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. 2017 Nov 22;61(12):e01292-17.
doi: 10.1128/AAC.01292-17. Print 2017 Dec.

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

Anne-Hortense Schmitt-Hoffmann  1 , Kota Kato  2 , Robert Townsend  3 , Michael J Potchoiba  4 , William W Hope  5 , David Andes  6 , Jochen Spickermann  1 , Marlowe J Schneidkraut  7
Affiliations

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

Anne-Hortense Schmitt-Hoffmann et al. Antimicrob Agents Chemother. .

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

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Figures

FIG 1
FIG 1
Structure of [cyano-14C]isavuconazonium sulfate. Red, isavuconazole; black, inactive prodrug moiety (BAL8728); 14C, the position of the radiolabel.
FIG 2
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
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).
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References

    1. Kontoyiannis DP, Marr KA, Park BJ, Alexander BD, Anaissie EJ, Walsh TJ, Ito J, Andes DR, Baddley JW, Brown JM, Brumble LM, Freifeld AG, Hadley S, Herwaldt LA, Kauffman CA, Knapp K, Lyon GM, Morrison VA, Papanicolaou G, Patterson TF, Perl TM, Schuster MG, Walker R, Wannemuehler KA, Wingard JR, Chiller TM, Pappas PG. 2010. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) database. Clin Infect Dis 50:1091–1100. doi:10.1086/651263. - DOI - PubMed
    1. Leventakos K, Lewis RE, Kontoyiannis DP. 2010. Fungal infections in leukemia patients: how do we prevent and treat them? Clin Infect Dis 50:405–415. doi:10.1086/649879. - DOI - PubMed
    1. Felton T, Troke PF, Hope WW. 2014. Tissue penetration of antifungal agents. Clin Microbiol Rev 27:68–88. doi:10.1128/CMR.00046-13. - DOI - PMC - PubMed
    1. Kethireddy S, Andes D. 2007. CNS pharmacokinetics of antifungal agents. Expert Opin Drug Metab Toxicol 3:573–581. doi:10.1517/17425255.3.4.573. - DOI - PubMed
    1. Thaler F, Bernard B, Tod M, Jedynak CP, Petitjean O, Derome P, Loirat P. 1995. Fluconazole penetration in cerebral parenchyma in humans at steady state. Antimicrob Agents Chemother 39:1154–1156. doi:10.1128/AAC.39.5.1154. - DOI - PMC - PubMed

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