Population Pharmacokinetics of Single Dose Itraconazole in California Sea Lions (Zalophus californianus)
Fungal diseases are a major cause of morbidity and mortality in marine mammals. Numerous reports exist of fungal organisms causing infections in pinnipeds ranging from superficial dermatopathies to fatal systemic infections. Despite the prevalence fungal diseases, pharmacokinetic studies that investigate antifungal drugs in pinniped species are lacking. Itraconazole is a popular triazole antifungal that is considered a first line therapeutic in cases of systemic fungal disease. Its spectrum of activity includes Microsporum spp., Trichophyton spp., and Malassezia spp., which are often associated with dermatopathies, as well as Coccidioides spp., Blastomyces spp., and Cryptococcus spp., genera more commonly associated with systemic disease and all of which have been reported in pinnipeds.1,2,3,4,5,6 In pinnipeds, protocols for itraconazole are typically extrapolated from recommendations for domestic dogs or cats, which start at 5–10 mg/kg daily dose. In dogs, generic formulations of itraconazole have similar pharmacokinetic profiles as the name brand formulation and are more economical.7 Twenty healthy California sea lion pups that were rehabilitated at The Marine Mammal Center (Sausalito, California, USA) were included in this study prior to their release. Generic itraconazole capsules were administered orally with food at a target dose of 5–10 mg/kg. Blood samples were collected from the caudal gluteal vein of each animal at 0 hours and at 2 of the following time points: 0.5, 1, 2, 4, 6, 8, 12, 24, 48, and 72 hours. Quantitative analysis of itraconazole in plasma samples was performed by high-pressure liquid chromatography. An average maximum concentration of 0.22 µg/mL±0.11 was detected 4 hours after administration. The average concentration fell to 0.12 µg/mL±0.12 by 6 hours and 0.02 µg/mL±0.2 at 8 hours. At no point did concentrations reach 0.5 µg/mL, the concentration commonly accepted for therapeutic efficacy. While this formulation was well tolerated by the sea lions, oral absorption was poor and highly variable among individuals. These data indicate that a single 5–10 mg/kg oral dose of generic itraconazole is likely ineffective in California sea lions for treatment of infections caused by susceptible organisms. A higher dose or alternative formulation, such as itraconazole solution or name brand formulation may be necessary to achieve therapeutic concentrations.
The authors thank Carlos Rios and all of the medical technicians and volunteers of The Marine Mammal Center for their valuable contributions to this project, and Delta Dise for laboratory analysis of samples.
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