Le, Thuy, Ly, Vo Trieu, Thu, Nguyen Thi Mai, Nguyen, Ashley, Thanh, Nguyen Tat, Vinh Chau, Nguyen Van, Thwaites, Guy, Perfect, John, Kolamunnage-Dona, Ruwanthi ORCID: 0000-0003-3886-6208 and Hope, William ORCID: 0000-0001-6187-878X
(2019)
Population Pharmacodynamics of Amphotericin B Deoxycholate for Disseminated Infection Caused by Talaromyces marneffei.
Antimicrobial Agents and Chemotherapy, 63 (2).
e01739-e01718.
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 colony forming units counts in blood also available for analysis. A population pharmacokinetics-pharmacodynamics model was fitted to the data. The relationships between 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/L. The maximal rate of drug induced kill was 0.133 log10CFU/mL/h, and the plasma concentration of the DAmB that induced half-maximal rate of kill was 0.02 mg/L. Fifty percent of patients sterilized their bloodstream by 83.16 hours (range 13-264 hours). A higher initial fungal burden was associated with longer time to sterilization (hazard ratio (HR): 0.51, 95% confidence interval (CI): 0.36-0.70, p<0.001). There was no relationship between AUC:MIC and the time to sterilization (HR: 1.03, 95% CI: 1.00-1.06, p=0.091). Furthermore, there was no relationship between the AUC:MIC and time to death (HR: 0.97, 95% CI: 0.88-1.08, p=0.607); or early fungicidal activity (slope= log(0.501-0.003*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 is a useful pharmacodynamic endpoint for future studies.
Item Type: | Article |
---|---|
Uncontrolled Keywords: | PK-PD, Talaromyces, amphotericin, antifungal, Penicillium, pharmacodynamics, population pharmacokinetics, talaromycosis |
Depositing User: | Symplectic Admin |
Date Deposited: | 29 Jan 2019 14:23 |
Last Modified: | 19 Jan 2023 01:05 |
DOI: | 10.1128/aac.01739-18 |
Open Access URL: | https://doi.org/10.1128/AAC.01739-18 |
Related URLs: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3031960 |