Single-Dose, Intravenous, and Oral Pharmacokinetics of Isavuconazole in Dogs

Abstract

Isavuconazole, a triazole antifungal used in humans for invasive fungal infections, may be effective for treating canine fungal infections, although data on its use in dogs is limited. This study aimed to determine the pharmacokinetics and safety of a single dose of isavuconazole in dogs, administered both intravenously and orally. Six healthy dogs received 186 mg isavuconazonium sulfate in a crossover design, with blood samples collected over 28 days and an 8-week washout period. Plasma isavuconazole and isavuconazonium concentrations were measured by liquid chromatography/mass spectrometry, and pharmacokinetic parameters were determined by non-compartmental analysis. Isavuconazole was well tolerated, with key findings including intravenous clearance at 350 ± 112 mL/kg/h, volume of distribution at steady state at 9.8 ± 4.5 L/kg, and a terminal half-life of 90 ± 44 h. For oral administration, the maximum concentration was 0.60 ± 0.27 μg/mL, time to maximum concentration was 6.73 ± 2.45 h, terminal half-life was 125 ± 80 h, and the area under the curve was 7.44 ± 2.39 μg h/mL. Oral bioavailability was 81.4% ± 12.8%. These results suggest isavuconazole has a long half-life in dogs and is well absorbed orally when administered in the fasted state. Further studies are warranted to establish a therapeutic regimen in dogs.

Keywords: antifungal; aspergillosis; dog; isavuconazole; pharmacokinetics; triazole.

FIGURE 1

Time‐concentration curves of isavuconazole (black dots) and its prodrug, isavuconazonium (open dots) following intravenous administration of isavuconazonium sulfate to dogs. Data are presented on (A) linear and (B) semi‐log plots for ease of visualization. Note the first 12‐h period post‐administration has been expanded on the x‐axis in panel A. Some datapoints are not represented in panel B because values of 0 cannot be plotted on a semi‐log graph.

FIGURE 2

Time‐concentration curves of isavuconazole (black dots) and its prodrug, isavuconazonium (open dogs) following oral administration of isavuconazonium sulfate to dogs. Data are presented on (A) linear and (B) semi‐log plots for ease of visualization. Note the first 24‐h period post‐administration has been expanded on the x‐axis in panel A. Some datapoints are not represented in panel B because values of 0 cannot be plotted on a semi‐log graph.