Ocular Physiologically Based Pharmacokinetic Modeling for Ointment Formulations

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.

Mechanistic modeling of ophthalmic, nasal, injectable, and implant generic drug products: A workshop summary report

“…The session provided an update on the current research efforts and status of using mechanistic models to support decision making for several areas of locally acting drug products. In the topical ophthalmic area, multiple ocular PBPK models have been developed in preclinical species where the focus was on the effect of formulation quality attributes on in vivo exposure and bioavailability 4,6–8 . For the nasal products, several hybrid CFD‐PBPK models have been developed where drug regional deposition was predicted by CFD models and local tissue and systemic distributions were predicted by PBPK models 10–16 .…”

“…In the topical ophthalmic area, multiple ocular PBPK models have been developed in preclinical species where the focus was on the effect of formulation quality attributes on in vivo exposure and bioavailability. 4,[6][7][8] For the nasal products, several hybrid CFD-PBPK models have been developed where drug regional deposition was predicted by CFD models and local tissue and systemic distributions were predicted by PBPK models. [10][11][12][13][14][15][16] In the complex injectable area, an in silico systems-based multiscale model integrated approach has been used to understand nanoparticle dispositions in the human body and the model is aimed to predict bioavailability in the target site (e.g., tumor tissue).…”

“…The model was then verified using literature PK data, with a focus on mean particle size and particle size distribution (PSD), nonlinear dose‐exposure relationship, formulation viscosity, and tear dynamics impact on ocular absorption 4,6 . For ophthalmic ointments, dexamethasone and fluorometholone ointment rabbit OCAT models were developed to understand the impact of ointment formulation changes on ocular exposure through an external research project (Simulations Plus HHSF223201810255P) 7 . For ophthalmic emulsions, a cyclosporine emulsion model was developed to study the impact of emulsion critical quality attributes (CQAs) on product performance 8 .…”

Clinical Ocular Exposure Extrapolation for Ophthalmic Solutions Using PBPK Modeling and Simulation

“…Starting in 2014, the FDA collaborated with Simulation Plus, Inc. to enhance and validate a state-of-the-art ocular PBPK model. As a result, the Ocular Compartmental Absorption and Transit (OCAT™) model within GastroPlus® had been expanded and validated for the simulation of ophthalmic suspensions and ointments in rabbit [ 1 , 14 , 15 ]. Since 2020, through grant 1U01FD006927-01, the Office of Generic Drugs in the FDA has collaborated with Simulation Plus, Inc. to further advance the ocular PBPK by expanding the existing knowledge base for ocular drug absorption and disposition.…”

Experimental Data and PBPK Modeling Quantify Antibody Interference in PEGylated Drug Carrier Delivery

“…PBPK models, coupled with the principle of allometric scaling, enable translations across species and populations (Huh et al 2011 ; Mordenti et al 1991 ; Ritschel et al 1992 ). Not surprisingly, PBPK models are broadly adopted in drug development and regulation (Jones and Rowland-Yeo 2013 ; Yuan et al 2019 ), including the prediction of drug-drug interactions (Stader et al 2021 ; Ueno et al 2021 ), dose adjustment in special populations (Lang et al 2020 ; Lutz et al 2021 ), bioequivalence assessment of complex drug formulations (Fan et al 2017 ; Le Merdy et al 2020 ), and many other mechanistic explorations (Cao and Jusko 2012 ; He et al 2018 , 2019 ; Nasu et al 2005 ; Walsh et al 2016 ).…”