Background: Area under the curve (AUC) has been reported as the pharmacokinetic/pharmacodynamic driver for treatment efficacy of triazole antifungal agents. Isavuconazole was evaluated in vivo in rats after p.o. administration (as isavuconazonium sulfate) to determine plasma and brain tissue concentrations.
Methods: A 25 mg/kg isavuconazole equivalent dose was administered orally (10 mL/kg of a NaCl 0.9% solution) as isavuconazonium sulfate to 24 non-fasting, non-infected Wistar rats. Blood (heparin) and brain (snap-frozen) samples were collected from three rats per time point (pre-dose, 0.25, 0.5, 1, 2, 3, 6, 8 and 24 h post-administration). Plasma and brain concentrations of isavuconazole were determined with a validated liquid chromatographymass spectrometry/mass spectrometry method.
Results: Isavuconazole in brain reached peak concentrations approximately twice that in plasma (average individual brain/plasma ratio of 1.8 +/-16%) and declined in parallel to those in plasma. The AUC0-∞ was 54.3 µg.h/mL in brain compared with 30.7 µg.h/mL in plasma (Table 1). The isavuconazole concentrations in the brain are consistent with previous distribution studies where radiolabeled material were administered (quantitative whole-body autoradiography in rat1).
Conclusion: Brain penetration of isavuconazole was efficient in rats, as levels and overall exposure in brain were almost 2-fold higher than plasma.
1Schmitt-Hoffmann A-H, Richter WF. Isavuconazole is widely distributed in rat tissue. Poster P863 presented at: 22nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); March 31, 2012; London, United Kingdom.
A. H. Schmitt-Hoffmann,
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