Voriconazole, a second-generation triazole that is available in IV and oral formulations, provides a new and improved treatment option for fungal infections.1 Voriconazole is modified from fluconazole by substitution of a fluoropyrimidine ring for one of the azole groups and addition of an α-methyl group. These modifications result in activity against a greater variety of fungal organisms. Voriconazole interacts with fungal cytochrome P-450, thereby inhibiting C-14 demethylation of lanosterol and preventing the conversion of lanosterol to ergosterol; ergosterol is necessary for cell membrane synthesis.2 This antifungal agent has good in vivo and in vitro activities against a variety of yeast and filamentous and dimorphic fungi (including Candida spp, Cryptococcus neoformans, and Aspergillus spp) but has little or no activity against zygomycetes.3–10 Voriconazole has been shown to be more effective than amphotericin B for the treatment of humans with invasive aspergillosis, and it is safer than amphotericin B in patients with renal dysfunction.11,12 Because of these properties, voriconazole has become the new standard of treatment for invasive aspergillosis in human medicine.1,12–14 Like other azoles, associated adverse effects and drug interactions in humans have also been reported.15–18
In most species, the pharmacokinetics of voriconazole are saturable and nonlinear; therefore, the drug's pharmacokinetics are dependent upon the administered dose.19–25 This occurs because voriconazole is extensively metabolized by the liver and this host enzyme system can be saturated when the plasma concentration of the agent is high. As the dose administered increases, elimination may be linear until saturation occurs. After saturation, plasma concentrations may be prolonged. Saturable nonlinear pharmacokinetics suggest that extrapolation of voriconazole doses among species might be inaccurate. Dose extrapolation is further complicated because voriconazole induces its own metabolism enzymes after repeated administration in some species but not in others. This indicates that results of single-dose studies may not accurately predict multiple-dose data in some species.19–25 Therefore, accurate determination of a safe and effective treatment regimen for voriconazole in any given species may require both single- and multiple-dose testing in that species.
Voriconazole has been used in birds for the treatment of aspergillosis,26,27 but the number of pharmacokinetic studies19–21,23,28 is limited. In chickens, the oral bioavailability of voriconazole was < 20% and the half-life was short (1.25 hours).20 Plasma concentrations achieved via oral administration of 10 mg of voriconazole/kg every 24 hours were low (< 0.5 μg/mL), but concentrations in some tissues were considerably higher, which suggested that such treatment would result in concentrations that were effective against Candida spp and Aspergillus spp in most tissues.20 In that study20 in chickens, nonlinear pharmacokinetics in single-dose experiments and autoinduction of metabolism enzymes in multiple-dose trials were not demonstrated. In a study23 involving falcons, the influence of food intake on voriconazole bioavailability and the safety of drug treatment were evaluated. Six falcons were administered voriconazole (12.5 mg/kg, PO [via crop gavage], q 12 h) for 14 days. Resultant peak plasma concentrations were high (> 1 μg/mL), but trough concentrations were low and sometimes undetectable.23 Compared with findings in that group, plasma concentrations in another falcon that received doses of voriconazole incorporated into meat were 21% to 26% lower.23 In another study19 in African grey parrots, the half-life of voriconazole was short (1.1 to 1.6 hours) and higher doses resulted in disproportional increases in plasma concentrations, suggesting nonlinear pharmacokinetics. Trough plasma concentrations achieved in the multiple-dose trial in that study19 were lower than those achieved after administration of single doses, suggesting that the drug induces its own metabolism. Dosages of 12 to 18 mg/kg administered orally every 12 hours were recommended as a starting point to target plasma concentrations > 0.4 μg/mL, but higher dosages could be needed for long-term treatment. In pigeons, oral bioavailability of voriconazole was determined to be 43.7%; in those birds, nonlinear voriconazole pharmacokinetics were determined in single-dose experiments and autoinduction of metabolism enzymes was identified in a multiple-dose trial.21 On the basis of those data, oral administration of 10 mg/kg every 12 hours or 20 mg/kg every 24 hours was recommended for pigeons. The reported differences in enteral absorption, saturable nonlinear pharmacokinetics, and induction of metabolism enzymes indicate the necessity of specific studies to determine dosage recommendations for different species.19,21,22
The purpose of the study reported here was to determine the pharmacokinetics and safety of voriconazole administered orally in single and multiple doses in Hispaniolan Amazon parrots (Amazona ventralis). These parrots were selected because of their availability and the popularity of Amazon parrots as companion animals. The small body size of these birds precluded collection of blood samples at all time points from any single bird, so naïve pooling of drug concentrations from multiple birds was used to plot concentration-versus-time curves and calculate pharmacokinetic values for the single-dose experiments. This method has been used successfully in previous studies.19,29
Area under the plasma concentration-versus-time curve
Clearance per fraction absorbed
Maximum plasma concentration
High-pressure liquid chromatography
Minimum inhibitory concentration
Nonlinear mixed-effects model
Volume of distribution per fraction absorbed
Exact Breeding Formula, Kaytee Products Inc, Chilton, Wis.
Stainless-steel feeding tubes, curved, Veterinary Specialty, Mission, Kan.
Vfend tablets, Pfizer, New York, NY.
Ora-Plus, Paddock Laboratories Inc, Minneapolis, Minn.
VetScan chemistry analyzer, Avian/Reptilian Profile Chemistry Rotor, Abaxis Inc, Union City, Calif.
Bond-Elut CN-E (1 mL), Varian Inc, Harbor City, Calif.
Zorbax RX-C8 4.6 × 150-mm reverse-phase column, Agilent Technologies, Wilmington, Del.
Voriconazole reference standard, Pfizer Ltd, Global Research and Development, Sandwich Laboratories, Sandwich, Kent, England.
WinNonlin professional, version 4.1, Pharsight Corp, Cary, NC.
WinNonMix, version 2.0, Pharsight Corp, Cary, NC.
Sigma Stat for Windows, version 2.03, SPSS Inc, Chicago, Ill.
Boucher HW, Groll AH, Chiou CC, et al.Newer systemic antifungal agents: pharmacokinetics, safety and efficacy. Drugs 2004;64:1997–2020.
Theuretzbacher U, Ihle F, Derendorf H. Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin Pharmacokinet 2006;45:649–663.
Serena C, Gilgado F, Marine M, et al.Efficacy of voriconazole in a guinea pig model of invasive trichosporonosis. Antimicrob Agents Chemother 2006;50:2240–2243.
Kirkpatrick WR, McAtee RK, Fothergill AW, et al.Efficacy of voriconazole in a guinea pig model of disseminated invasive aspergillosis. Antimicrob Agents Chemother 2000;44:2865–2868.
Silvanose C, Bailey T, Di Somma A. Antifungal susceptibility testing of fungi isolated from the respiratory tract of falcons in the United Arab Emirates, in Proceedings. 8th Eur Assoc Avian Vet Conf 2005;479–481.
Diekema D, Messer SA, Hollis RJ, et al.Activities of caspofungin, itraconazole, posaconazole, ravuconazole, voriconazole, and amphotericin B against 448 recent clinical isolates of filamentous fungi. J Clin Microbiol 2003;41:3623–3626.
Espinel-Igroff. In vitro fungicidal activities of voriconazole, itraconazole, and amphotericin B against opportunistic moniliaceous and dematiaceous fungi. J Clin Microbiol 2001;39:954–958.
Abraham OC, Manavathu EK, Cutright JL, et al.In vitro susceptibilities of Aspergillus species to voriconazole, itraconazole and amphotericin B. Mycology 1999;33:7–11.
Herbrecht R, Denning DW, Patterson TF, et al.Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408–415.
Stiefel M, Reiss T, Staege MS, et al.Successful treatment with voriconazole of Aspergillus brain abscess in a boy with medulloblastoma. Pediatr Blood Cancer 2005;49:203–207.
Eiden C, Peyriere H, Cociglio M, et al.Adverse effects of voriconazole: analysis of the French Pharmacovigilance Database. Ann Pharmacother 2007;41:755–763.
Tan K, Brayshaw N, Tomaszewski K, et al.Investigation of the potential relationships between plasma voriconazole concentrations and visual adverse events or liver function test abnormalities. J Clin Pharmacol 2006;46:235–243.
Saad AH, DePestel DD, Carver PL. Factors influencing the magnitude and clinical significance of drug interactions between azole antifungals and select immunosuppressants. Pharmacotherapy 2006;26:1730–1744.
Flammer K, Nettifee Osborne JA, Webb DJ, et al.Pharmacokinetics of voriconazole after oral administration of single and multiple doses in African grey parrots (Psittacus erithacus timneh). Am J Vet Res 2008;69:114–121.
Burhenne J, Haefeli W, Hess M, et al.Pharmacokinetics, tissue concentrations, and safety of the antifungal agent voriconazole in chickens. J Avian Med Surg 2008;22:199–207.
Beernaert LA, Baert K, Marin P, et al.Designing voriconazole treatment for racing pigeons: balancing between hepatic enzyme auto induction and toxicity. Med Mycol 2009;47:276–285.
Scope A, Burhenne J, Haefeli WE, et al.Species dependent differences and evaluation of possible influences on the enteral absorption of voriconazole in birds, in Proceedings. 9th Eur Assoc Avian Vet Conf 2007;236–239.
Davis JL, Salmon JH, Papich MG. Pharmacokinetics of voriconazole after oral and intravenous administration to horses. Am J Vet Res 2006;67:1070–1075.
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.
Langhofer B. Emerging antifungals and the use of voriconazole with amphotericin to treat Aspergillus, in Proceedings. 25th Assoc Avian Vet Conf 2004;21–24.
Di Somma A, Bailey T, Silvanose C, et al.The use of voriconazole for the treatment of aspergillosis in falcons (Falco species). J Avian Med Surg 2007;21:307–316.
Scope A, Burhenne J, Haefeli WE, et al.Pharmacokinetics and pharmacodynamics of the antifungal agent voriconazole in birds, in Proceedings. 8th Eur Assoc Avian Vet Conf 2005;217–221.
Flammer K, Papich M. Pharmacokinetics of fluconazole after oral administration of single and multiple doses in African grey parrots. Am J Vet Res 2006;67:417–422.
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.
Krishnan S, Manavathu EK, Chandrasekar PH. A comparative study of fungicidal activities of voriconazole and amphotericin B against hyphae of Aspergillus fumigatus. J Antimicrob Chemother 2005;55:914–920.
Manavathu EK, Cutright JL, Chandrasekar PH. Organism-dependent fungicidal activities of azoles. Antimicrob Agents Chemother 1998;42:3018–3021.
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.
US FDA. Briefing document for voriconazole. Washington, DC: US FDA, 2001. Available at: www.fda.gov/ohrms/dockets/ac/01/briefing/3792b2.htm. Accessed Oct 29, 2009.