June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Clinical Ocular Exposure Extrapolation Using PBPK Modeling and Simulation: Besifloxacin Suspension Case Study
Author Affiliations & Notes
  • Maxime Le Merdy
    Simulations Plus Inc, Lancaster, California, United States
  • Farah AlQaraghuli
    Simulations Plus Inc, Lancaster, California, United States
  • Viera Lukacova
    Simulations Plus Inc, Lancaster, California, United States
  • Footnotes
    Commercial Relationships   Maxime Le Merdy None; Farah AlQaraghuli None; Viera Lukacova None
  • Footnotes
    Support  1U01FD006927-01
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 2729. doi:
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      Maxime Le Merdy, Farah AlQaraghuli, Viera Lukacova; Clinical Ocular Exposure Extrapolation Using PBPK Modeling and Simulation: Besifloxacin Suspension Case Study. Invest. Ophthalmol. Vis. Sci. 2023;64(8):2729.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : 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 its physiology with ophthalmic drugs. New methods are mandatory to promote the development of ophthalmic generic drug products. Ocular physiologically based pharmacokinetic (PBPK) models can provide insight into drug partitioning in eye tissues that are not accessible and/or are challenging to sample in humans. This approach has successfully been validated to translate ocular exposure from rabbit to human for ophthalmic solutions. This study aims to demonstrate the utility of an ocular PBPK model to predict human exposure following the administration of ophthalmic suspension. Besifloxacin (Bes) suspension is presented as a case study.

Methods : The Ocular Compartmental Absorption and Transit (OCAT™) model within GastroPlus® v9.8.3 was used to build a PBPK for Bes ophthalmic suspension (Besivance® 0.6%) that accounts for nasolacrimal drainage, suspended particle dissolution in the tears, ocular absorption, and distribution in the rabbit eye. The model was subsequently used to predict Bes exposure after its topical administration in humans. Drug-specific parameters were used as validated for rabbits. The physiological parameters were adjusted to match human ocular physiology. Simulated human ocular pharmacokinetic profiles were compared with the observed ocular tissues concentration data to assess the OCAT models’ ability to predict human ocular exposure.

Results : OCAT model simulations for rabbits well described the observed concentrations in the eye tissues following the topical administration of Bes suspension. Systemic exposure was also well described by the model. After adjustment of physiological parameters to represent the human eye, the clinical ocular exposure following ocular administration of Bes suspension was predicted within 2-fold of observed exposures. Clinical plasma exposure was also well predicted.

Conclusions : The OCAT model reasonably predicted Bes ocular exposure in humans. More case studies for other ophthalmic suspension drug products will be needed to confirm this study’s results. Nevertheless, the positive clinical extrapolation outcomes of Bes represent an important step in the validation process of the extrapolation method used to predict human ocular exposure using an ocular PBPK model.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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