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.).

• Authors: Thuy Le, Vo Trieu Ly, Nguyen Thi Mai Thu, Ashley Nguyen, Nguyen Tat Thanh, Nguyen Van Vinh Chau, Guy Thwaites, John Perfect, Ruwanthi Kolamunnage-Dona, William Hope
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 63 Issue 2 (02 2019) ISSN: 1098-6596 [Electronic] United States
• PMID: 30420478 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Le et al.

Chemical References

• Antifungal Agents
• Drug Combinations
• Deoxycholic Acid
• Amphotericin B
• amphotericin B, deoxycholate drug combination

Topics

• Adult
• Amphotericin B (pharmacokinetics, therapeutic use)
• Antifungal Agents (pharmacokinetics, therapeutic use)
• Area Under Curve
• Deoxycholic Acid (pharmacokinetics, therapeutic use)
• Drug Combinations
• Female
• Humans
• Male
• Microbial Sensitivity Tests
• Penicillium (drug effects, pathogenicity)
• Talaromyces (drug effects, pathogenicity)