Tissue Distribution and Penetration of Isavuconazole at the Site of Infection in Experimental Invasive Aspergillosis in Mice with Underlying Chronic Granulomatous Disease

Abstract

Isavuconazole, the active moiety of the prodrug isavuconazonium sulfate, has potent activity against a wide spectrum of fungal pathogens and is approved for the treatment of invasive aspergillosis, yet little is known about the tissue penetration of isavuconazole at the target sites of infection. Here, we explored the spatial and quantitative distribution of isavuconazole in tissue lesions in experimental pulmonary aspergillosis established in mice with chronic granulomatous disease (CGD) (gp91^phox-). Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed high-pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) were used to analyze infected lungs and brain tissues collected 1, 3, 6, and 24 h after a single oral administration of the prodrug at a dose of 256 mg/kg of body weight (corresponding to 122.9 mg/kg of isavuconazole). Drug enrichment within granulomatous lesions was observed in lung tissue at 1 h postdose, although drug levels quickly equilibrated afterwards between lesion and nonlesion areas. A prominent antifungal effect in the infected lung tissue was revealed by histopathological analysis. Isavuconazole also penetrated into the brain with high efficiency. These data further support the value of isavuconazole to treat patients with invasive aspergillosis.

Keywords: chronic granulomatous disease; drug penetration; invasive aspergillosis; isavuconazole; isavuconazonium sulfate; laser capture microdissection; matrix-assisted laser desorption ionization mass spectrometry imaging.