Application of Mechanistic Ocular Absorption Modeling and Simulation to Understand the Impact of Formulation Properties on Ophthalmic Bioavailability in Rabbits: a Case Study Using Dexamethasone Suspension
“…Secondly, increased retention of the particles on the ocular surface results in higher AUC in the aqueous humor, but this increase is also non-linear (about 4-fold increase in AUC, whereas the elimination rate constants vary over a 6-fold range). Previous simulations also suggest non-linear behavior of ophthalmic dexamethasone suspensions [26]. We do not know the absolute bioavailability of indomethacin in the aqueous humor because intracameral clearance of indomethacin is not known.…”
Eye drops of poorly soluble drugs are frequently formulated as suspensions. Bioavailability of suspended drug depends on the retention and dissolution of drug particles in the tear fluid, but these factors are still poorly understood. We investigated seven ocular indomethacin suspensions (experimental suspensions with two particle sizes and three viscosities, one commercial suspension) in physical and biological tests. The median particle size (d50) categories of the experimental suspensions were 0.37–1.33 and 3.12–3.50 µm and their viscosity levels were 1.3, 7.0, and 15 mPa·s. Smaller particle size facilitated ocular absorption of indomethacin to the aqueous humor of albino rabbits. In aqueous humor the AUC values of indomethacin suspensions with different particle sizes, but equal viscosity, differed over a 1.5 to 2.3-fold range. Higher viscosity increased ocular absorption 3.4–4.3-fold for the suspensions with similar particle sizes. Overall, the bioavailability range for the suspensions was about 8-fold. Instillation of larger particles resulted in higher tear fluid AUC values of total indomethacin (suspended and dissolved) as compared to application of smaller particles. Despite these tear fluid AUC values of total indomethacin, instillation of the larger particles resulted in smaller AUC levels of indomethacin in the aqueous humor. This suggests that the small particles yielded higher concentrations of dissolved indomethacin in the tear fluid, thereby leading to improved ocular bioavailability. This new conclusion was supported by ocular pharmacokinetic modeling. Both particle size and viscosity have a significant impact on drug concentrations in the tear fluid and ocular drug bioavailability from topical suspensions. Viscosity and particle size are the key players in the complex interplay of drug retention and dissolution in the tear fluid, thereby defining ocular drug absorption and bioequivalence of ocular suspensions.
“…Secondly, increased retention of the particles on the ocular surface results in higher AUC in the aqueous humor, but this increase is also non-linear (about 4-fold increase in AUC, whereas the elimination rate constants vary over a 6-fold range). Previous simulations also suggest non-linear behavior of ophthalmic dexamethasone suspensions [26]. We do not know the absolute bioavailability of indomethacin in the aqueous humor because intracameral clearance of indomethacin is not known.…”
Eye drops of poorly soluble drugs are frequently formulated as suspensions. Bioavailability of suspended drug depends on the retention and dissolution of drug particles in the tear fluid, but these factors are still poorly understood. We investigated seven ocular indomethacin suspensions (experimental suspensions with two particle sizes and three viscosities, one commercial suspension) in physical and biological tests. The median particle size (d50) categories of the experimental suspensions were 0.37–1.33 and 3.12–3.50 µm and their viscosity levels were 1.3, 7.0, and 15 mPa·s. Smaller particle size facilitated ocular absorption of indomethacin to the aqueous humor of albino rabbits. In aqueous humor the AUC values of indomethacin suspensions with different particle sizes, but equal viscosity, differed over a 1.5 to 2.3-fold range. Higher viscosity increased ocular absorption 3.4–4.3-fold for the suspensions with similar particle sizes. Overall, the bioavailability range for the suspensions was about 8-fold. Instillation of larger particles resulted in higher tear fluid AUC values of total indomethacin (suspended and dissolved) as compared to application of smaller particles. Despite these tear fluid AUC values of total indomethacin, instillation of the larger particles resulted in smaller AUC levels of indomethacin in the aqueous humor. This suggests that the small particles yielded higher concentrations of dissolved indomethacin in the tear fluid, thereby leading to improved ocular bioavailability. This new conclusion was supported by ocular pharmacokinetic modeling. Both particle size and viscosity have a significant impact on drug concentrations in the tear fluid and ocular drug bioavailability from topical suspensions. Viscosity and particle size are the key players in the complex interplay of drug retention and dissolution in the tear fluid, thereby defining ocular drug absorption and bioequivalence of ocular suspensions.
“…4 ). Therefore, we can conclude that an ocular PBPK model, previously validated for solution and suspension formulations ( 28 ), can be extended to ointment formulation to describe the ocular concentration following a single administration to the rabbit eye. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…The understanding of ocular absorption mechanism is necessary for both the pharmaceutical industries and the regulatory agencies to support the development and the evaluation of new and generic drug products. Previous work presented the development and validation of an OCAT™-PBPK model by investigating the impact of physiochemical properties of ophthalmic suspensions on in vivo ocular drug absorption and disposition ( 28 ). This study done in rabbits was a proof of concept of the benefit of in silico approaches for the development of ophthalmic drug product.…”
Section: Discussionmentioning
confidence: 99%
“…An ocular model of Dex was previously developed and verified ( 28 ). For this case study, all model parameters were unchanged.…”
Section: Methodsmentioning
confidence: 99%
“…However, most of these studies focused on drug distribution within only a limited number of ocular tissues and addressed only limited aspects of formulation behavior. An ocular PBPK and mechanistic absorption model was recently developed and validated for multiple formulations and characteristics of ophthalmic suspensions in rabbit, such as particle size, viscosity, and dose ( 28 ). To our knowledge, a mathematical PBPK model has not been developed for ointment formulation yet.…”
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.
Establishing bioequivalence (BE) for dermatological drug products by conducting comparative clinical end point studies can be costly and the studies may not be sufficiently sensitive to detect certain formulation differences. Quantitative methods and modeling, such as physiologically-based pharmacokinetic (PBPK) modeling, can support alternative BE approaches with reduced or no human testing. To enable PBPK modeling for regulatory decision making, models should be sufficiently verified and validated (V&V) for the intended purpose. This report illustrates the US
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