medicine
Research in my laboratory focuses around several aspects of medical mycology. We
are investigating antifungal agents (new and old) in animal models of candida and
cryptococcal infections. We have examined clinical correlation of in vitro antifungal
susceptibility testing and with in vivo outcome. Our basic science project examines
the molecular pathogenesis of cryptococcal infections. We have developed a molecular
foundation for C. neoformans, including transformation systems, gene disr
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