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

• Published in: Veterinary ophthalmology 2020-07, Vol.23 (4), p.640-647
• Main Authors: Tamura, Norihisa, Okano, Atsushi, Kuroda, Taisuke, Niwa, Hidekazu, Kusano, Kanichi, Matsuda, Yoshikazu, Fukuda, Kentaro, Mita, Hiroshi, Nagata, Shunichi
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antifungal Agents - administration & dosage; Antifungal Agents - pharmacokinetics; Antifungal Agents - pharmacology; Antifungal Agents - therapeutic use; Area Under Curve; Aspergillus; Aspergillus - drug effects; Eye Infections, Fungal - drug therapy; Eye Infections, Fungal - veterinary; Female; horse; Horse Diseases - blood; Horse Diseases - drug therapy; Horses - metabolism; keratomycosis; Male; Microbial Sensitivity Tests; Original; pharmacodynamics; pharmacokinetics; tear fluid; Tears - metabolism; Voriconazole - administration & dosage; Voriconazole - pharmacokinetics; Voriconazole - pharmacology; Voriconazole - therapeutic use
• ISSN: 1463-5216; 1463-5224
• DOI: 10.1111/vop.12764

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 AUC0–24 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.