Population Pharmacokinetics and Pharmacodynamics of Itraconazole for Disseminated Infection Caused by Talaromyces marneffei.



Stott, Katharine E ORCID: 0000-0001-7079-7957, Le, Thuy, Nguyen, Thu, Whalley, Sarah, Unsworth, Jennifer, Ly, Vo Trieu, Kolamunnage-Dona, Ruwanthi ORCID: 0000-0003-3886-6208 and Hope, William ORCID: 0000-0001-6187-878X
(2021) Population Pharmacokinetics and Pharmacodynamics of Itraconazole for Disseminated Infection Caused by Talaromyces marneffei. Antimicrobial agents and chemotherapy, 65 (11). e0063621-e0063621.

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Abstract

First-line treatment of talaromycosis with amphotericin B deoxycholate (DAmB) is labor-intensive and toxic. Itraconazole is an appealing alternative antifungal agent. Pharmacokinetic data were obtained from 76 patients who were randomized to itraconazole in the Itraconazole versus Amphotericin B for Talaromycosis (IVAP) trial. Plasma levels of itraconazole and its active metabolite, hydroxyitraconazole, were analyzed alongside longitudinal fungal CFU counts in a population model. Itraconazole and hydroxyitraconazole pharmacokinetic variability was considerable, with areas under the concentration-time curve over 24 h (AUC<sub>24</sub>) of 3.34 ± 4.31 mg·h/liter and 3.57 ± 4.46 mg·h/liter (mean ± standard deviation), respectively. Levels of both analytes were low; itraconazole minimum concentration (<i>C</i><sub>min</sub>) was 0.11 ± 0.16 mg/liter, and hydroxyitraconazole <i>C</i><sub>min</sub> was 0.13 ± 0.17 mg/liter. The mean maximal rates of drug-induced killing were 0.206 and 0.208 log<sub>10</sub> CFU/ml/h, respectively. There were no associations between itraconazole <i>C</i><sub>min</sub>/MIC and time to sterilization of the bloodstream (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.99 to 1.03; <i>P</i> = 0.43), time to death (HR, 0.99; 95% CI, 0.96 to 1.02; <i>P</i> = 0.77), or early fungicidal activity (EFA) (coefficient, -0.004; 95% CI, -0.010 to 0.002; <i>P</i> = 0.18). Similarly, there was no relationship between AUC/MIC and time to sterilization of the bloodstream (HR, 1.00; 95% CI, 0.99 to 1.00; <i>P</i> = 0.50), time to death (HR, 1.00; 95% CI, 0.99 to 1.00; <i>P</i> = 0.91), or EFA (coefficient, -0.0001; 95% CI, -0.0003 to 0.0001; <i>P</i> = 0.19). This study raises the possibility that the failure of itraconazole to satisfy noninferiority criteria against DAmB for talaromycosis in the IVAP trial was a pharmacokinetic and pharmacodynamic failure.

Item Type: Article
Uncontrolled Keywords: Talaromyces, clinical trials, mycology, pharmacodynamics, population pharmacokinetics
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Population Health
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 07 Feb 2022 09:37
Last Modified: 18 Jan 2023 21:14
DOI: 10.1128/aac.00636-21
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3148220