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.
1. Middleton SM, Kubier A, Dirikolu L, et al. Alternate-day dosing of itraconazole in healthy adult cats. J Vet Pharmacol Ther 2016; 39: 27–31.
3. Scott LJ, Simpson D. Voriconazole: a review of its use in the management of invasive fungal infections. Drugs 2007; 67: 269–298.
4. Owusu Obeng A, Egelund EF, Alsultan A, et al. CYP2C19 polymorphisms and therapeutic drug monitoring of voriconazole: are we ready for clinical implementation of pharmacogenomics? Pharmacotherapy 2014; 34: 703–718.
5. Okabayashi K, Imaji M, Osumi T, et al. Antifungal activity of itraconazole and voriconazole against clinical isolates obtained from animals with mycoses. Nihon Ishinkin Gakkai Zasshi 2009; 50: 91–94.
6. Lat A, Thompson GR III. Update on the optimal use of voriconazole for invasive fungal infections. Infect Drug Resist 2011; 4: 43–53.
7. Smith LN, Hoffman SB. A case series of unilateral orbital aspergillosis in three cats and treatment with voriconazole. Vet Ophthalmol 2010; 13: 190–203.
8. Barrs VR, Halliday C, Martin P, et al. Sinonasal and sino-orbital aspergillosis in 23 cats: aetiology, clinicopathological features and treatment outcomes. Vet J 2012; 191: 58–64.
9. Quimby JM, Hoffman SB, Duke J, et al. Adverse neurologic events associated with voriconazole use in 3 cats. J Vet Intern Med 2010; 24: 647–649.
10. Kano R, Kitagawat M, Oota S, et al. First case of feline systemic Cryptococcus albidus infection. Med Mycol 2008; 46: 75–77.
12. Roffey SJ, Cole S, Comby P, et al. The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human. Drug Metab Dispos 2003; 31: 731–741.
13. Davis JL, Salmon JH, Papich MG. Pharmacokinetics of voriconazole after oral and intravenous administration to horses. Am J Vet Res 2006; 67: 1070–1075.
14. Chan HM, Duran SH, Walz PH, et al. Pharmacokinetics of voriconazole after single dose intravenous and oral administration to alpacas. J Vet Pharmacol Ther 2009; 32: 235–240.
15. Sanchez-Migallon Guzman D, Flammer K, Papich MG, et al. Pharmacokinetics of voriconazole after oral administration of single and multiple doses in Hispaniolan Amazon parrots (Amazona ventralis). Am J Vet Res 2010; 71: 460–467.
16. Hsu AJ, Dabb A, Arav-Boger R. Autoinduction of voriconazole metabolism in a child with invasive pulmonary aspergillosis. Pharmacotherapy 2015; 35: e20–e26.
17. Mulanovich V, Lewis RE, Raad II, et al. Random plasma concentrations of voriconazole decline over time. J Infect 2007; 55: e129–e130.
18. Moriyama B, Elinoff J, Danner RL, et al. Accelerated metabolism of voriconazole and its partial reversal by cimetidine. Antimicrob Agents Chemother 2009; 53: 1712–1714.
19. Ashbee HR, Barnes RA, Johnson EM, et al. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. J Antimicrob Chemother 2014; 69: 1162–1176.
20. Lemetayer JD, Dowling PM, Taylor SM, et al. Pharmacokinetics and distribution of voriconazole in body fluids of dogs after repeated oral dosing. J Vet Pharmacol Ther 2015; 38: 451–456.
21. United States Pharmacopeia and National Formulary (USP 30-NF 25). Vol 2. Rockville, Md: United States Pharmacopeia Convention, 2007;1553–1554.
22. ICH. Validation of analytical procedures: text and methodology Q2 (R1), in Proceedings. International conference on harmonisation of technical requirements for registration of pharmaceutical for human use, 2005.
23. Yamaoka K, Nakagawa T, Uno T. Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm 1978; 6: 165–175.
24. Perrier D, Gibaldi M. General derivation of the equation for time to reach a certain fraction of steady state. J Pharm Sci 1982; 71: 474–475.
25. Yáñez JA, Remsberg CM, Sayre CL, et al. Flip-flop pharmacokinetics—delivering a reversal of disposition: challenges and opportunities during drug development. Ther Deliv 2011; 2: 643–672.
27. Pascual A, Calandra T, Bolay S, et al. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis 2008; 46: 201–211.
28. Smith J, Safdar N, Knasinski V, et al. Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother 2006; 50: 1570–1572.
29. Eiden C, Peyrière H, Cociglio M, et al. Adverse effects of voriconazole: analysis of the French Pharmacovigilance Database. Ann Pharmacother 2007; 41: 755–763.
30. Taxvig C, Vinggaard AM, Hass U, et al. Endocrine-disrupting properties in vivo of widely used azole fungicides. Int J Androl 2008; 31: 170–177.
31. Theuretzbacher U, Ihle F, Derendorf H. Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin Pharmacokinet 2006; 45: 649–663.
32. Zrenner E, Tomaszewski K, Hamlin J, et al. Effects of multiple doses of voriconazole on the vision of healthy volunteers: a double-blind, placebo-controlled study. Ophthalmic Res 2014; 52: 43–52.
34. Tsiodras S, Zafiropoulou R, Kanta E, et al. Painful peripheral neuropathy associated with voriconazole use. Arch Neurol 2005; 62: 144–146.
35. Zonios DI, Gea-Banacloche J, Childs R, et al. Hallucinations during voriconazole therapy. Clin Infect Dis 2008; 47: e7–e10.