Date of Award

2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Department

Pharmaceutical Sciences

First Advisor

David Taft

Second Advisor

Robert Bellantone

Committee Chair and Members

David Taft, Co-Chair

Robert Bellantone

Rutesh Dave

Kevin Sweeney

Keywords

Dosing interval, Nepafenac, Ophthalmology, PBPK, R, Suspension

Abstract

Nepafenac is a nonsteroidal anti-inflammatory drug (NSAID) for the treatment of inflammation associated with cataract surgery. It is marketed as two ophthalmic suspensions—NEVANAC® (0.1% administered three times a day) and ILEVRO® (0.3% administered once a day). The primary mediator of pain relief is amfenac, which is a metabolite of nepafenac. The primary goal of this project was to explain how was the dosing interval affected by changes in formulation properties. The approach incorporated three novel elements. 1) A physiologically based pharmacokinetic (PBPK) model that is specific to this application for nepafenac and amfenac was constructed, which allowed tracking the specific pharmacokinetics while minimizing the use of unnecessary compartments and variables. 2) A precorneal model was constructed to allow the modeling of interactions between formulations and the tear layer and other components on the ocular surface, which allowed assessing differences in formulation properties on the resulting pharmacokinetics. 3) A novel dissolution test (IVDT) was performed on NEVANAC® and ILEVRO® separately to determine the specific drug dissolution and distribution in each formulation and allow improved modeling of the in vivo nepafenac drug delivery. The model was written in the programming language “R” and was used for in silico simulations to assess the reasons for the dosing interval change in terms of formulation properties. This approach aligned with current FDA initiatives in quantitative modeling methods (QMM). This work facilitated explaining the dosing interval question, created increased knowledge of how to construct and evaluate ocular PBPK models, and contributed to advancing the art of ocular PBPK modeling.

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