Abstract
Aspergillosis is a common respiratory fungal disease in African penguins (Spheniscus demersus) managed under human care.1 Triazole antifungal drugs, such as itraconazole, are the most common treatment of choice; however, treatment failures due to drug resistance are becoming more common, requiring newer treatment options.2,3 As no voriconazole pharmacokinetic (PK) studies have been performed in African penguins, empirical dosing based on other avian studies4-7 has led to drug toxicity and even potential death.8 The objective of this study was to determine the PK parameters of orally administered voriconazole based on 5 mg/kg SID single- and multiple-dose trials in African penguins in order to calculate dosing requirements for treatment of aspergillosis. A maximum of 18 adult African penguins were used in each of these trials with a 4-month washout period between trials. To minimize handling, blood collection and blood volume throughout the dosing interval, birds were assigned to different groups so that not every bird had blood collected at each time point. Plasma voriconazole concentrations were determined via high pressure liquid chromatography. Single-dose PK analysis determined peak concentrations in the first hour of starting voriconazole to range 1.18–2.01 µg/ml which were above the recommended minimum inhibitory concentration for Aspergillus sp. (0.4 µg/ml).9 In the multiple-dose trial, plasma voriconazole concentrations were significantly higher on Days 4 and 7 compared to Day 2. Single and multiple dose data were co-modeled together using a population methodology. A three-compartment structural pharmacokinetic model representing the gut, central compartment and peripheral compartment was used with first-order elimination. The model fit the data well with a coefficient of determination of 82.3% for the linear regression of observed-predicted values after the Bayesian step. The median estimates for volume and clearance were 3.99 L and 0.11 L/h, respectively. Monte Carlo simulations were performed creating 1000 simulated penguins each receiving voriconazole 5 mg/kg. The simulated mean area under the curve (AUC) determined between 96 and 120 hours was 44.55 mg·h/L. This drug exposure is comparable to the average AUC in humans receiving the recommended dosage.10 During the course of the study, no penguins exhibited signs of voriconazole toxicity. This study suggests that 5 mg/kg PO SID is likely to be a safe and effective regimen for African penguins for treatment of invasive aspergillosis. Due to potential drug accumulation and toxicity, therapeutic drug monitoring with dosage adjustments is recommended.
Acknowledgements
The authors thank the Adventure Aquarium Bird and Mammal husbandry team for their care of the penguins and their assistance with this study. This research was funded in part by the Riverbanks Zoo and Gardens Conservation Support Fund and the American Association of Zoo Veterinarians' Wild Animal Health Fund.
* Presenting author
Literature Cited
1. Phalen DN. Respiratory medicine of caged and aviary birds. Vet Clin North Am Exot Anim Pract. 2000;3:423–452.
2. Beernaert LA, Pasmans F, Van Waeyenberghe L, Dorrestein GM, Verstappen F, Vercammen F, Haesebrouck F, Martel A. Avian Aspergillus fumigatus strains resistant to both itraconazole and voriconazole. Antimicrob Agents Chemother. 2009;53(5):2199–2201.
3. Lockart SR, Frade JP, Etienne KA, Pfaller MA, Diekema DJ, Balajee SA. Azole resistance in Aspergillus fumigatus isolates from the ARTEMIS global surveillance study is primarily due to the TR/L98H mutation in the cyp51A gene. Antimicrob Agents Chemother. 2011;55(9):4465–4468.
4. Beernaert LA, Baert K, Marin P, Chiers K, De Backer P, Pasmans F, Martel A. Designing voriconazole treatment for racing pigeons: balancing between hepatic enzyme auto induction and toxicity. Med Mycol. 2009;47:276–285.
5. Burhenne J, Haefeli WE, Hess M, Scope A. Pharmacokinetics, tissue concentrations, and safety of the antifungal agent voriconazole in chickens. J Avian Med Surg. 2008;22(3):199–207.
6. Flammer K, Nettifee Osborne JA, Webb DJ, Foster LE, Dillard SL, Davis JL. Pharmacokinetics of voriconazole after oral administration of single and multiple doses in African grey parrots (Psittacus erithacus timneh). Am J Vet Res. 2008;69(1):114–121.
7. Guzman DS-M, Flammer K, Papich MG, Grooters AM, Shaw S, Applegate J, Tully TN. Pharmacokinetics of voriconazole after oral administration of single and multiple doses in Hispaniolan Amazon parrots (Amazona ventralis). Am J Vet Res. 2010;71(4):460–467.
8. Hyatt MW, Georoff TA, Nollens HH, Wells RL, Clauss TM, Ialeggio DM, Harms CA, Wack AN. Voriconazole toxicity in multiple penguin species. J Zoo Wildl Med. 2015;46(4):880–888.
9. Silvanose CD, Bailey TA, Di Somma A. Susceptibility of fungi isolated from the respiratory tract of falcons to amphotericin B, itraconazole and voriconazole. Vet Rec. 2006;159(9):282–284.
10. Hope WW. Population pharmacokinetics of voriconazole in adults. Antimicrob Agents Chemother. 2012;56(1):526–531.