(W1230-02-10) Clinical Ocular Exposure Extrapolation Using PBPK Modeling and Simulation: Gatifloxacin Solution Case Study

Purpose: The complex structure of the eye, its high resistance to foreign compounds, and difficulties with clinical measurements of drug concentrations at the site of action, all contribute to the challenges of testing the interplay between physiology and ophthalmic formulations. Therefore, the development of generic ophthalmic drug products is a challenge for the pharmaceutical industry. The rabbit eye physiology is comparable to human eye physiology in most respects 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.

Methods: PK data after intravenous (IV), oral (PO), and topical ocular administration in rabbit and human were collected from literature. IV and PO data were used to build and calibrate a baseline PBPK model that describes the systemic distribution and clearance of gatifloxacin in rabbit and human. The Ocular Compartmental Absorption and Transit (OCAT™) model within GastroPlus® v9.8.2 was then used to calibrate the model describing gatifloxacin ocular absorption in rabbits. Cornea epithelium permeability and iris-ciliary body (ICB) systemic absorption rate constants were fitted to match the observed concentration-time courses for one New Zealand (NZ) rabbit study. All the remaining parameters were kept at default values estimated by GastroPlus®. Additional NZ rabbit studies were used to validate the fitted parameter values. Fraction unbound to melanin was fitted to match ICB concentration-time course in Dutch Belted (DB) rabbits. The same fraction unbound was used in all tissues containing melanin. The model was subsequently used to predict gatifloxacin exposure after its ocular solution administration in humans. Drug-specific parameters for human simulations were equal to the ones fitted for rabbit. The physiological parameters were adjusted to match human ocular physiology. The dose, dose volume, and dose administration schedule were defined to match the human trials. Simulated human ocular PK profiles were compared with observed concentration data to assess the OCAT™ models’ ability to predict human ocular exposure based on preclinical data.

Results: A total of eleven preclinical ocular studies were collected (9 in NZ Rabbits and 2 in DB rabbit) and used to develop and validate the rabbit ocular model. OCAT model simulations for rabbit were able to describe the observed concentrations in the anterior segment of the eye following gatifloxacin solution administration at different doses and various administration schedules. Nineteen clinical studies were found with observed gatifloxacin ophthalmic concentrations. Adjusting the physiological parameters of the OCAT model to describe the human eye allowed for a reasonable prediction (within 2-fold) of clinical ocular exposure following ocular administration of gatifloxacin solution at different doses and various administration schedules. No impact due to human sampling methods was observed, as data obtained from cataract, vitrectomy and keratoplasty surgeries were reasonably predicted by the OCAT model. However, significant interstudy variability was noticed.

Conclusion: The OCAT model can provide a reasonable prediction of gatifloxacin ocular exposure in humans, once validated based on preclinical rabbit data. The predictions may be made independently of the sampling method. The significant human intersubject and interstudy variability observed in all ocular tissues’ exposures render the conclusion on extrapolation method using a PBPK model premature based solely on this case study. However, the successful clinical extrapolation of gatifloxacin solution, combined with previous results for other fluoroquinolones, represents an important step in the validation process of the extrapolation method used to predict human ocular exposure for all ophthalmic drug products. This PBPK model extrapolation approach is expected to have a significant impact on ophthalmic generic drug product development.

Disclaimer: This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies