Population Pharmacodynamics of Amphotericin B Deoxycholate for Disseminated Infection Caused by Talaromyces marneffei

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).

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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
Depositing User: Symplectic Admin
Date Deposited: 29 Jan 2019 14:23
Last Modified: 22 Sep 2021 15:11
DOI: 10.1128/aac.01739-18
Open Access URL: https://doi.org/10.1128/AAC.01739-18
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3031960