How well are compounded itraconazole formulations absorbed in healthy cats?

In today’s VETgirl online veterinary continuing education podcast, we review the use of compounded itraconazole in cats – can you use it?

If one of your feline patients was just diagnosed with ringworm, pay attention. What medication are you going to reach for?

Out of the available antifungals, itraconazole is a preferred antifungal in cats due its lower incidence of gastrointestinal side effects. Vomiting, diarrhea, and lack of appetite can occur from any of the systemically absorbed antifungal medications, but thankfully, itraconazole is a bit more tolerable to our feline friends. Unfortunately, the cost of this medication can be a limiting factor for owners. To help ease the financial burden, some veterinarians have this medication compounded by licensed veterinary compounding pharmacies. They use bulk stores of the chemical to compound itraconazole into either a capsule formulation or an oral suspension. When using compounded medications, veterinarians must consider whether the compounded product will be as effective as the available reference formulation. Problems arise with compounded medications regarding quality of the chemicals used, and the bioavailability of the final product.

So, Mawby et al wanted to evaluate how well two known reference formulations of itraconazole were absorbed. According to these authors, researchers have already identified problems with the bioavailability of compounded itraconazole in dogs and in birds, so they focused this study on testing the bioavailability of compounded itraconazole in cats as compared to 2 known reference formulations.

In a randomized, crossover design, prospective study, 8 healthy, fasted research cats were used in this study and each cat received 50 mg of itraconazole in all four formulations of itraconazole with a 21-day wash out period between formulations. The four formulations of itraconazole evaluated included Sporanox capsules (100 mg capsules that were repackaged at the University of Tennessee College of Veterinary Medicine pharmacy into 50-mg capsules), Sporanox solution (10 mg/mL), and an itraconazole powder was utilized to make a compounded capsule and a compounded liquid formulation by a licensed veterinary compounding pharmacist. (NOTE: The itraconazole powder used for compounding was “authenticated with a certificate of analysis”). When cats received either of the liquid formulations, they had nasoesophageal feeding tubes placed to ensure that the entire dose was delivered. When the cats received the capsule formulation, they were administered a small meal to help increase bioavailability via increased stomach acidity per drug recommendations. All cats also had jugular or femoral catheters placed for venipuncture purposes.

Blood samples were taken for itraconazole analysis (at NCSU Clinical Pharmacology Laboratory) at times 0, 1, 2, 4, 8, 12, 24, 36, 48, 72, 84, 96 and 120 hours), and analyzed by high-pressure liquid chromatography. Plasma drug concentrations were then analyzed for pharmacokinetic analysis using complex-over-VETgirl’s-head-formulas-using-pharmacokinetic software to evaluate area under the curve (AUC) and peak concentration (CMAX). In the end, one cat was excluded in the study due to temperament, leaving data for 5 cats in the compounded suspension group and 6 cats in all the other treatment groups.

So, what’d they find in this study? Results from this study showed unacceptably low absorption of either compounded itraconazole formulations as compared to the reference formulations of itraconazole. The compounded itraconazole suspension achieved only 2% of the bioavailability of the reference formulation. The compounded itraconazole capsule achieved only 8% of the bioavailability of the reference formulation. This is similar to previous studies (2) that evaluated compounded itraconazole formulations in healthy dogs, where AUC and CMAX values were only 5% for compounded products compared to reference formulations. In this feline study, the suspension reference formulation outperformed the reference capsule formulation in bioavailability, which lead the authors to create differing dosing recommendations for the Sporanox capsules versus the Sporanox suspension.

So, what do we take away from this VETgirl podcast? This study aimed to provide us with dose recommendations for all four formulations. However, since bioavailability of both compounded itraconazole formulations were so poor, this study instead recommends not to use compounded itraconazole at all.

We do not know the clinically effective serum concentrations of itraconazole in cats so our current guidelines are to mimic what we achieve in human medicine. Based on a target human trough itraconazole level of ≥ 0.5 to 1.0 μg/mL, these authors recommend a 12.5 mg/kg dose of the reference capsule itraconazole (to be given with a meal), or 4 mg/kg of the reference suspension itraconazole (to be given on an empty stomach). This lower dose with the reference suspension was used based on the absorption being markedly higher as compared to the reference capsules.

Most importantly, your takeaway is PLEASE don’t compound itraconazole. Instead, use the now FDA-approved oral intraconazole solution (Itrafungol, made by Elanco), for the treatment of dermatophytosis instead.

Abbreviations:
NE = Nasoesophageal

References:
1. Mawby DI, Whittemore JC, Fowler LE, Papich MG. Comparison of absorption characteristics of oral reference and compounded itraconazole formulations in healthy cats. J Am Vet Med Assoc 2018;252(2):195-200.

2. Mawby DI, Whittemore JC, Genger S, et al. Bioequivalence of orally administered generic, compounded, and innovator-formulated itraconazole in healthy dogs. J Vet Intern Med 2014;28:72-77.

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