Provided that about half of the currently marketed innovator ophthalmic drugs have at least one approved generic competitor and most are ophthalmic solutions ( 5), further research into the role of formulation physicochemical properties on ocular bioavailability is warranted and can be used to support product development and alternative BE approaches. For complex (i.e., non-solution) ophthalmic dosage forms, such as ointments, establishing BE without an in vivo study may be permissible if, in addition to the compositional similarity, the generic formulation demonstrates similar physicochemical properties to the RLD ( 4) otherwise, additional evidence of BE such as an in vivo study would be recommended. However, these in vivo clinical studies have inherent study design and sampling challenges that may limit the development of ophthalmic generic drugs ( 3). Different approaches, such as a combination of in vitro characterization studies, aqueous humor (AH) pharmacokinetic (PK) BE studies and/or comparative clinical endpoint BE studies have been recommended to demonstrate BE for ophthalmic products depending on the drug product’s active pharmaceutical ingredient (API), dosage form, indication, mechanism of action, and scientific understanding of drug release and disposition in the eye ( 2). In general, BE testing should use the most accurate, sensitive, and reproducible approach that is able to capture differences between the test and reference products in terms of drug concentrations at the site of action ( 1). The selection of the method depends upon the most current understanding of FDA in relation to the information collected by the study, the analytical methods available, and the nature of the drug product. The United States (US) Food and Drug Administration (FDA) may recommend in vivo and/or in vitro testing to establish the bioequivalence (BE) of ocular drug products with complex dosage forms.
This initial model for ointment ophthalmic formulations is a first step to better understand the interplay between physiological factors and ophthalmic formulation physicochemical properties and their impact on in vivo ocular drug pharmacokinetic performance in rabbits. While application time was found to have a significant impact on the time of maximal concentration in AH, both the application SA and the Higuchi release constant significantly influenced both the maximum concentration and the ocular exposure. Parameter sensitivity analysis was performed to understand the impact of ointment formulation changes on ocular exposure.
The model uses the following parameters: application surface area (SA), a fitted application time, and the fitted Higuchi release constant to characterize the rate of passage of the active pharmaceutical ingredient from the ointment formulations into the tears in vivo. MethodsĪ newly OCAT™ model developed for fluorometholone, as well as a previously verified model for dexamethasone, were used to characterize the aqueous humor (AH) concentration following the administration of multiple ointment formulations to rabbit. The purpose of this study is to show how the Ocular Compartmental Absorption & Transit (OCAT™) model in GastroPlus ® can be used to characterize ocular drug pharmacokinetic performance in rabbits for ointment formulations.
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