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Antimicrobial Agents and Chemotherapy, October 2003, p. 3165-3169, Vol. 47, No. 10
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.10.3165-3169.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

In Vivo Pharmacokinetics and Pharmacodynamics of a New Triazole, Voriconazole, in a Murine Candidiasis Model

D. Andes,1,2* K. Marchillo,2 T. Stamstad,2 and R. Conklin2

University of Wisconsin,1 William S. Middleton Veterans Affairs Hospital, Madison, Wisconsin2

Received 21 May 2003/ Returned for modification 3 July 2003/ Accepted 14 July 2003

In vivo studies have described the pharmacodynamic (PD) characteristics of several triazoles. These investigations have demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio is the critical pharmacokinetic (PK)-PD parameter associated with treatment efficacy. Further analyses from these in vivo studies have demonstrated that a triazole free drug 24-h AUC/MIC of 20 to 25 is predictive of treatment success. We used a neutropenic murine model of disseminated Candida albicans infection to similarly characterize the PK-PD of the new triazole voriconazole. PK and PD parameters (percentage of time that the concentration remains above the MIC [T > MIC], AUC/MIC ratio, and peak level in serum/MIC ratio) were correlated with in vivo efficacy, as measured by the organism number in kidney cultures after 24 h of therapy. Voriconazole kinetics and protein binding were studied in infected neutropenic mice. Peak level/dose and AUC/dose values ranged from 0.1 to 0.2 and 0.1 to 0.7, respectively. The serum elimination half-life ranged from 0.7 to 2.9 h. The level of protein binding in mouse serum was 78%. 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 (R2 for AUC/MIC ratio = 82%, R2 for peak level/MIC ratio = 63%, R2 for T > MIC = 75%). Similar studies were conducted with nine additional C. albicans isolates with various voriconazole susceptibilities (MICs, 0.007 to 0.25 µg/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The voriconazole free drug AUC/MIC ratios were similar for all of the organisms studied (range, 11 to 58; mean ± standard deviation, 24 ± 17 [P = 0.45]). These AUC/MIC ratios observed for free drug 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, October 2003, p. 3165-3169, Vol. 47, No. 10
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.10.3165-3169.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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