2004 Resident/Graduate Student Pharmacology Research Award Abstract

The Pharmacokinetics of itraconazole in the horse.  Jennifer L. Davis , Brian C. Gilger, Mark G. Papich.  North Carolina State University, College of Veterinary Medicine, Raleigh, NC.

   Itraconazole is an oral triazole antifungal drug used for the treatment of infections caused by Aspergillus sp., Histoplasma sp., and Blastomyces sp. in humans and animals.   Itraconazole is extremely lipophilic and has a very high affinity for tissues, including lung, kidney, brain, skin and esophageal tissue, with concentrations often higher in the tissue than in plasma.  Fungal infections can be difficult to treat and often have devastating consequences.  Very few systemic antifungal drugs have been studied in the horse, so treatment options are limited.  Itraconazole at a dose of 3 mg/kg orally, twice a day has been recommended for the treatment of fungal diseases in horses, however no pharmacokinetic data is available.  The purpose of this study is to test the hypothesis that itraconazole will be absorbed after oral administration in horses and exhibit a long half-life to allow for intermittent dosing to produce therapeutic concentrations for the treatment of fungal diseases. 

   Horses were given itraconazole capsules (Sporanox, Janssen Pharmaceuticals, Inc.) by mouth at 3 mg/kg twice a day for 5 days, or 5 mg/kg once.  Plasma samples were collected at 0, 30, and 60 minutes and 2, 4, 8, 12, and 24 hours following the last dose administered.  Concentrations of itraconazole and its active metabolite, hydroxy-itraconazole in the plasma were determined by reverse-phase high performance liquid chromatography (HPLC) with solid-phase extraction using an assay developed in our laboratory.  The assay was linear for itraconazole and hydroxy-itraconazole at concentrations between 0.02 and 10 μg/mL in plasma.  Plasma protein binding of itraconazole and hydroxy-itraconazole was determined using an in vitro microcentrifugation technique (CentrifreeT Micropartition system, Amicon).  Pharmacokinetic parameters were determined using a one-compartment model (WinNonlin, Version 4.0, Pharsight).

  Following multiple oral doses of 3 mg/kg, itraconazole exhibited a slow absorption phase (Tmax = 2.6 hr), a maximum plasma concentration of 0.16 μg/mL, and a long elimination half-life (T1/2 = 32 hr).  Following a single oral dose of 5 mg/kg, itraconazole showed similar pharmacokinetic properties.  Hydroxy-itraconazole was not detected in any plasma samples.  Plasma protein binding of itraconazole and hydroxy-itraconazole were >99% and >93%, respectively.  No adverse affects were noted following administration of the drug.

   The results of this study indicate that itraconazole is absorbed following oral administration in the horse.  Furthermore, its pharmacokinetic properties, such as a long half-life may make it possible to use intermittent pulse dosing, which will make treatment convenient and affordable.  This drug is safe for use in horses at a dose of 5 mg/kg orally, once daily, with no detectable side effects.