Maxime Le Merdy1, Farah AlQaraghuli2, Ming-Liang Tan3, Ross Walenga3, Andrew Babiskin3, Liang Zhao3, Viera Lukacova2. 1. Simulations Plus, Inc., 42505 10th Street West, Lancaster, CA, 93534, USA. maxime.lemerdy@simulations-plus.com. 2. Simulations Plus, Inc., 42505 10th Street West, Lancaster, CA, 93534, USA. 3. Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
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 levofloxacin (Lev), moxifloxacin (Mox), and gatifloxacin (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-specific parameters were used as fitted 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 different doses and various administration schedules. The clinical ocular exposure following ocular administration of Lev, Mox, and Gat solutions at different doses and various administration schedules was well predicted. CONCLUSION: Even though additional case studies for different 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.
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 levofloxacin (Lev), moxifloxacin (Mox), and gatifloxacin (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-specific parameters were used as fitted 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 different doses and various administration schedules. The clinical ocular exposure following ocular administration of Lev, Mox, and Gat solutions at different doses and various administration schedules was well predicted. CONCLUSION: Even though additional case studies for different 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.
Authors: Marcelle O Koeppe; Rodrigo Cristofoletti; Eduardo F Fernandes; Silvia Storpirtis; Hans E Junginger; Sabine Kopp; Kamal K Midha; Vinod P Shah; Salomon Stavchansky; Jennifer B Dressman; Dirk M Barends Journal: J Pharm Sci Date: 2011-01-21 Impact factor: 3.534
Authors: E Kłosińska-Szmurło; F A Pluciński; M Grudzień; K Betlejewska-Kielak; J Biernacka; A P Mazurek Journal: J Biol Phys Date: 2014-07-18 Impact factor: 1.365
Authors: Maxime Le Merdy; Jessica Spires; Viera Lukacova; Ming-Liang Tan; Andrew Babiskin; Xiaoming Xu; Liang Zhao; Michael B Bolger Journal: Pharm Res Date: 2020-11-19 Impact factor: 4.200