Fungal infections of dogs are common in the southeastern United States, with blastomycosis and histoplasmosis being the most commonly recognized systemic diseases. Itraconazole is one of the drugs used for their treatment. The original innovator itraconazole1 was first introduced onto the market in 1992 as an oral capsule; it is also now available in an oral liquid formulation. Itraconazole is highly lipophilic and practically insoluble in water. Absorption of oral itraconazole capsules is variable because the drug requires an acidic environment for dissolution; administration with a meal is suggested to further aid in bioavailability. To verify adequate dosage or overdose, plasma itraconazole concentrations can be measured; however, this is not usually carried out.
In dogs infected with blastomycosis, a 74% response rate occurs when treating with 5 mg/kg/d of the original innovator formulation of itraconazole. Blastomycosis requires a minimum of 60 days' treatment; and treatment is usually continued for 30 days beyond resolution of clinical signs. Unfortunately, the original formulation can be cost prohibitive for owners, especially those with large-breed dogs that need extended treatment. Recently, approved human generic oral formulations of itraconazole became available. Itraconazole has also been compounded for veterinary patients by pharmacists using bulk itraconazole powder, but use of compounded formulations is not recommended[2, 3] because their pharmacokinetics are unknown. Treatment failures can occur, in which case the innovator formulation might need to be used for successful treatment (authors' anecdotal observations).
According to the US Food and Drug Administration (FDA), compounding of a drug is acceptable when there is a need for a different concentration or a more palatable oral formulation, such as for small animals. Under the Animal Medical Drug Clarification Act (AMDUCA), compounding is legal if conditions listed in the AMDUCA extralabel drug use regulations are followed. The US Pharmacopeial Convention lists precise requirements for compounding nonsterile dosage formulations, and compounded products must be made from commercial sources of drug rather than bulk drugs, which are defined as active ingredients used in the manufacture of finished dosage forms.
The purpose of this study was to determine the bioequivalence of 3 formulations of itraconazole in healthy dogs. For our comparison, we used a descriptive analysis of the oral pharmacokinetic parameters derived from each formulation: original innovator capsules, generic capsules,2 and compounded capsules.3 In addition, we performed bioequivalence analysis using the tests accepted by the FDA. Bioequivalence tests examine the average ratios of each test formulation to the reference formulation for 2 critical pharmacokinetic parameters: area under the plasma concentration versus time curve (AUC) and peak concentration (CMAX).
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Lack of bioequivalence was found for generic and compounded itraconazole in comparison with the reference formulation in this study. The average AUC for the generic formulation was higher, the half-life similar, and CMAX only slightly lower than for the reference standard. Although the generic formulation did not meet the statistical criteria to claim bioequivalence to the brand name product, the absolute ratio of generic formulation to brand name formulation was higher for AUC with a value of 104.2%. In contrast, the compounded formulation of itraconazole had very low absorption and bioavailability.
The most likely reason for the lack of statistical bioequivalence between the generic and brand name products is low statistical power. Posthoc calculations revealed the power of the test was only 0.25 and 0.26 for AUC and CMAX, respectively (Table 4). The 2 most common reasons for underpowered tests are high interindividual variability and low numbers of subjects in a study. High interindividual variability in this study, as evidenced by the high coefficients of variation for measured parameters, is the likely cause of poor power. It is likely that bioequivalence could have been demonstrated for the generic product if a larger number of subjects had been used.
High interindividual variability, because of drug insolubility and variable metabolism among dogs, is an inherent problem with itraconazole administration. Itraconazole is a highly lipophilic but poorly soluble (Biopharmaceutics Classification System Class II) drug. It must dissolve in the gastrointestinal tract to be absorbed, which is difficult to accomplish. Once dissolved, however, it is highly permeable and will easily diffuse across the intestinal epithelium. The original innovator, itraconazole is formulated with specially designed sugar spheres coated with the drug in the capsule to increase surface area and solubility of the drug. The absorption of this formulation of itraconazole is also improved with a low gastric pH and the presence of food, though feeding induces high variability in gastric emptying time in dogs. For these reasons, the absorption of itraconazole capsules in dogs is variable, as was observed in this study.
Generic itraconazole, available as capsules, has been approved for use in people and has been commercially available since 2004. There are 3 companies that supply generic capsules. The product we selected for this study was manufactured by the parent company of the original innovator formulation of itraconazole. It is not known whether results of this study would be applicable to the other 2 formulations of generic itraconazole. Based on the results of this study, use of this generic form of itraconazole in dogs with systemic fungal infections could produce equivalent therapeutic results while substantially decreasing treatment costs. Clinicians should be wary that the generic and innovator itraconazole are not interchangeable, and treatment failure remains possible. Clinicians can have blood samples tested to ensure that adequate plasma concentrations are attained, but therapeutic plasma itraconazole concentrations have not been established for dogs. In people, trough serum itraconazole concentrations of at least 0.5–1.0 μg/mL, measured by HPLC, have been associated with therapeutic success. If a bioassay method is used to measure itraconazole concentrations, the values in people are 3.3 times higher than those obtained by HPLC because of presence of the bioactive metabolite hydroxyitraconazole.
There are no reported bioequivalence studies for compounded itraconazole, to the authors' knowledge. Regardless, compounding pharmacies promote their use for animals, and veterinarians and pet owners trust that they will be therapeutically equivalent to the brand name product. Veterinarians must be cognizant of the limitations of compounding medications. Compounding from bulk chemicals can produce a product that is much inferior to an original or generic formulation. In addition, compounding veterinary itraconazole from a bulk powder is prohibited by federal regulations. Very low absorption and bioinequivalence of compounded itraconazole were demonstrated in this study. The most likely reason is that the compounded formulation does not facilitate dissolution and thus absorption of the drug. The bulk form of itraconazole is a powder and does not contain any excipients or other formulation properties to improve oral absorption. Without modifications, this powder will not dissolve in water-based liquids, such as those found in the stomach. Also, itraconazole can adsorb to glassware or plastics used during compounding, thus decreasing the potency of the product. The compounded product used in this study produced AUC and CMAX concentrations in dogs that were approximately 5% of the innovator product. Because of the poor performance of the compounded formulation, it should not be used as a substitute for brand name or generic itraconazole formulations.
The mean terminal half-life of itraconazole in the dog is 28.0 ± 2.9 hours. Ordinarily, a minimum washout period between crossover studies is 7 half-lives, which allows for >99% of the drug to be eliminated. The reported half-life corresponds to a washout period of 7.6 days; therefore, this study used a washout of 8 days. Because very low, but detectable, itraconazole concentrations were observed in some dogs in samples collected at the zero time point, a longer washout period would have been desirable. Another limitation of the study is that samples were not collected long enough for a complete delineation of the AUC. The AUC left to be extrapolated beyond the last measured time point was very high (approximately 30% for generic and 40% for compounded itraconazole). This limitation could have been avoided if samples had been collected for a longer period of time and if there were more samples.
In conclusion, this study validates the recommendation against the use of compounded itraconazole for treatment of systemic fungal infections in dogs. The generic itraconazole used in this study was not bioequivalent to the original innovator itraconazole, but it could be considered for use in fungal infection because of the favorable oral pharmacokinetics observed with the added benefit of a lower cost.