Application of different pharmacokinetic models to describe and predict pharmacokinetics of voriconazole in magellanic penguins following oral administration

Abstract

Aspergillosis is a condition causing serious morbidity and mortality in captive penguins and other bird species. It can be treated with antifungal drugs, such as voriconazole. However, the pharmacokinetics of voriconazole are variable between different animal and bird species. Therefore, the pharmacokinetics of voriconazole were investigated in this study in Magellanic penguins. Pharmacokinetic models were constructed and applied to predict the pharmacokinetics of voriconazole during long-term treatment in Magellanic penguins, since the voriconazole treatment duration in chronic aspergillosis cases can last up to several months. Plasma voriconazole concentration-time data from adult Magellanic penguins (Spheniscus magellanicus; n = 15) following a single oral (PO) dose of either 2.5 mg/kg or 5 mg/kg in a herring in three separate study periods 7-12 months apart were collected. Mean plasma voriconazole concentrations were above the targeted MIC for Aspergillus fumigatus for 2 hr following a single 2.5 mg/kg voriconazole dose while the plasma concentrations exceeded the MIC for least 24 hr following a 5 mg/kg dose. Nonlinear mixed-effects modeling was used to fit two pharmacokinetic models, one with first-order and another with saturable elimination, to the single-dose data. Fits were good for both, as long as dose was included as a covariate for the first-order model so that clearance was lower and the half-life longer for animals receiving the 5 mg/kg dose. Although the single-dose data suggested saturated elimination at higher concentrations, the model with saturable elimination did not predict plasma voriconazole concentrations well for a clinical aspergillosis case receiving long-term treatment, possibly because of induction of metabolizing enzymes with chronic exposure. Pharmacokinetic models should accurately predict plasma drug concentrations for different dosage regimens in order to be applicable in the field. Future studies should focus on determining clearance at steady-state to be able to refine the pharmacokinetic models presented here and improve model performance for long-term oral voriconazole administration in Magellanic penguins.

Pharmacokinetics in Penguins Compared to Other Avian Species: A Review of Enrofloxacin and Voriconazole

“…The possibility of different genes in these two species of penguin is supported by findings by Almeida et al An evolutionary phylogeny of the loss/gain of CYP2 subfamilies shows that the CYP2C subfamily has been lost in the Adelie penguin species but has remained in the emperor penguin . In agreement with Parsley et al, given the differences identified between Adelie and emperor penguin species, the possibility that Magellanic penguins lack or express specific CYP enzymes to a different extent should not be excluded. The results presented here may suggest that the CYP2C subfamily has been lost or has reduced expression in the Magellanic penguins but has remained in the African penguins.…”

“…When drugs are given orally to birds, they can be given as the tablet or capsule directly into the esophagus of the bird or, more commonly, can be included in a solution formulation that the bird either drinks or is given in a syringe. For fisheating birds such as penguins, it is also common that a drug suspension is incorporated into a fish (e.g., herring) that is then fed to the bird (e.g., Parsley et al 43 ). When a liquid is prepared extemporaneously for a bird, it is often mixed with water and a commercial suspending agent to make a suspension.…”

“…The AUC in Magellanic penguins after a 5 mg/kg dose of voriconazole is 7 times higher than the AUC after a 2.5 mg/ kg dose, although it is noted that the pharmacokinetic study was conducted over 96 h for the 5 mg/kg dose compared to 24 h for the 2.5 mg/kg dose. 43 According to Lin, 50 a greater than proportional increase in AUC is most likely due to a decrease in elimination of the drug as opposed to an increase in absorption. In the case of voriconazole, a decrease in elimination with an increase in dose and therefore a higher AUC could be the result of saturation of metabolic clearance.…”

“…The study by Parsley et al 43 on voriconazole dosing in Magellanic penguins highlights the challenges of working with wildlife when there is little existing data to guide the design of PK studies. In their study, Parsley et al report a T 1/2 for the high dose (5 mg/kg) of 33.71 h (Table S1), and this was estimated based on the longer sampling time of 96 h. This differs from the T 1/2 reported for the lower 2.5 mg/kg dose of voriconazole of 7.26 h that was estimated from sampling over 24 h. This difference in sample time collection is a potential limitation because the difference in sampling time may have biased the estimates of PK parameters.…”

“…For penguins specifically, there is some evidence that the pharmacokinetics of voriconazole may be dose-dependent. The AUC in Magellanic penguins after a 5 mg/kg dose of voriconazole is 7 times higher than the AUC after a 2.5 mg/kg dose, although it is noted that the pharmacokinetic study was conducted over 96 h for the 5 mg/kg dose compared to 24 h for the 2.5 mg/kg dose . According to Lin, a greater than proportional increase in AUC is most likely due to a decrease in elimination of the drug as opposed to an increase in absorption.…”