Dataset Information

Bioequivalence of orally administered generic, compounded, and innovator-formulated itraconazole in healthy dogs.

ABSTRACT:

Background

Itraconazole is commonly used to treat systemic fungal infections in dogs, but problems exist with absorption and cost.

Objective

To determine oral bioequivalence of generic and compounded itraconazole compared to original innovator (brand name) itraconazole in healthy dogs.

Animals

Nine healthy, adult research Beagle dogs.

Methods

A randomized, 3-way, 3-period, crossover design with an 8-day washout period. After a 12-hour fast, each dog received 100 mg (average: 10.5 mg/kg) of either innovator itraconazole, an approved human generic capsule, or compounded itraconazole (compounded using a commercially available compounding vehicle) with a small meal. Plasma was collected at predetermined intervals for high pressure liquid chromatography analysis. Concentration data were analyzed using noncompartmental pharmacokinetics to determine area under the curve (AUC), peak concentration (C(MAX)), and terminal half-life. Bioequivalence tests compared generic and compounded itraconazole to the reference formulation.

Results

Average ratios of compounded and generic formulations to the reference formulation of itraconazole for AUC were 5.52% and 104.2%, respectively, and for C(MAX) were 4.14% and 86.34%, respectively. A test of bioequivalence using 2 one-sided tests and 90% confidence intervals did not meet bioequivalence criteria for either formulation.

Conclusion and clinical importance

Neither generic nor compounded itraconazole is bioequivalent to the reference formulation in dogs. However, pharmacokinetic data for generic formulation were similar enough that therapeutic concentrations could be achieved. Compounded itraconazole produced such low plasma concentrations, it is unlikely to be effective; therefore, compounded itraconazole should not be used in dogs.

SUBMITTER: Mawby DI

PROVIDER: S-EPMC4895533 | biostudies-literature | 2014 Jan-Feb

REPOSITORIES: biostudies-literature

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Publications

Bioequivalence of orally administered generic, compounded, and innovator-formulated itraconazole in healthy dogs.

Mawby D I DI Whittemore J C JC Genger S S Papich M G MG

Journal of veterinary internal medicine 20131101 1

<h4>Background</h4>Itraconazole is commonly used to treat systemic fungal infections in dogs, but problems exist with absorption and cost.<h4>Objective</h4>To determine oral bioequivalence of generic and compounded itraconazole compared to original innovator (brand name) itraconazole in healthy dogs.<h4>Animals</h4>Nine healthy, adult research Beagle dogs.<h4>Methods</h4>A randomized, 3-way, 3-period, crossover design with an 8-day washout period. After a 12-hour fast, each dog received 100 mg ( ...[more]

PMID: 24428315

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Project description:Super bioavailability (SUBA) itraconazole (S-ITZ), which releases drug in the duodenum, and conventional itraconazole (C-ITZ), which releases drug in the stomach, were compared in two pharmacokinetic (PK) studies: a 3-day loading dose study and a 15-day steady-state administration study. These were crossover oral bioequivalence studies performed under fed conditions in healthy adult volunteers. In the loading dose study, C-ITZ (two doses of 100?mg each) and S-ITZ (two doses of 65?mg each) were administered three times daily for 3?days and once on day 4 (n?=?15). For the steady-state administration study, C-ITZ (two doses of 100?mg each) and S-ITZ (two doses of 65?mg each) were administered twice daily for 14?days and a last dose was administered 30?min after a meal on day 15 (n?=?16). Blood samples collected throughout both studies were analyzed for ITZ and hydroxy-ITZ (OH-ITZ) levels. Least-squares geometric means were used to compare the maximum peak concentration of drug after administration at steady state prior to administration of the subsequent dose (C max_ss), the minimum drug level after administration prior to the subsequent dose (C trough), and the area under the curve over the dosing interval (AUCtau) of each formulation. The ratios of itraconazole (ITZ) and OH-ITZ for S-ITZ to C-ITZ were between 107% and 118% in both studies for C max_ss, C trough, and AUCtau, which were within the U.S. FDA-required bioequivalence range of 80% to 125%. At the end of the steady-state administration study, 13 of 16 volunteers obtained higher mean ITZ blood C trough levels of >1,000?ng/ml when they were administered S-ITZ (81%) than when they were administered C-ITZ (44%). The study drugs were well tolerated in both studies, with similar adverse events (AEs). All treatment-emergent AEs resolved after study completion. One volunteer receiving C-ITZ discontinued due to a treatment-unrelated AE in the steady-state administration study. No serious AEs were reported. Total, trough, and peak ITZ and OH-ITZ exposures were similar between the two formulations. Therefore, SUBA-ITZ, which has 35% less drug than C-ITZ, was bioequivalent to C-ITZ in healthy adult volunteers and exhibited a safety profile similar to that of C-ITZ.

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Dataset Information

Bioequivalence of orally administered generic, compounded, and innovator-formulated itraconazole in healthy dogs.

Background

Objective

Animals

Methods

Results

Conclusion and clinical importance

Publications

Bioequivalence of orally administered generic, compounded, and innovator-formulated itraconazole in healthy dogs.

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