Oral fluconazole has variable pharmacokinetics in dogs

The purpose of this study was to assess the effects of food and manufacturer on the oral bioavailability of fluconazole in dogs. We hypothesized feeding would decrease fluconazole bioavailability and large variability between manufacturers would occur. Six healthy purpose-bred dogs aged 2-3 years, weighing 9.5-13.7 kg, were enrolled. Each dog was administered a 100 mg fluconazole tablet from three FDA approved manufacturers (1-Glenmark, 2-Citron, 3-Harris) in a randomized crossover block study, fasted for 12 h (fasted) or 15 min after feeding (fed); each dog had 6 treatments. Blood was collected for 72 h after dosing with a 10-day washout between treatments. Fluconazole plasma concentrations were determined with mass spectrometry. Overall variability in dose-normalized drug exposure (AUC/dose) was large (range 1.9-2.9x) within each treatment, while the overall range across all treatments was 3.3-fold. The inter-dog variability in the terminal half-life was also large, 3.1-fold. The mean fed relative oral bioavailability was lower (82%-90%) compared to fasted for each formulation. Due to the large variability, the formulations were not bioequivalent. These data suggest the variability in the half-life was a major contributor to the large variability in fluconazole pharmacokinetics in dogs, while the feeding status and manufacturer were minor contributors.