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Antimicrobial Agents and Chemotherapy, January 2004, p. 137-142, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.137-142.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

D. Andes,1,2* K. Marchillo,2 R. Conklin,2 Gopal Krishna,3 Farkad Ezzet,3 Anthony Cacciapuoti,3 and David Loebenberg3

University of Wisconsin,1 William S. Middleton VA Hospital, Madison, Wisconsin,2 Schering-Plough Research Institute, Kenilworth, New Jersey3

Received 21 July 2003/ Returned for modification 11 September 2003/ Accepted 9 October 2003

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 {infty} 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 R2 = 83%; peak serum drug/MIC ratio R2 = 85%; time that serum levels of posaconazole remained above the MIC R2 = 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.

* Corresponding author. Mailing address: University of Wisconsin, 600 Highland Ave., Room H4/572, Madison, WI 53792. Phone: (608) 263-1545. Fax: (608) 263-4464. E-mail: dra{at}medicine.wisc.edu.

Antimicrobial Agents and Chemotherapy, January 2004, p. 137-142, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.137-142.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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