Efficacy of TAK-457, a novel intravenous triazole, against invasive pulmonary Aspergillosis in neutropenic mice

Abstract

TAK-457 is an injectable prodrug of TAK-456, which is a novel oral triazole compound with potent antifungal activity. The in vivo efficacy of TAK-457 was evaluated in two models of invasive pulmonary aspergillosis with CDF(1) mice and CBA/J mice with transient neutropenia induced by cyclophosphamide. Against the infection in CDF(1) mice, treatment with 10 mg of TAK-457 and 1 mg of amphotericin B/kg reduced the fungal burden in lungs and rescued all mice. In the infection model with CBA/J mice, TAK-457 at a dose of 10 mg/kg significantly prolonged the survival time of mice, showing significant reduction of lung chitin levels and the plasma beta-D-glucan levels. On the other hand, amphotericin B at 1 mg/kg which was a maximum tolerable dose showed slight but not significant prolongation of survival time of mice, although it also reduced the lung chitin levels and the plasma beta-D-glucan levels to a lower extent but still significantly. These results suggest that TAK-457 is a promising candidate for development for the treatment of invasive aspergillosis in humans.

FIG. 1.

Chemical structure of TAK-457.

FIG. 2.

Effects of TAK-457 and reference antifungal agents against pulmonary infection caused by A. fumigatus 437 in neutropenic CDF₁ mice. Antifungal agents were administered intravenously once a day for 5 days starting 2 h after infection (n = 10). Agents: vehicle (•), TAK-457 at 10 mg/kg (○) and 3 mg/kg (◊), amphotericin B at 1 mg/kg (□), fluconazole at a dose of 10 mg/kg (▵).

FIG. 3.

Effects of TAK-457 and reference antifungal agents on lung chitin levels of neutropenic CDF₁ mice inoculated intranasally with A. fumigatus 437. Antifungal agents were administered intravenously once a day on days 0, 1, and 2 of infection, and chitin levels were determined for the surviving mice on day 3. One vehicle-treated and three fluconazole-treated mice died by day 3 after infection (n = 5). Circles indicate chitin levels of individual mouse, and bars indicate means. *, P < 0.05 versus the vehicle-treated group. AMPH-B, amphotericin B; FLCZ, fluconazole.

FIG. 4.

Effects of TAK-457 and reference antifungal agents against pulmonary infection caused by A. fumigatus 437 in neutropenic CBA/J mice. Antifungal agents were administered intravenously once a day for 5 days starting 2 h after infection (n = 10). Agents: vehicle (•), TAK-457 at 10 mg/kg (○), amphotericin B at 1 mg/kg (□), fluconazole at 10 mg/kg (▵).

FIG. 5.

Effects of TAK-457 and reference antifungal agents on plasma β-d-glucan levels of neutropenic CBA/J mice inoculated intranasally with A. fumigatus 437. Antifungal agents were administered intravenously once a day on days 0 and 1 of infection, and the β-d-glucan levels were determined on day 2. Data are expressed as means ± the standard error of the mean (SEM; n = 8). **, P < 0.01 versus the vehicle-treated group as determined by Dunnett test. AMPH-B, amphotericin B; FLCZ, fluconazole.

FIG. 6.

Effects of TAK-457 and reference antifungal agents on lung chitin levels of neutropenic CBA/J mice inoculated intranasally with A. fumigatus 437. Antifungal agents were administered intravenously once a day on days 0 and 1 of infection, and the chitin levels in lungs were determined on day 2 (n = 5). Circles indicate the chitin levels of individual mice, and the bars indicate means. **, P < 0.01 versus the vehicle-treated group. AMPH-B, amphotericin B; FLCZ, fluconazole.