Pharmacokinetics of Voriconazole in Horses and Alpacas
Type of DegreeDissertation
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Voriconazole is a new antifungal drug that has shown effectiveness in treating serious fungal infections and has the potential for being used in large animal veterinary medicine. The objectives of this study were to determine the plasma concentrations and pharmacokinetic parameters of voriconazole after single-dose intravenous (IV) and oral administration to alpacas and horses. In addition, the pharmacokinetics after oral multiple administrations to horses were determined. Voriconazole concentrations were measured by the use of high-performance liquid chromatography throughout this study. After single 4 mg/kg intravenous and oral administrations of voriconazole to four alpacas, the mean terminal half-life (t1/2ß) following IV and oral administration was 8.011 ± 2.879 and 8.748 ± 4.307 hours, respectively; mean maximum plasma concentrations (Cmax) were 5.930 ± 1.132 and 1.700 ± 2.707 mg/L, respectively; and area under the curve from time zero extrapolated to infinity (AUC0-inf) was 38.50 ± 11.11 and 9.484 ± 6.983 mg-hr/L, respectively. The mean apparent systemic oral availability (F) was low with a value of 22.74 ± 9.48 %. Two horses were used for the treatment of 2 mg/kg single dose IV and 3 mg/kg oral administration of a crushed tablet formulation of voriconazole, and four horses were used for the treatment of 4 mg/kg single dose intravenous and oral administration of a powder formulation of voriconazole. The mean t1/2ß following IV, oral crushed tablet, and oral powder administrations were 12.22 ± 3.54, 9.482 ± 0.899, and 15.284 ± 3.497 hours, respectively. The mean extents of oral absorption for the crushed tablet and the powder formulations were 57.88 ± 8.62% and 103.07 ± 9.15%, respectively. Two horses were dosed 3 mg/kg orally by a crushed tablet formulation of voriconazole, and four horses were given 4 mg/kg orally as a powder formulation of voriconazole every 24 hours. On day 14/15 of the treatment, the mean t1/2ß following oral 3 mg/kg/day crushed tablet and 4 mg/kg/day powder administration were 10.046 and 7.141 hours, respectively; mean Cmax were 1.977 and 1.892 µg/mL, respectively; mean dose-adjusted area under the curve from time zero to 24 hours (AUC0-24/Dose) were 9.433 and 5.944 kg-hr/L, respectively. The mean accumulation factor calculated from the AUC values on day 14/15 compared to that of day 1 were 2.202 and 1.062, respectively, for the crushed tablet and the powder formulations. This difference in accumulation factor suggests a dosage form effect on drug accumulation during multiple dosing, possibly related to completeness of oral absorption.