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Cited by 177Antifungal resistance and susceptibilityAntibiotics Pharmacokinetics and EfficacyFungal Infections and Studies

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Pharmacodynamics of a New Triazole, Posaconazole, in a Murine Model of Disseminated Candidiasis

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Andes, D., Marchillo, K., Conklin, R., Krishna, Gopal, Ezzet, Farkad, Cacciapuoti, Anthony, Loebenberg, David·2004·Antimicrobial Agents and Chemotherapy
DOI 10.1128/aac.48.1.137-142.2004PMC PMC310197
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Abstract

Previous in vivo studies have characterized the pharmacodynamic characteristics of two triazole compounds, fluconazole and ravuconazole. These investigations demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio is the critical pharmacokinetic-pharmacodynamic (PK-PD) parameter associated with treatment efficacy. Further analysis demonstrated that a free-drug triazole 24-h AUC/MIC ratio of 20 to 25 was predictive of treatment success in both experimental models and clinical trials. We used a neutropenic murine model of disseminated Candida albicans infection to similarly characterize the time course activity of the new triazole, posaconazole. The PK-PD parameters (percent time above MIC, AUC/MIC ratio, and peak serum drug level/MIC ratio) were correlated with in vivo efficacy, as measured by organism number in kidney cultures after 48 h of therapy. Kinetics and protein binding following oral posaconazole dosing were performed in neutropenic infected mice. Peak levels and AUC from 0 h to ∞ values were nonlinear over the 16-fold dose range studied. Serum drug elimination half-life ranged from 12.0 to 17.7 h. Protein binding was 99%. Single dose postantifungal effect studies demonstrated prolonged suppression of organism regrowth after serum posaconazole levels had fallen below the MIC. Treatment efficacy with the four dosing intervals studied was similar, supporting the AUC/MIC ratio as the PK-PD parameter predictive of efficacy. Nonlinear regression analysis also suggested that the AUC/MIC ratio was strongly predictive of treatment outcomes (AUC/MIC ratio R 2 = 83%; peak serum drug/MIC ratio R 2 = 85%; time that serum levels of posaconazole remained above the MIC R 2 = 65%). Similar studies were conducted with 11 additional C. albicans isolates with various posaconazole susceptibilities (MIC, 0.015 to 0.12 μg/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The posaconazole free-drug AUC/MIC ratios were similar for all of the organisms studied (6.12 to 26.7, mean ± SD = 16.9 ± 7.8, P value, 0.42). These free-drug AUC/MIC ratios are similar to those observed for other triazoles in this model.

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Research works printed but not linked: 2

  1. Craig W. A. and B. Suh. 1996. Protein binding and the antimicrobial effects: methods for the determination of protein binding p. 367-402. In V. Lorian (ed.) Antibiotics in laboratory medicine 4th ed. Williams and Wilkins Baltimore Md.
  2. Kunin, C. M. 1965. The importance of serum protein binding in determining antimicrobial activity and concentration in serum. Clin. Pharmacol. Ther.7:168-179.

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Metadata

Authors
Andes, D., Marchillo, K., Conklin, R., Krishna, G., Ezzet, F., Cacciapuoti, A., & Loebenberg, D.
Affiliations
  • University of Wisconsin System (US)
  • William S. Middleton Memorial Veterans Hospital (US)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
ORCID
Venue
Antimicrobial Agents and Chemotherapy
Publisher
American Society for Microbiology
Published
2004-01
Volume
48
Issue
1
Pages
137-142
ISSN
  • 0066-4804 (ISSN-L)
  • 1098-6596
DOI
10.1128/aac.48.1.137-142.2004
PMC
PMC310197
OpenAlex
W2126064588
Cited by
177
References
26
Citations by year
2026: 1 · 2025: 7 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 4 · 2020: 6 · 2019: 5 · 2018: 8 · 2017: 4 · 2016: 5 · 2015: 8 · 2014: 8 · 2013: 12 · 2012: 9
FWCI
4.47
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Antimicrobial Agents and Chemotherapy (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Health Sciences › Medicine › Pharmacology (medical) › Antibiotics Pharmacokinetics and Efficacy
  • Health Sciences › Medicine › Infectious Diseases › Fungal Infections and Studies
Keywords
posaconazole, triazole antifungals, pharmacodynamics, pharmacokinetics, systemic candidiasis, Candida albicans, AUC/MIC ratio, neutropenic mice, free drug concentration, drug-protein binding, elimination half-life, fluconazole, ravuconazole, treatment efficacy prediction, nonlinear pharmacokinetics
MeSH terms
Animals, Antifungal Agents, Candida albicans, Candidiasis, Dose-Response Relationship, Drug, Female, Mice, Inbred ICR, Microbial Sensitivity Tests, Neutropenia, Triazoles, Colony Count, Microbial, Area Under Curve, Mice

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