Search

E1224 is a prodrug of ravuconazole (RVZ), an antifungal drug with promising anti-Trypanosoma cruzi activity, the causative organism of Chagas disease (CD). This study was designed to assess the pharmacokinetics (PK) and safety interactions of benznidazole (BNZ), the drug of choice for treatment of CD, and E1224 in healthy volunteers., E1224 is a prodrug of ravuconazole (RVZ), an antifungal drug with promising anti-Trypanosoma cruzi activity, the causative organism of Chagas disease (CD). This study was designed to assess the pharmacokinetics (PK) and safety interactions of benznidazole (BNZ), the drug of choice for treatment of CD, and E1224 in healthy volunteers. This open-label, single-center, sequential, single- and multiple-oral-dose study enrolled 28 healthy male subjects. These subjects received BNZ (2.5 mg/kg) once daily on days 1 and 9 and twice daily from day 12 to day 15 and E1224 once daily from day 4 to day 15 (loading dose of 400 mg for 3 days and maintenance dose of 100 mg for 9 days). The maximum concentration (Cmax) and area under the concentration curve from zero to infinity for BNZ were comparable, whether BNZ was given alone or with E1224 at steady state, with ratios of geometric means for BNZ-RVZ to BNZ of 0.96 and 0.83 and corresponding 90% confidence intervals (CIs) of 0.91 to 1.10 and 0.80 to 0.87, respectively. However, RVZ Cmax and area under the concentration curve from zero to 24 h increased by about 35% when concomitantly administered with BNZ at steady state (ratio of geometric means for RVZ-BNZ/RVZ of 1.31 and 1.36 and corresponding 90% CIs of 1.23 to 1.39 and 1.31 to 1.41, respectively). Both compounds were well tolerated. There were no clinically relevant safety interactions between E1224 and BZN. Given these results, coadministration of RVZ and BNZ should not require any adaptation of E1224 dosing.

E1210 is a first-in-class, broad-spectrum antifungal with a novel mechanism of action—inhibition of fungal glycosylphosphatidylinositol biosynthesis. In this study, the efficacies of E1210 and reference antifungals were evaluated in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. Oral E1210 demonstrated dose-dependent efficacy in infections caused by Candida species, Aspergillus spp., and Fusarium solani . In the treatment of oropharyngeal candidiasis, E1210 and fluconazole each caused a significantly greater reduction in the number of oral CFU than the control treatment ( P < 0.05). In the disseminated candidiasis model, mice treated with E1210, fluconazole, caspofungin, or liposomal amphotericin B showed significantly higher survival rates than the control mice ( P < 0.05). E1210 was also highly effective in treating disseminated candidiasis caused by azole-resistant Candida albicans or Candida tropicalis . A 24-h delay in treatment onset minimally affected the efficacy outcome of E1210 in the treatment of disseminated candidiasis. In the Aspergillus flavus pulmonary aspergillosis model, mice treated with E1210, voriconazole, or caspofungin showed significantly higher survival rates than the control mice ( P < 0.05). E1210 was also effective in the treatment of Aspergillus fumigatus pulmonary aspergillosis. In contrast to many antifungals, E1210 was also effective against disseminated fusariosis caused by F. solani . In conclusion, E1210 demonstrated consistent efficacy in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. These data suggest that further studies to determine E1210's potential for the treatment of disseminated fungal infections are indicated.