Utility of systemic voriconazole in equine keratomycosis based on pharmacokinetic‐pharmacodynamic analysis of tear fluid following oral administration

Abstract

Objective To clarify the detailed pharmacokinetics (PK) of orally administered voriconazole in tear fluid (TF) of horses for evaluating the efficacy of voriconazole secreted into TF against equine keratomycosis. Animals studied Five healthy Thoroughbred horses. Procedures Voriconazole was administrated through a nasogastric tube to each horse at a single dose of 4.0 mg/kg. TF and blood samples were collected before and periodically throughout the 24 hours after administration. Voriconazole concentrations in plasma and TF samples were analyzed using liquid chromatography‐electrospray tandem‐mass spectrometry. The predicted voriconazole concentration in both samples following multiple dosing every 24 hours was simulated by the superposition principle. Results The mean maximum voriconazole concentrations in plasma and TF were 3.3 μg/mL at 1.5 h and 1.9 μg/mL at 1.6 h, respectively. Mean half‐life in both samples were 16.4 and 25.2 h, respectively. The ratio of predicted AUC 0–24 at steady state in TF (51.3 μg∙h/mL) to previously published minimum inhibitory concentration (MIC) of Aspergillus and Fusarium species was >100 and 25.7, respectively. Conclusions This study demonstrated the detailed single‐dose PK of voriconazole in TF after oral administration and simulated the predicted concentration curves in a multiple oral dosing. Based on the analyses of PK‐PD, the simulation results indicated that repeated oral administration of voriconazole at 4.0 mg/kg/d achieves the ratio of AUC to MIC associated with treatment efficacy against Aspergillus species. The detailed PK‐PD analyses against pathogenic fungi in TF can be used to provide evidence‐based medicine for equine keratomycosis.

Kinetics and minimal inhibitory concentrations of ceftiofur in tear film following extended-release parenteral administration (Excede®) in dogs

“…Potential benefits of systemic therapy include ease of administration, improved owner/patient compliance, and possibly sustained drug levels when compared to topical instillation (due to rapid drug loss via nasolacrimal drainage, tear volume turnover, and mechanical forces from eyelid blinking) ( 1 – 3 ). Although promising, tear film levels are only described for select (oral or parenteral) medications in veterinary medicine such as doxycycline ( 4 – 6 ), minocycline, ( 7 ) pradofloxacin ( 6 ), famciclovir ( 8 ), voriconazole ( 9 ) and prednisone ( 10 ). Unfortunately, tear film pharmacology cannot be extrapolated from one drug to another given unique physicochemical properties ( e.g ., molecular weight, lipophilicity, protein binding) that influence drug distribution from the blood to tear film or other peripheral compartments; for instance, pradofloxacin but not doxycycline was quantifiable in tear film of cats receiving the same oral dose (5 mg/kg) ( 6 ).…”