1952. Brain Penetration of Isavuconazole following Single Dose Oral Administration to Wistar Rats
Session: Poster Abstract Session: Antimicrobial Pharmacokinetics and Pharmacodynamics
Saturday, October 29, 2016
Room: Poster Hall
Posters
  • BS001-15 Tissue Distribution poster_ch09_UPLOAD.pdf (164.0 kB)
  • 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 chromatography–mass 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.

     

     

    Anne-Hortense Schmitt-Hoffmann, PhD, PharmD1, Marlowe J. Schneidkraut, PhD2, Nkechi Azie, MD3, Robert Townsend, PhD3 and Jochen Spickermann, Diplom-Chemiker, Dr. rer. nat.1, (1)Basilea Pharmaceutica International Ltd, Basel, Switzerland, (2)Astellas Research Institute of America, Northbrook, IL, (3)Astellas Pharma Global Development, Inc., Northbrook, IL

    Disclosures:

    A. H. Schmitt-Hoffmann, Basilea Pharmaceutica International Ltd: Employee , Salary

    M. J. Schneidkraut, Astellas Pharma: Employee , Salary

    N. Azie, Astellas Pharma Global Development, Inc: Employee , Salary

    R. Townsend, Astellas Pharma Global Development, Inc: Employee , Salary

    J. Spickermann, Basilea Pharmaceutica International Ltd: Employee , Salary

    Findings in the abstracts are embargoed until 12:01 a.m. CDT, Wednesday Oct. 26th with the exception of research findings presented at the IDWeek press conferences.