Abstract

Background

The development of generic ophthalmic drug products is challenging due to the complexity of the ocular system, and a lack of sensitive testing to evaluate the interplay of physiology with ophthalmic formulations. While measurements of drug concentration at the site of action in humans are typically sparse, these measurements are more easily obtained in rabbits. 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.

Method

The Ocular Compartmental Absorption and Transit (OCAT™) model within GastroPlus® v9.8.2 was used to build PBPK models for levofoxacin (Lev), moxifoxacin (Mox), and gatifoxacin (Gat) ophthalmic solutions. in the rabbit eye. The models were subsequently used to predict Lev, Mox, and Gat exposure after ocular solution administrations in humans. Drug-specifc parameters were used as ftted and validated in the rabbit OCAT model. The physiological parameters were scaled to match human ocular physiology.

Results

OCAT model simulations for rabbit well described the observed concentrations in the eye compartments following Lev, Mox, and Gat solution administrations of diferent doses and various administration schedules. The clinical ocular exposure following ocular administration of Lev, Mox, and Gat solutions at diferent doses and various administration schedules was well predicted.

Conclusion

Even though additional case studies for diferent types of active pharmaceutical ingredients (APIs) and formulations will be needed, the current study represents an important step in the validation of the extrapolation method to predict human ocular exposure for ophthalmic drug products using PBPK models.

By Maxime Le Merdy, Farah AlQaraghuli, Ming‑Liang Tan, Ross Walenga, Andrew Babiskin, Liang Zhao, Viera Lukacova