Abstract
ABSTRACTQuantitative 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.
Highlights
Invasive fungal infections (IFIs), such as invasive aspergillosis (IA), present a considerable therapeutic challenge, among immunocompromised patient populations, such as hematopoietic stem cell transplant recipients [1] or those with hematological malignancies [2]
To assess the tissue penetration and distribution of isavuconazole with single oral doses of isavuconazonium sulfate, rats were given 14C-labeled isavuconazonium sulfate orally at 5 mg/kg of body weight, with labeling being on the active moiety (Fig. 1), prior to sacrifice between 1 and 672 h later
Following a single oral dose of radiolabeled prodrug, the maximum concentrations of isavuconazole-associated radioactivity were reached by 2 h in most tissues and fluids and by 8 h in all tissues and fluids
Summary
Invasive fungal infections (IFIs), such as invasive aspergillosis (IA), present a considerable therapeutic challenge, among immunocompromised patient populations, such as hematopoietic stem cell transplant recipients [1] or those with hematological malignancies [2]. In vivo antifungal activity has been shown in animal models of invasive systemic and pulmonary aspergillosis as well as mucormycosis [9, 14,15,16,17,18,19] In these murine models of disseminated fungal infections, isavuconazole treatment reduced the fungal burden in the lung, liver, kidney, and brain, suggesting that isavuconazole achieved effective concentrations at these sites. We report the results of studies conducted using radiolabeled isavuconazonium sulfate to determine the tissue penetration and distribution of isavuconazole drug-derived radioactivity in various tissues of rats following single or repeated oraldose administration in rats using quantitative whole-body autoradiography (QWBA). The penetration of isavuconazole in rat brain was compared with that of voriconazole following a single oral dose of either drug
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
