Development and Validation of a PBPK/PD Modeling Strategy for Ophthalmic Drug Products to Support Translation from Preclinical Species to Human

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Ocular PBPK/PD Model Extrapolation from Animal to Human – Abstract The Office of Generic Drugs (OGD) is tasked, among other things, with reviewing sponsor applications for ocular dosage forms that purport to be bioequivalent to the approved formulations for the same drug. Sponsor companies want to have high confidence that applications they submit for locally acting dosage forms thought to be bioequivalent (BE) will receive favorable reviews. Software that embodies physiologically-based pharmacokinetics (PBPK) / pharmacodynamics (PD) modeling can serve as a useful alternative to conventional BE approaches to evaluate the likelihood that a new locally acting formulation will be BE to an approved dosage form in the target patient population. Developing a state-of-the-art capability for ocular PBPK/PD software and defining strategies for interspecies translation of models requires an extensive knowledge base to serve as the scientific foundation. Talented scientists apply the knowledge base in the development of useful equations and logic suitable for software, high-level computer programming skills to encode the equations and logic into user- friendly software, and other experienced scientists to test, validate, document, and support the software for the desired application by others not involved in its development. The goal of this project is to develop and validate a PBPK/PD modeling strategy for ophthalmic drug products to support translation from preclinical species to human. This will be achieved through a combination of an exhaustive review expanding the knowledge base of preclinical and clinical PK/PD data sets and legacy models for ophthalmic products, developing mechanistic PBPK/PD models in preclinical species in the Ocular Compartmental Absorption and Transit™ (OCAT™) model within the GastroPlus® software program and extrapolating to human PBPK/PD models, and validating and documenting the resulting software for use by others. By basing the analyses on the well-established and validated OCAT™ model, which has been funded previously by the FDA and is utilized by both pharmaceutical and generic drug companies today, we will be able to focus project resources entirely on identifying knowledge gaps and new strategies to support interspecies translation for ocular drug delivery and establishing scientific and regulatory standards for supporting innovative development and performing bioequivalence assessments, rather than having to develop new code for the core program and its many support capabilities (e.g., integration, plotting, Parameter Sensitivity Analysis, Virtual BE Trial Simulations). Throughout the effort, we will maintain close contact with the FDA program manager and the Consortium for Ocular PBPK/PD Model Extrapolation that we propose to form with our collaboration partners and the FDA to ensure the team focuses on data compilation and model development activities that will result in successful completion of the specific aims within the scope of the project.