Cassette Dosing Pharmacokinetic Studies for Evaluation of Ophthalmic Drugs for Posterior Ocular Diseases

• Published in: Journal of pharmaceutical sciences Vol. 97; no. 8; pp. 3411 - 3421
• Main Authors: Proksch, Joel W., Ward, Keith W.
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.08.2008; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: Animals; Biological and medical sciences; choroid; Chromatography, Liquid; distribution; eye; General pharmacology; Medical sciences; ocular pharmacokinetics; Pharmaceutical Preparations - administration & dosage; Pharmaceutical technology. Pharmaceutical industry; Pharmacokinetics; Pharmacology. Drug treatments; preclinical pharmacokinetics; Rabbits; retina; Retina - metabolism; site-specific absorption; site-specific delivery; Tandem Mass Spectrometry; tissue partition; vitreous humor; site-specific absorption; eye; choroid; ocular pharmacokinetics; retina; site-specific delivery; tissue partition; vitreous humor; distribution; preclinical pharmacokinetics; Drug; Site; Evaluation; Partition; Pharmaceutical technology; Preclinical trial; Eye; Tissue; Target; Eye disease; Absorption; Distribution; Pharmacokinetics
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.21188

The purpose of this investigation was to evaluate the utility of cassette dosing as a means for increasing throughput and decreasing animal usage for intravitreal ocular pharmacokinetic studies. Pigmented rabbits received a single intravitreal injection of test article containing either a single compound or a mixture of up to five compounds. Samples of vitreous, choroid and retina were collected at predetermined intervals through 7 or 28 days after dosing. Concentrations of each compound were determined by LC/MS/MS, with subsequent pharmacokinetic data analysis. The ocular pharmacokinetic properties of four test compounds administered as a cassette were in agreement with the ocular pharmacokinetics of each compound when administered as a single entity. Cassette dosing was subsequently used to screen an additional 15 compounds, with injection of 5 compounds per study. Based on the results from these cassette-dosing studies, some compounds demonstrated favorable ocular pharmacokinetics, with sustained concentrations above 300 ng/g in retina for at least 1 week after dosing while other compounds showed either considerably less penetration into retina or a shorter residence time in the retina. These findings suggest that the cassette dosing approach can be used in evaluating the intravitreal ocular pharmacokinetic properties of compounds intended for ocular use.