Fungal infections in cats may respond poorly to treatment with commonly used azole antifungal drugs (itraconazole and fluconazole), and use of these drugs as well as amphotericin B can be limited by expense and toxic effects.1 One newer alternative is voriconazole, a synthetic triazole antifungal agent available in IV and oral formulations.2,3 Voriconazole inhibits fungal 14-alpha-sterol-demethylase (a CYP-dependent enzyme) and disrupts the fungal cell membrane and halts fungal growth. In humans, the drug is extensively transported across the blood-brain and blood-retinal barriers. Voriconazole is recommended as a first-line treatment for acute invasive aspergillosis in humans4 and is also used to treat serious and refractory fungal infections caused by Scedosporium spp, Paecilomyces spp, Fusarium spp, and Candida spp.2,5 Voriconazole also has activity against Cryptococcus spp and endemic fungi such as Blastomyces spp, Histoplasma capsulatum, and Coccidioides spp.2 In vitro experiments have revealed that fungal isolates obtained from cats (Cryptococcus spp, Candida spp, and Aspergillus fumigatus) are susceptible to voriconazole.5 Cryptococcosis is the most common systemic mycosis in cats, and the organism has a propensity to invade the CNS; therefore, voriconazole represents an attractive antifungal drug for cats that fail to respond adequately to fluconazole treatment. Voriconazole also has properties that make it desirable for treatment of sino-orbital and sinonasal aspergillosis in cats, and the drug may be useful for treatment of histoplasmosis and opportunistic mold infections.
Voriconazole has been used with some success to treat systemic mold and yeast infections in dogs.3,6 However, when a dosage used to treat humans and dogs (5 mg/kg, PO, q 12 h) was administered to cats with naturally occurring fungal infections, severe adverse events were reported, including death of some cats.7–10 Signs of toxicosis in cats include visual abnormalities, mydriasis, ataxia, hypokalemia, and arrhythmias. Signs resolve after the drug is discontinued. Plasma concentrations of voriconazole were not measured in these studies,7–10 and pharmacokinetics of voriconazole in cats was not known. This suggests that cats are inherently more sensitive to adverse effects of voriconazole or the pharmacokinetics of voriconazole in cats differs from those in humans and dogs.
In healthy human volunteers, oral bioavailability of voriconazole in 1 study11 was > 90%, but it may be < 20% when given with food. The CSF and vitreous humor concentrations are > 50% and 40% of serum concentrations, respectively.2 In humans, voriconazole undergoes extensive metabolism by hepatic CYP isoenzymes, with < 2% to 5% eliminated unchanged in the urine.2,3 Large variability in voriconazole trough plasma concentrations has been observed in human therapeutic drug monitoring studies, and there is an association between voriconazole concentrations and adverse effects.4
Voriconazole pharmacokinetic properties have also been studied in dogs, guinea pigs, rats, rabbits,12 horses,13 alpacas,14 and Amazon parrots.15 In most species, including dogs and humans, pharmacokinetics of voriconazole is nonlinear, which indicates that enzymes for metabolism become saturated. Therefore, drug clearance is lower with high doses, with an increased risk of toxicosis.4,15 Saturable nonlinear pharmacokinetics can be species-specific and cannot be extrapolated to other species, such as cats.12–15 Extrapolation of doses is further complicated because repeated administration of voriconazole to mice, rats, and dogs,12 and sometimes humans,16–18 results in induction of metabolizing enzymes, which lowers plasma drug concentrations. Hence, single-dose experiments may not accurately predict pharmacokinetics when multiple doses are administered.12,15
Because toxicosis for voriconazole in humans is a concentration-dependent phenomenon, it is possible that voriconazole can be administered to cats if concentrations can be maintained within a safe range. To avoid toxic effects in humans, it is recommended that doses be adjusted to achieve trough concentrations no higher than 4 to 6 μg/mL.19 If voriconazole can be administered safely to cats and concurrently maintain therapeutic plasma drug concentrations, it would be an attractive treatment option because of its activity against important fungal pathogens of cats and reduced cost (because of the reduced quantity of drug required).
The purpose of the study reported here was to characterize pharmacokinetics and adverse effects after IV or oral administration of a single dose of voriconazole to healthy cats and after oral administration to healthy cats for 14 days. We intended to use the resulting pharmacokinetic information to determine whether an oral dose of voriconazole could be identified for cats that would maintain plasma drug concentrations within a safe and effective range.
Supported by the Center for Companion Animal Health at the University of California-Davis.
Presented in abstract form at the 17th Annual Congress of the American College of Veterinary Internal Medicine, Indianapolis, June 2015.
The authors thank Delta R. Dise for assistance with the HPLC and Taylor Calloway, Adam Schawel, Kristen Elliot, Cody Blumenshine, Arash Sarlati, Sarai Milliron, and Adriana Manrique for technical assistance.
Area under the time-concentration curve
Systemic drug clearance
Coefficient of variation
Absolute fraction of the dose absorbed
High-performance liquid chromatography
Time to maximum concentration
Purina Adult Formula, Nestle Purina, Wilkes-Barre, Pa.
Arrow International Inc, Reading, Pa.
Vfend IV, Pfizer Ltd, Sandwich, Kent, England.
Vfend suspension, Pfizer Ltd, Sandwich, Kent, England.
Voriconazole tablets (generic Vfend), Mylan Inc, Canonsburg, Pa.
Cyano-bonded cartridges, Bond-Elut CN-E, 1 mL, Varian Inc, Harbor City, Calif.
Zorbax RX-C8 4.6 × 150-mm, Agilent Technologies, Wilmington, Del.
Pfizer Ltd, Global Research and Development, Sandwich, Kent, England.
Phoenix WinNonlin, version 6.1, Pharsight Corp, Cary, NC.
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