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 (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.

Effect of isavuconazole on tacrolimus and sirolimus serum concentrations in allogeneic hematopoietic stem cell transplant patients: A drug‐drug interaction study

“…Forty‐seven percent of patients had the concentration measured within the first week of therapy, 20% of patients had the concentration measured within the second week of therapy, and the remaining patients had no concentration measured. Isavuconazole has been shown to penetrate most tissues rapidly, reaching a steady state in most or all tissues or fluids after 7‐14 days . Thus, some of our patients might not have reached an isavuconazole steady‐state concentration at the time of measurement.…”

Isavuconazole for Treatment of Experimental Fungal Endophthalmitis Caused by Aspergillus fumigatus

“…Based on our findings, it is reasonable to assume that, following oral administration in mice, isavuconazole crosses the blood-retinal barrier to exert antifungal properties. While a prior study demonstrated widespread tissue distribution of isavuconazole following oral administration (30), the pharmacokinetics and pharmacodynamics of the drug in the eye need to be studied further, specifically within the context of fungal endophthalmitis.…”

“…Exogenous endophthalmitis occurs due to postoperative or posttraumatic complications or because of problems with post-intravitreal injection, whereas endogenous endophthalmitis occurs due to the hematogenous spread of pathogens into the eye, primarily among immunocompromised individuals (4). The overall incidence of endophthalmitis ranges from 0.03% to 1.3% following cataract surgery and can be as high as 30 to 40% following open globe injuries. Among microbial pathogens, mycotic or fungal endophthalmitis accounts for 8.6% to 18.6% of culture-positive cases (2) and has steadily increased over the last 20 years, in part due to the growing number of immunosuppressed patients (5)(6)(7).…”

Therapeutic Challenges of Non- Aspergillus Invasive Mold Infections in Immunosuppressed Patients

“…Voriconazole is the treatment of choice for cerebral aspergillosis (28,29), while posaconazole achieves modest brain concentrations (50 to 80% of serum) (30). The new broad-spectrum triazole isavuconazole can achieve brain concentrations comparable to that of voriconazole (about twice that in plasma) (31)(32)(33). Brain concentrations are relatively low for all formulations of amphotericin B (24,34), although they are effective and recommended for treatment of cryptococcal meningitis and represent an alternative for cerebral aspergillosis (29).…”