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Antimicrobial Agents and Chemotherapy, August 2009, p. 3453-3461, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.01601-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics and Pharmacodynamics of a Novel Triazole, Isavuconazole: Mathematical Modeling, Importance of Tissue Concentrations, and Impact of Immune Status on Antifungal Effect{triangledown}

Peter A. Warn, Andrew Sharp, Arvind Parmar, Jayesh Majithiya, David W. Denning, and William W. Hope*

School of Translational Medicine, 1.800 Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom

Received 3 December 2008/ Returned for modification 24 March 2009/ Accepted 12 May 2009

Isavuconazole is a triazole with broad-spectrum activity against medically important fungal pathogens. We investigated the pharmacokinetics and pharmacodynamics of isavuconazole in a murine model of disseminated candidiasis. We determined the pharmacokinetics in both plasma and kidney. The relationship between tissue concentrations and the resultant antifungal effect was described using a mathematical model. The pharmacodynamic parameter that optimally links drug exposure with the antifungal effect was determined using dose fractionation studies. The impact of the immune status of mice receiving isavuconazole was determined in persistently and temporarily neutropenic animals. The pharmacokinetics of 1.6 to 28 mg isavuconazole/kg of body weight were linear. Exposure-response relationships demonstrated near-maximal effect following the administration of >15 mg/kg. The mathematical model showed that exposures in the kidney were 5.77 times higher than those in plasma, and there was persistence of the drug at this site despite concentrations in plasma falling to undetectable levels. The in vitro and in vivo postantifungal effects were 2 to 5 and 8.41 h, respectively. The area under the concentration-time curve (AUC)/MIC ratio was the parameter that optimally linked drug exposure with the observed antifungal effect. The total drug AUC/MIC ratios associated with a 90% probability of survival in temporarily and persistently neutropenic mice were 270 and 670, respectively. Once corrected for protein binding, these values are similar to the magnitude of drug exposure associated with a high probability of a successful therapeutic outcome for other triazoles. This study provides the experimental foundation for the use of isavuconazole in patients with disseminated candidiasis.

* Corresponding author. Mailing address: School of Translational Medicine, 1.800 Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom. Phone: 44 161 275 3918. Fax: 44 161 275 5656. E-mail: william.hope{at}manchester.ac.uk

{triangledown} Published ahead of print on 18 May 2009.

Antimicrobial Agents and Chemotherapy, August 2009, p. 3453-3461, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.01601-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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