In vivo Rabbit Model for Rapid Pharmacokinetic and Tissue Distribution Assessment of Topical Linezolid Ophthalmic Formulations

Abstract

Abstract: : Purpose: We have developed and optimized a rapid in vivo screen for assessment of anterior eye tissue distribution and pharmacokinetics of topically administered drugs in albino rabbits. Acute bacterial conjunctivitis is a common eye infection that is becoming increasingly resistant to the currently marketed ophthalmic fluoroquinolones. Due to its potent gram-positive antibacterial activity, Linezolid was chosen as a model compound for the development and validation of a pharmacokinetic rabbit screen. Optimal dosing frequency requirements driven by physicians, their patients and public health initiatives require that MIC₉₀ drug concentration must be attained at one-half the dosing interval. Intraocular concentrations of linezolid after topical application have been determined to guide development of ophthalmic formulations with enhanced ocular exposure. Methods: Pharmacokinetic studies were performed in New Zealand rabbits to determine formulation-based differences in anterior ocular tissue penetration. Prior to testing, formulations were spiked with ¹⁴C-linezolid. New Zealand white rabbits received a single topical ocular dose administration of approximately 25 µL/eye. Anterior eye tissues (bulbar conjunctiva, cornea, aqueous humor, and tears) were collected at 0.5 to 4 hours post-dosing and tissue linezolid concentration determined by radioanalysis. Results: Results from theses studies indicate that it is possible to obtain adequate anterior ocular tissue drug levels for an appropriate time interval to effectively treat bacterial conjunctivitis, i.e., ≥ 4ug linezolid/gram tissue for 2 hours. Conclusions: This in vivo model allows for the rapid assessment of prototype topical ophthalmic formulations.

Keywords: antibiotics/antifungals/antiparasitics • anterior chamber • animal model