Pharmacokinetics and Concentration-Dependent Efficacy of Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis

Abstract

We studied the pharmacokinetics and efficacy of the broad-spectrum triazole isavuconazole for the treatment of experimental invasive pulmonary aspergillosis (IPA) in persistently neutropenic rabbits. Treatment started 24 h after endotracheal administration of Aspergillus fumigatus inoculum; study subjects included rabbits receiving orally administered prodrug isavuconazonium sulfate (BAL8557) equivalent to active moiety isavuconazole (ISA; BAL4815) at 20 (ISA20), 40 (ISA40), and 60 (ISA60) mg/kg (of body weight)/day, with an initial loading dose of 90 mg/kg (ISA90), and untreated rabbits (UC). There were significant concentration-dependent reductions of residual fungal burden (log CFU/gram) and of organism-mediated pulmonary injury, lung weights, and pulmonary infarct scores in ISA40- and ISA60-treated rabbits in comparison to those of UC (P < 0.001). ISA20-treated (P < 0.05), ISA40-treated, and ISA60-treated (P < 0.001) rabbits demonstrated significantly prolonged survival in comparison to that of UC. ISA40- and ISA60-treated animals demonstrated a significant decline of serum (1→3)-β-d-glucan levels (P < 0.05) and galactomannan indices (GMIs) during therapy following day 4 in comparison to progressive GMIs of UC (P < 0.01). There also were significantly lower concentration-dependent GMIs in bronchoalveolar lavage (BAL) fluid from ISA40- and ISA60-treated rabbits (P < 0.001). There was a direct correlation between isavuconazole plasma area under the concentration-time curve from 0 to 24 h (AUC0-24) and residual fungal burdens in lung tissues, pulmonary infarct scores, and total lung weights. In summary, rabbits treated with isavuconazole at 40 and 60 mg/kg/day demonstrated significant dose-dependent reduction of residual fungal burden, decreased pulmonary injury, prolonged survival, lower GMIs in serum and BAL fluid, and lower serum (1→3)-β-d-glucan levels.

FIG 1

Response of primary pulmonary aspergillosis in persistently neutropenic rabbits to antifungal therapy measured by mean pulmonary tissue residual fungal burden (log CFU/gram), mean lung weight, mean pulmonary infarct score, and survival in untreated controls (UC) and rabbits receiving oral isavuconazole (BAL4815). An initial loading dose of 90 mg/kg of isavuconazole was administered orally, and thereafter the drug was administered daily at 20 mg/kg (ISA20), 40 mg/kg (ISA40), and 60 mg/kg (ISA60). Values are means ± SEMs. For the measure of survival, the values on the y axis are probability of survival. Survival was plotted by Kaplan-Meier analysis. Differences in survival of treatment groups and untreated controls were analyzed by log rank test. P values are indicated as follows: *, P < 0.05, decreased infarct score in ISA20-treated rabbits in comparison to that of UC; ∫, P < 0.001, decreased residual fungal burden, lung weight, and infarct score in ISA40- and ISA60-treated rabbits in comparison to that of UC; * and ∫, P values were obtained by comparison to UC by ANOVA with Bonferroni's correction for multiple comparisons; £, P < 0.001, prolonged survival of rabbits treated with ISA40 and ISA60 in comparison to that of UC; §, P < 0.05, prolonged survival of rabbits treated with ISA20 in comparison to that of UC.

FIG 2

(Top) Expression of galactomannan antigenemia in persistently neutropenic rabbits with pulmonary aspergillosis in untreated controls and rabbits receiving oral dosing of isavuconazole (BAL4815). An initial loading dose of 90 mg/kg of isavuconazole was administered orally, and thereafter the drug was administered daily at 20, 40, and 60 mg/kg. Values are means ± SEMs. (Bottom) BAL fluid galactomannan antigen levels in persistently neutropenic rabbits with pulmonary aspergillosis in untreated controls and rabbits treated with isavuconazole at 20, 40, and 60 mg/kg/day p.o. Values are means ± SEMs. P values are indicated as follows: †, P < 0.01, lower GMI in ISA40- and ISA60-treated rabbits than in UC; ∫, P < 0.001, lower GMI in BAL from rabbits treated with ISA40 and ISA60 than in that of UC (P values were obtained by comparison to UC by ANOVA with Bonferroni's correction for multiple comparisons).

FIG 3

Serum (1→3)-β-d-glucan levels in persistently neutropenic rabbits of the experimental pulmonary aspergillosis model in groups of untreated controls and rabbits receiving oral doses of isavuconazole (BAL4815). An initial loading dose of 90 mg/kg of isavuconazole was administered orally, and thereafter the drug was administered daily at 20, 40, and 60. Values are (1→3)-β-d-glucan concentrations. P values are indicated as follows: *, P < 0.05, decrease of plasma (1→3)-β-d-glucan concentrations in ISA20-treated rabbits in comparison to that of UC; ¶, P < 0.01, decrease of plasma (1→3)-β-d-glucan concentrations in ISA40- and ISA60-treated rabbits in comparison to that of UC.

FIG 4

(Top) Mean plasma profiles of BAL4815 after single oral-dose administration of BAL8557 prodrug equivalent to active compound of 20, 40, 60, and 90 mg/kg/day. (Bottom) Mean plasma profiles of isavuconazole after oral dose administration of prodrug isavuconazonium sulfate for 6 days to the infected animals. A loading oral dose of 90 mg/kg of isavuconazole was administered, followed by once-daily maintenance doses of 20, 40, and 60 mg/kg.

FIG 5

(Top) Concentrations of isavuconazole (BAL4815) in the lung tissue after oral administration of BAL8557 for 12 days to the infected animals. An initial loading dose of 90 mg/kg of isavuconazole was administered orally, and thereafter the drug was administered daily at 20, 40, and 60. (Bottom) Concentrations of isavuconazole in the BAL fluid and BAL fluid supernatant after oral administration of prodrug isavuconazonium sulfate for 12 days to the infected animals. An initial loading dose of 90 mg/kg of isavuconazole was administered orally, and thereafter the drug was administered daily at 20, 40, and 60 mg/kg.

FIG 6

Correlation of AUC_0–24 and outcome variables. (A) Residual fungal burden in the lung tissues; (B) infarct score; (C) total lung weight. Calculations of r and P values were performed using Pearson's correlation method.