RO0098557, a Novel Water Soluble Azole Prodrug for Parenteral and Oral Administration (II) Prodrug Principle and Broad Spectrum Antifungal

T. YAMAZAKI, T. TSUKAGUCHI, Y. ONO, Y. SATOH, T. FUJII, Y. INAGAKI, S. ICHIHARA, J. OHWADA, I. UMEDA, K. KOBAYASHI, N. SHIMMA, M. ARISAWA

Author address: 

Nippon Roche Research Center, Kamakura, Japan

Abstract: 

Background: Currently available azoles with a broad spectrum are better suited for oral administration than
for parenteral administration due to their limited solubility. RO0098557, is a new water soluble prodrug of
RO0094815.

Method: In vitro antifungal activity against 122 reference strains and 83 clinical isolates was
tested by microdilution method. In vivo efficacies against systemic or pulmonary infections due to C. albicans
or A. fumigatus in normal and immunosuppressed rats were evaluated. Treatments were performed by IV or
PO. The minimal effective concentration (MEC) in plasma against systemic candidiasis or aspergillosis was
estimated using a rat infusion model. PK profiles of RO0094815 after administration of RO0098557 to rats and
monkeys were evaluated.

Results: RO0094815 showed a broad antifungal spectrum with C. albicans (Geometric Mean of MIC = 0.008
μg/ml), C. glabrata (0.09), C. krusei (0.10), and A. fumigatus (0.1). In vivo, RO0098557 showed efficacy
superior to voriconazole (VCZ) and equivalent to itraconazole (ICZ) against systemic candidiasis in normal
rats. ED50s (μmol/kg) were in the range of 1.5-4.2 by PO or IV [FCZ (PO) 0.85-1.8; ICZ (PO) 1.7-4.7; VCZ (PO
or IV) 2.3->22]. Against aspergillosis, RO0098557 was comparably effective to VCZ or ICZ with ED50s ranges
of 6-14 (systemic) and 6.8-11 (pulmonary). Its MEC against both systemic infections was 0.05 μg/ml in plasma.
RO0094815 in monkey after RO0098557 administration showed t1/2 = 9.8h (IV), 12.8h (PO), and 87% oral
bioavailability.

Conclusion: The combination of a high water solubility, good oral bioavailability, t1/2, broad
spectrum will allow to treat once-a-day mycoses both orally and parenterally. These results warrant further
evaluation of RO0098557 for clinical studies.

    • ICAAC 42nd