1 Treatment A: TOLSURA
2 Treatment B: Omeprazole
*Tmax is given as median (Range)
12.4 Microbiology
Mechanism of Action
In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent,14C-demethylation of ergosterol, which is a vital component of fungal cell membranes.
Resistance
Isolates from several fungal species with decreased susceptibility to itraconazole have beenisolated in vitro and from patients receiving prolonged therapy. Several in vitro studies havereported that some fungal clinical isolates with reduced susceptibility to one azole antifungalagent may also be less susceptible to other azole derivatives. The finding of cross-resistance isdependent on a number of factors, including the species eva luated, its clinical history, the
particular azole compounds compared, and the type of susceptibility test performed.
Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp.and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.
Interaction with Other Antimicrobials
Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressedby prior azole antifungal therapy. Ergosterol is the active site for amphotericin B. In one study,the antifungal activity of amphotericin B against Aspergillus fumigatus infections in mice wasinhibited by ketoconazole therapy. The clinical significance of this finding is unknown.
Antifungal Activity
Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum,Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, and Trichophyton species [seeIndications and Usage (1)]. Correlation between minimum inhibitory concentration (MIC)results in vitro and clinical outcome has yet to be established for azole antifungal agents.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23months at dosage levels up to 80 mg/kg/day (approximately 12MRHD, based on mg/kgcomparisons). Male rats treated with 25 mg/kg/day (4MRHD) had a slightly increasedincidence of soft tissue sarcoma. These sarcomas may have been a consequence ofhypercholesterolemia, which is a response of rats, but not dogs or humans, to chronicitraconazole administration. Female rats treated with 50 mg/kg/day (8MRHD) had anincreased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreatedgroup. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommonin untreated rats, the increase in this study was not statistically significant.
Mutagenesis
Itraconazole produced no mutagenic effects when assayed in DNA repair test (unscheduled DNAsynthesis) in pr