Clinical Ocular Exposure Extrapolation for an Ophthalmic Ointment Using PBPK Modeling and Simulation

Abstract Generic ophthalmic drug product development is challenging, and innovative methodologies to complement traditional bioequivalence (BE) studies for BE assessment are desirable to promote their evaluation. Ocular physiologically based pharmacokinetic (PBPK) models can provide insight into drug partitioning in eye tissues that are too invasive to access in humans. An approach has been previously validated to translate ocular exposure from rabbits to humans for some ophthalmic solutions and suspensions. This study aims to demonstrate the utility of an ocular PBPK model to predict human exposure following the administration of ophthalmic ointment. Ofloxacin (OFL) ointment is presented as a case study. The Ocular Compartmental Absorption and Transit (OCAT™) model within GastroPlus® v9.9 was used to build a PBPK model for OFL ophthalmic solution and ointment that accounts for OFL release from the formulation into the tears and eye tissues where it is applied, ointment application time, ocular absorption, and distribution in the rabbit eye. The model was subsequently used to predict OFL exposure in humans after topical administration of solution or ointment. Drug and formulation-specific parameters were used as validated in the mode for rabbits. Physiological parameters were adjusted to match human ocular physiology. Simulated human ocular pharmacokinetic (PK) profiles were compared with the observed ocular tissue concentration data to assess the OCAT model’s ability to predict human ocular exposure. The OCAT model for rabbits accurately described the observed concentrations in aqueous humor following the topical administration of OFL solution or ointment. For the ointment formulation, the Higuchi release rate and the application time of the formulation were fitted to describe the observed data. After adjustment of physiological parameters to represent the human eye, the predicted aqueous humor concentrations following ocular administration of OFL solution or ointment were within the range of observed values. More case studies for other ophthalmic ointment drug products will be needed to confirm this study’s results. Nevertheless, the positive preclinical to clinical extrapolation for OFL represents an important step in the validation process of human exposure using an ocular PBPK model validated in the rabbit. Graphical Abstract