Tissue Distribution and Elimination of Isavuconazole following Single and Repeat Oral-Dose Administration of Isavuconazonium Sulfate to Rats

• Published in: Antimicrobial agents and chemotherapy 2017-12, Vol.61 (12)
• Main Authors: Schmitt-Hoffmann, Anne-Hortense, Kato, Kota, Townsend, Robert, Potchoiba, Michael J, Hope, William W, Andes, David, Spickermann, Jochen, Schneidkraut, Marlowe J
• Format: Article
• Language: English
• Subjects: Brain; Nitriles; Pharmacology; Pyridines; Triazoles; Voriconazole
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01292-17

Quantitative whole-body autoradiography was used to assess the distribution and tissue penetration of isavuconazole in rats following single and repeated oral-dose administration of radiolabeled isavuconazonium sulfate, the prodrug of isavuconazole. Following a single-dose administration of radiolabeled isavuconazonium sulfate (labeled on the active moiety), radioactivity was detectable within 1 h postdose in 56 of 65 tissue/fluid specimens. The highest maximum concentrations ( ) were observed in bile and liver (66.6 and 24.7 μg eq/g, respectively). The lowest values were in bone and eye lens (0.070 and 0.077 μg eq/g, respectively). By 144 h postdose, radioactivity was undetectable in all tissues/fluids except liver (undetectable at 336 h) and adrenal gland tissues (undetectable at 672 h). Following daily administration for up to 21 days, 1-h-postdose values were the highest on or before day 14 in all except seven tissues/fluids, of which only rectum mucosa and small intestine mucosa had values >25% higher than all other 1-h-postdose values. For 24-h-postdose values, only large intestine, large intestine mucosa, and urine had the highest values at day 21. The penetration of single oral doses of unlabeled isavuconazole (25 mg/kg of body weight isavuconazonium sulfate) and voriconazole (50 mg/kg) into rat brain (assessed using liquid chromatography-tandem mass spectrometry) was also compared. Brain concentration/plasma concentration ratios reached approximately 1.8:1 and 2:1, respectively. These data suggest that isavuconazole penetrates most tissues rapidly, reaches a steady state in most or all tissues/fluids within 14 days, does not accumulate in tissues/fluids over time, and achieves potentially efficacious concentrations in the brain.