| Mechanism-based pharmacokinetic-pharmacodynamic models of in vitro fungistatic and fungicidal effects against Candida albicans. | |
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MedLine Citation:
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PMID: 18180347 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) models describing the fungistatic activity of fluconazole and the fungicidal activity of caspofungin were developed using dynamic in vitro models. Antifungal-drug pharmacokinetics was simulated in vitro, assuming a one-compartment model with an elimination half-life of 3 h and using a wide (1 to 10,000) range of initial concentrations. The number of CFUs over time was determined for up to 31 h and used for PK-PD modeling. A model incorporating first-order natural growth and natural death, plus a maximum number of viable Candida cells, was used to characterize Candida growth in the absence of a drug. Fluconazole was considered to inhibit Candida growth and caspofungin to stimulate Candida death according to an Emax pharmacodynamic model. The data were analyzed with Nonmem, using a population approach. A good fit of the data was obtained with satisfactory estimates of PK-PD parameters, especially with drug concentrations producing 50% of the maximal effect: 50% inhibitory concentrations for fluconazole growth inhibition and 50% effective concentrations for caspofungin death stimulation. In conclusion, mechanistic PK-PD models were successfully developed to describe, respectively, the fungistatic and fungicidal activities of fluconazole and caspofungin in vitro. These models provide much better information on the drug effects over time than the traditional PK-PD index based on MICs. However, they need to be further characterized. |
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Authors:
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Nicolas Venisse; Nicolas Grégoire; Manuella Marliat; William Couet |
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Publication Detail:
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Type: Journal Article Date: 2008-01-07 |
Journal Detail:
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Title: Antimicrobial agents and chemotherapy Volume: 52 ISSN: 0066-4804 ISO Abbreviation: Antimicrob. Agents Chemother. Publication Date: 2008 Mar |
Date Detail:
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Created Date: 2008-02-26 Completed Date: 2008-09-02 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 0315061 Medline TA: Antimicrob Agents Chemother Country: United States |
Other Details:
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Languages: eng Pagination: 937-43 Citation Subset: IM |
Affiliation:
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Inserm ERI-23, 40 avenue du Recteur Pineau, 86022 Poitiers, France. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antifungal Agents*
/
pharmacokinetics,
pharmacology,
therapeutic use Candida albicans* / drug effects, growth & development Candidiasis* / drug therapy, microbiology Colony Count, Microbial Dose-Response Relationship, Drug Drug Resistance, Fungal Echinocandins* / pharmacokinetics, pharmacology, therapeutic use Fluconazole* / pharmacokinetics, pharmacology, therapeutic use Humans Microbial Sensitivity Tests Models, Biological* |
| Chemical | |
Reg. No./Substance:
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0/Antifungal Agents; 0/Echinocandins; 0/caspofungin; 86386-73-4/Fluconazole |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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