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

Abstract

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 (C_max) were observed in bile and liver (66.6 and 24.7 μg eq/g, respectively). The lowest C_max 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 C_max 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 C_max values >25% higher than all other 1-h-postdose values. For 24-h-postdose C_max values, only large intestine, large intestine mucosa, and urine had the highest C_max 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.

Keywords: isavuconazole; isavuconazonium sulfate; quantitative whole-body autoradiography; rat; tissue distribution; tissue penetration.

FIG 1

Structure of [cyano-¹⁴C]isavuconazonium sulfate. Red, isavuconazole; black, inactive prodrug moiety (BAL8728); ¹⁴C, the position of the radiolabel.

FIG 2

Tissue concentration/blood concentration ratios of ¹⁴C radioactivity determined by quantitative whole-body autoradiography (QWBA) at specified time points after single oral administration (A) or repeated oral administration (B) of [cyano-¹⁴C]isavuconazonium sulfate to male rats.

FIG 3

Mean concentrations ± standard deviations of isavuconazole (A, B) and voriconazole (C, D) in rats (n = 3 at each time point) following a single oral dose of 25 mg/kg isavuconazole (administered as isavuconazonium sulfate) or voriconazole. (A, C) Log-linear scale; (B, D) linear-linear scale (note the differences in the y axis scales).