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Antimicrobial Agents and Chemotherapy, November 2009, p. 4885-4890, Vol. 53, No. 11
0066-4804/09/$08.00+0     doi:10.1128/AAC.00319-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Effect of Mild and Moderate Liver Disease on the Pharmacokinetics of Isavuconazole after Intravenous and Oral Administration of a Single Dose of the Prodrug BAL8557{triangledown}

A. Schmitt-Hoffmann,1* B. Roos,1 J. Spickermann,1 M. Heep,1 É. Peterfaí,2 D. J. Edwards,3 and K. Stoeckel4

Basilea Pharmaceutica International Ltd., Basel, Switzerland,1 DRC, Balatonfüred, Hungary,2 Department of Pharmacy Practice, Wayne State University, Detroit, Michigan,3 Clinpharm Support, Basel, Switzerland4

Received 9 March 2009/ Returned for modification 23 June 2009/ Accepted 3 August 2009

Isavuconazole is a promising new antifungal drug with favorable pharmacokinetic properties and excellent activity against a number of fungi. It is administered as a water-soluble prodrug (BAL8557) that is cleaved by plasma esterases to isavuconazole, which is eliminated primarily by hepatic metabolism. The objective of this investigation was to assess the effect of alcohol-related liver disease on the pharmacokinetics of isavuconazole. Subjects were 16 healthy individuals, 16 with mild liver impairment, and 16 with moderate liver impairment who were randomized to receive a single oral or intravenous dose of BAL8557 equivalent to 100 mg isavuconazole. Blood samples were collected for 21 days following drug administration, and plasma concentrations of isavuconazole, BAL8557, and the cleavage product BAL8728 were measured using high-pressure liquid chromatography coupled with tandem mass spectrometry. Following intravenous administration, the half-life of isavuconazole increased from 123 h for healthy volunteers to 224 h and 302 h for subjects with mild and moderate liver impairment, respectively. The systemic clearance of isavuconazole following intravenous administration decreased from 2.73 liters/h for healthy subjects to 1.43 liters/h for subjects with moderate liver impairment (47.6% decrease [P < 0.05]). A similar decrease (23.5%) was observed after oral administration. These results suggest that a dose adjustment may be needed when isavuconazole is used to treat fungal infections in patients with liver disease.

* Corresponding author. Mailing address: Basilea Pharmaceutica International Ltd., 487 Grenzacherstrass, CH-4005 Basel, Switzerland. Phone: 41 61 606 13 79. Fax: 41 61 606 13 78. E-mail: anne.schmitt-hoffmann{at}basilea.com

{triangledown} Published ahead of print on 10 August 2009.

Antimicrobial Agents and Chemotherapy, November 2009, p. 4885-4890, Vol. 53, No. 11
0066-4804/09/$08.00+0     doi:10.1128/AAC.00319-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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