Dataset Information

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.

SUBMITTER: Le Merdy M

PROVIDER: S-EPMC7677276 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Publications

Ocular Physiologically Based Pharmacokinetic Modeling for Ointment Formulations.

Le Merdy Maxime M Spires Jessica J Lukacova Viera V Tan Ming-Liang ML Babiskin Andrew A Xu Xiaoming X Zhao Liang L Bolger Michael B MB

Pharmaceutical research 20201119 12

<h4>Purpose</h4>The purpose of this study is to show how the Ocular Compartmental Absorption & Transit (OCAT™) model in GastroPlus<sup>®</sup> can be used to characterize ocular drug pharmacokinetic performance in rabbits for ointment formulations.<h4>Methods</h4>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 t ...[more]

PMID: 33215336

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Project description:BackgroundModeling of pharmacokinetic parameters and pharmacodynamic actions requires knowledge of the arterial blood concentration. In most cases, experimental measurements are only available for a peripheral vein (usually antecubital) whose concentration may differ significantly from both arterial and central vein concentration.MethodsA physiologically based pharmacokinetic (PBPK) model for the tissues drained by the antecubital vein (referred to as "arm") is developed. It is assumed that the "arm" is composed of tissues with identical properties (partition coefficient, blood flow/gm) as the whole body tissues plus a new "tissue" representing skin arteriovenous shunts. The antecubital vein concentration depends on the following parameters: the fraction of "arm" blood flow contributed by muscle, skin, adipose, connective tissue and arteriovenous shunts, and the flow per gram of the arteriovenous shunt. The value of these parameters was investigated using simultaneous experimental measurements of arterial and antecubital concentrations for eight solutes: ethanol, thiopental, 99Tcm-diethylene triamine pentaacetate (DTPA), ketamine, D2O, acetone, methylene chloride and toluene. A new procedure is described that can be used to determine the arterial concentration for an arbitrary solute by deconvolution of the antecubital concentration. These procedures are implemented in PKQuest, a general PBPK program that is freely distributed http://www.pkquest.com.ResultsOne set of "standard arm" parameters provides an adequate description of the arterial/antecubital vein concentration for ethanol, DTPA, thiopental and ketamine. A significantly different set of "arm" parameters was required to describe the data for D2O, acetone, methylene chloride and toluene - probably because the "arm" is in a different physiological state.ConclusionsUsing the set of "standard arm" parameters, the antecubital vein concentration can be used to determine the whole body PBPK model parameters for an arbitrary solute without any additional adjustable parameters. Also, the antecubital vein concentration can be used to estimate the arterial concentration for an arbitrary input for solutes for which no arterial concentration data is available.

Dataset Information

Ocular Physiologically Based Pharmacokinetic Modeling for Ointment Formulations.

Purpose

Methods

Results

Conclusions

Publications

Ocular Physiologically Based Pharmacokinetic Modeling for Ointment Formulations.

Similar Datasets

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