Dosing and therapeutic drug monitoring of voriconazole in bottlenose dolphins (Tursiops truncatus)

Abstract

Bottlenose dolphins (Tursiops truncatus) can suffer from fungal infections, which can be treated with voriconazole. In common practice, the voriconazole doses are extrapolated from human doses by adjusting for body weight only, because no dose regimen is available yet. Therefore, the aim of this study was to define a dose regimen for voriconazole in bottlenose dolphins. Dolphins treated with voriconazole between November 2005 and September 2015 at the Dolfinarium Harderwijk, the Netherlands, and TDM was performed were included. Voriconazole plasma concentrations were analyzed with a HPLC-UV method. A population pharmacokinetic model was developed using Mw/Pharm in which the elimination rate constant (ke) and apparent total distribution volume (Vd) was calculated. The loading dose was calculated using the central Vd (Vdc). The maintenance dose was simulated in Mw/Pharm using ke and total Vd.Eleven dolphins were included. Ke was estimated to be 0.0026 ± 0.0007 hour(-1) (mean ± SD), Vd 5.3 ± 3.2 l/kg (mean ± SD), and Vdc ranged between 1.8 and 2.8 l/kg (mean 2.2 l/kg). In order to obtain a median top plasma concentration of 5 mg/l, the loading dose was calculated to be 10 mg/kg (range 9.0-14.2 mg/kg) divided in three administrations (3.3 mg/kg every 24 hours). The maintenance dose was calculated to be 4 mg/kg once a week (range 1.7-6.0 mg/kg); 17% of the dolphins did not reach the therapeutic window of 1-5 mg/l without TDM. A TDM-guided dosing algorithm was developed in order to obtain therapeutic plasma concentrations in this population.