Interspecies comparison of the oral absorption of itraconazole in laboratory animals

Yoo, Sun Dong; Kang, Eun-Hee; Shin, Beom Soo; Jun, Hun; Lee, Sang‐Heon; Lee, Kang Choon; Lee, Kyuhyun

doi:10.1007/bf02976644

Cited by 21 publications

(14 citation statements)

References 12 publications

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“…The mean terminal half‐life of itraconazole in the dog is 28.0 ± 2.9 hours 16. Ordinarily, a minimum washout period between crossover studies is 7 half‐lives, which allows for >99% of the drug to be eliminated.…”

Section: Discussionmentioning

confidence: 99%

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Bioequivalence of Orally Administered Generic, Compounded, and Innovator‐Formulated Itraconazole in Healthy Dogs

Mawby

Whittemore

Genger

et al. 2013

Veterinary Internal Medicne

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BackgroundItraconazole is commonly used to treat systemic fungal infections in dogs, but problems exist with absorption and cost.ObjectiveTo determine oral bioequivalence of generic and compounded itraconazole compared to original innovator (brand name) itraconazole in healthy dogs.AnimalsNine healthy, adult research Beagle dogs.MethodsA 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 (CMAX), and terminal half‐life. Bioequivalence tests compared generic and compounded itraconazole to the reference formulation.ResultsAverage ratios of compounded and generic formulations to the reference formulation of itraconazole for AUC were 5.52% and 104.2%, respectively, and for CMAX 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 ImportanceNeither 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.

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Section: Discussionmentioning

confidence: 99%

“…The mean terminal half-life of itraconazole in the dog is 28.0 AE 2.9 hours. 16 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.…”

Section: Discussionmentioning

confidence: 99%

Bioequivalence of Orally Administered Generic, Compounded, and Innovator‐Formulated Itraconazole in Healthy Dogs

Mawby

Whittemore

Genger

et al. 2013

Veterinary Internal Medicne

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“…The pharmacokinetics of T max and T 1/2 for dogs receiving oral administration of itraconazole was reported to be the most similar to those for humans in comparison with rats and rabbits (Wlaker et al, 1999;Yoo et al, 2002). The pharmacokinetics of T max and T 1/2 for dogs receiving oral administration of itraconazole was reported to be the most similar to those for humans in comparison with rats and rabbits (Wlaker et al, 1999;Yoo et al, 2002).…”

Section: Discussionmentioning

confidence: 94%

Effects of Combined Treatment with Sildenafil and Itraconazole on the Cardiovascular System in Telemetered Conscious Dogs

Kim

Seo

Hwang

et al. 2005

Drug and Chemical Toxicology

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Sildenafil, a potent PDE5 inhibitor, is widely prescribed as a treatment of erectile dysfunction. Itraconazole is an inhibitor of CYP3A4, a metabolic enzyme of sildenafil. In the current study, we investigated the effects of single treatment with sildenafil and combined treatment with sildenafil and itraconazole on blood pressure, heart rate, and QT interval in conscious beagle dogs. After a transmitter was implanted to beagle dogs for conscious state experiments, a single oral dose of sildenafil was administered to the beagle dogs at dose levels of 3, 15, and 30 mg/kg. Blood pressure, heart rate, and lead II ECG were measured prior to dosing and at 0.5, 1, 2, 4, 6, and 24 h postdosing. In the study of combined treatment with sildenafil and itraconazole, the 100 mg/kg dose of itraconazole was orally administered 1 h prior to oral administration of sildenafil. No changes in blood pressure were observed at any doses in animals receiving either single treatment with sildenafil or combined treatment with sildenafil and itraconazole. Increased heart rate from 0.5 h to 6 h postdosing and decreased QT interval were observed in animals receiving single treatment with sildenafil at 15 or 30 mg/kg. When 30 mg/kg of sildenafil was coadministered with 100 mg/kg of itraconazole, drug-related effects such as increased heart rate and decreased QT interval were significantly enhanced as compared to sildenafil-alone administration at 6 h postadministration. These results demonstrated that increased heart rate and decreased QT interval, the adverse effects of sildenafil, were enhanced and prolonged when sildenafil was coadministered with itraconazole. Therefore, caution should be taken when sildenafil is coadministered with itraconazole, a CYP3A4 inhibitor, or when administered to elderly patients or patients with hepatic or renal impairment who cannot metabolize and excrete sildenafil normally.

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“…The blood kinetics of itraconazole following oral administration was studied in Sprague-Dawley rats, New Zealand white rabbits, and beagle dogs (Yoo et al, 2002). The half-life of the parent compound was similar in the rat (5.2 hours) and the rabbit (9.4 hours), but considerably longer (28 hours) in the dog.…”

Section: Example N Species Differences In Blood Kinetics (Itraconazole)mentioning

confidence: 99%

The Acquisition and Application of Absorption, Distribution, Metabolism, and Excretion (ADME) Data in Agricultural Chemical Safety Assessments

Barton

Pastoor

Baetcke

et al. 2006

Critical Reviews in Toxicology

128

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A proposal has been developed by the Agricultural Chemical Safety Assessment (ACSA) Technical Committee of the ILSI Health and Environmental Sciences Institute (HESI) for an improved approach to assessing the safety of crop protection chemicals. The goal is to ensure that studies are scientifically appropriate and necessary without being redundant, and that tests emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. Incorporation of pharmacokinetic studies describing absorption, distribution, metabolism, and excretion is an essential tool for improving the design and interpretation of toxicity studies and their application for safety assessment. A tiered approach is described in which basic pharmacokinetic studies, similar to those for pharmaceuticals, are conducted for regulatory submission. Subsequent tiers provide additional information in an iterative manner, depending on pharmacokinetic properties, toxicity study results, and the intended uses of the compound.

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Interspecies comparison of the oral absorption of itraconazole in laboratory animals

Cited by 21 publications

References 12 publications

Bioequivalence of Orally Administered Generic, Compounded, and Innovator‐Formulated Itraconazole in Healthy Dogs

Bioequivalence of Orally Administered Generic, Compounded, and Innovator‐Formulated Itraconazole in Healthy Dogs

Effects of Combined Treatment with Sildenafil and Itraconazole on the Cardiovascular System in Telemetered Conscious Dogs

The Acquisition and Application of Absorption, Distribution, Metabolism, and Excretion (ADME) Data in Agricultural Chemical Safety Assessments

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