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

Publication ,  Journal Article
Stott, KE; Le, T; Nguyen, T; Whalley, S; Unsworth, J; Ly, VT; Kolamunnage-Dona, R; Hope, W
Published in: Antimicrob Agents Chemother
October 18, 2021

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 (AUC24) 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 (Cmin) was 0.11 ± 0.16 mg/liter, and hydroxyitraconazole Cmin was 0.13 ± 0.17 mg/liter. The mean maximal rates of drug-induced killing were 0.206 and 0.208 log10 CFU/ml/h, respectively. There were no associations between itraconazole Cmin/MIC and time to sterilization of the bloodstream (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.99 to 1.03; P = 0.43), time to death (HR, 0.99; 95% CI, 0.96 to 1.02; P = 0.77), or early fungicidal activity (EFA) (coefficient, -0.004; 95% CI, -0.010 to 0.002; P = 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; P = 0.50), time to death (HR, 1.00; 95% CI, 0.99 to 1.00; P = 0.91), or EFA (coefficient, -0.0001; 95% CI, -0.0003 to 0.0001; P = 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.

Duke Scholars

Published In

Antimicrob Agents Chemother

DOI

EISSN

1098-6596

Publication Date

October 18, 2021

Volume

65

Issue

11

Start / End Page

e0063621

Location

United States

Related Subject Headings

  • Talaromyces
  • Mycoses
  • Microbiology
  • Itraconazole
  • Humans
  • Antifungal Agents
  • 3214 Pharmacology and pharmaceutical sciences
  • 3207 Medical microbiology
  • 3107 Microbiology
  • 1115 Pharmacology and Pharmaceutical Sciences
 

Citation

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MLA
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Stott, K. E., Le, T., Nguyen, T., Whalley, S., Unsworth, J., Ly, V. T., … Hope, W. (2021). Population Pharmacokinetics and Pharmacodynamics of Itraconazole for Disseminated Infection Caused by Talaromyces marneffei. Antimicrob Agents Chemother, 65(11), e0063621. https://doi.org/10.1128/AAC.00636-21
Stott, Katharine E., Thuy Le, Thu Nguyen, Sarah Whalley, Jennifer Unsworth, Vo Trieu Ly, Ruwanthi Kolamunnage-Dona, and William Hope. “Population Pharmacokinetics and Pharmacodynamics of Itraconazole for Disseminated Infection Caused by Talaromyces marneffei.Antimicrob Agents Chemother 65, no. 11 (October 18, 2021): e0063621. https://doi.org/10.1128/AAC.00636-21.
Stott KE, Le T, Nguyen T, Whalley S, Unsworth J, Ly VT, et al. Population Pharmacokinetics and Pharmacodynamics of Itraconazole for Disseminated Infection Caused by Talaromyces marneffei. Antimicrob Agents Chemother. 2021 Oct 18;65(11):e0063621.
Stott, Katharine E., et al. “Population Pharmacokinetics and Pharmacodynamics of Itraconazole for Disseminated Infection Caused by Talaromyces marneffei.Antimicrob Agents Chemother, vol. 65, no. 11, Oct. 2021, p. e0063621. Pubmed, doi:10.1128/AAC.00636-21.
Stott KE, Le T, Nguyen T, Whalley S, Unsworth J, Ly VT, Kolamunnage-Dona R, Hope W. Population Pharmacokinetics and Pharmacodynamics of Itraconazole for Disseminated Infection Caused by Talaromyces marneffei. Antimicrob Agents Chemother. 2021 Oct 18;65(11):e0063621.

Published In

Antimicrob Agents Chemother

DOI

EISSN

1098-6596

Publication Date

October 18, 2021

Volume

65

Issue

11

Start / End Page

e0063621

Location

United States

Related Subject Headings

  • Talaromyces
  • Mycoses
  • Microbiology
  • Itraconazole
  • Humans
  • Antifungal Agents
  • 3214 Pharmacology and pharmaceutical sciences
  • 3207 Medical microbiology
  • 3107 Microbiology
  • 1115 Pharmacology and Pharmaceutical Sciences