Ocular Physiologically Based Pharmacokinetic Modeling for Ointment Formulations
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RESEARCH PAPER
Ocular Physiologically Based Pharmacokinetic Modeling for Ointment Formulations Maxime Le Merdy 1 Michael B. Bolger 1
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& Jessica Spires & Viera Lukacova & Ming-Liang Tan & Andrew Babiskin & Xiaoming Xu & Liang Zhao &
Received: 5 August 2020 / Accepted: 27 October 2020 # The Author(s) 2020
ABSTRACT Purpose 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. Methods A 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 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. Results Parameter sensitivity analysis was performed to understand the impact of ointment formulation changes on ocular exposure. 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. Conclusions 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.
* Maxime Le Merdy [email protected]
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Simulations Plus, Inc., 42505 10th Street West Lancaster, California 93534, USA
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Food and Drug Administration, CDER/OGD/ORS/DQMM, 10903 New Hampshire Avenue Silver Spring, Maryland 20993, USA
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Food and Drug Administration, CDER/OPQ/OTR/DPQR, 10903 New Hampshire Avenue Silver Spring, Maryland 20993, USA
KEY WORDS ocular PBPK . ophthalmic ointment . PBPK . product development
INTRODUCTION 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. 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. 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). 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
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