Abstract
Purpose :
The development of generic ophthalmic drug products is challenging due to the complexity of the ocular system, difficulties with clinical measurements of drug concentrations at the site of action, and a lack of sensitive testing to evaluate the interplay of physiology with ophthalmic formulations. The rabbit eye physiology is comparable to human eye physiology and is commonly used as a preclinical model to investigate the impact of formulation changes on the ocular exposure of an Active Pharmaceutical Ingredient (API). The purpose of this study is to demonstrate the utility of an ocular physiologically based pharmacokinetic (PBPK) model for translation of ocular exposure from rabbit to human. Ophthalmic moxifloxacin (Mox) solution is presented as a case study.
Methods :
The Ocular Compartmental Absorption and Transit (OCAT™) model within GastroPlus® v9.8.2 was used to build a PBPK for Mox ophthalmic solution that accounts for nasolacrimal drainage, ocular absorption, and distribution in the rabbit eye. The model was subsequently used to predict Mox exposure after ocular solution administration in humans. Drug-specific parameters were used as fitted and validated in the rabbit. The physiological parameters were adjusted to match human ocular physiology. Simulated human ocular PK profiles were compared with observed cornea and aqueous humor (AH) concentration data to assess the OCAT models’ ability to predict human ocular exposure based on preclinical data.
Results :
OCAT model simulations for rabbit well described the observed concentrations in the anterior segment (cornea, AH) of the eye following Mox solution administration of different doses and various administration schedules. After adjustment of physiological parameters to represent the human eye, the clinical ocular exposure (cornea, AH) following ocular administration of Mox solution at different doses and various administration schedules was predicted within 2-fold of observed exposures.
Conclusions :
The OCAT model reasonably predicted Mox ocular exposure in humans. Even though more case studies for different types of APIs and formulations will be needed, the positive clinical extrapolation outcomes of Mox solution from this study represents an important step in the validation process of the extrapolation method used to predict human ocular exposure for other ophthalmic drug products using PBPK models.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.