The purpose of this study was to develop a physiologically based pharmacokinetic (PBPK) model predicting the pharmacokinetics (PK) of different compounds in pregnant subjects. This model considers the differences in tissue sizes, blood flow rates, enzyme expression levels, glomerular filtration rates, plasma protein binding, and other factors affected during pregnancy in both the maternal and fetal models. The PBPKPlus™ module in GastroPlus® was used to model the PK of cefuroxime and cefazolin. For both compounds, the model was first validated against PK data in healthy non-pregnant volunteers and then applied to predict pregnant groups PK. The model accurately described the PK in both non-pregnant and pregnant groups and explained well differences in the plasma concentration due to pregnancy. The fetal plasma and amniotic fluid concentrations were also predicted reasonably well at different stages of pregnancy. This work describes the use of a PBPK approach for drug development and demonstrates the ability to predict differences in PK in pregnant subjects and fetal exposure for compounds excreted renally. The prediction for pregnant groups is also improved when the model is calibrated with postpartum or non-pregnant female group if such data are available.
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.
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