According to FDA guidelines, generic drug products must demonstrate pharmaceutical equivalence and bioequivalence to the reference listed drug (RLD) to gain FDA approval. For generic ophthalmic solutions that are qualitatively (Q1) and quantitatively (Q2) the same as the RLD, bioequivalence is considered to be self-evident and a waiver for in vivo studies can be requested. Unlike solutions, ophthalmic implants have additional steps before the drug is absorbed;these steps collectively referred to as """"""""drug release"""""""", exhibit a complex behavior and depend on drug diffusion as well as polymer degradation. Pharmaceutically equivalent implants can have varying physicochemical properties due to the differences introduced during their manufacturing;these physicochemical differences in turn may affect drug release and ocular bioavailability. FDA guidelines recommend that for ophthalmic implants that are Q1 and Q2 the same as the RLD, bioequivalence must be demonstrated. Currently there are no suitable bioequivalence methods for generic products of complex dosage forms including intravitreal implants. An understanding of the relationship between physicochemical properties of implants and their effect on ocular bioavailability is crucial in designing pharmaceutically equivalent implants that are bioequivalent. However, there is sparse literature explaining how the differences in physicochemical properties of ophthalmic implants influence ocular bioavailability. Moreover, a key hurdle in biopharmaceutics research is development of a perfect correlation between in vitro drug release information of various drug formulations and their in vivo drug release profiles;this requires development of robust in vitro release study designs as well as reliable in vivo drug release monitoring. There is little or no information regarding predictive in vitro-in vivo correlation (IVIVC) for various complex ophthalmic formulations, especially ocular implants. We hypothesize that key physicochemical properties such as implant surface area, porosity, tensile strength, and polymer degradation (due to polymer procurement from different sources) can differ for Q1/Q2 implants, resulting in differences in drug release and bioavailability. For such implants differing in their physicochemical properties, we will develop suitable in vitro release studies and predictive IVIVC. To address the project hypothesis and objectives, we will vary manufacturing aspects to prepare several intravitreal implants that are Q1/Q2 but differ in physicochemical properties. The implants will be characterized for their physicochemical properties and in vitro dissolution/release to identify in vivo test formulations. An in vivo pharmacokinetic study will be conducted to assess drug distribution in eye tissues and plasma at several time points. An in vitro release study that correlates with in vivo outcomes will be identified/developed. Through collaborative consultations with FDA counterparts for optimal design of studies, this project will identify key physicochemical and mechanical properties of Q1 and Q2 implant dosage forms that alter ocular drug bioavailability and develop appropriate in vitro dissolution studies to predict in vivo drug release from ocular implants with good accuracy. The findings of this project would lay a foundation for developing guidelines for conducting bioequivalence studies for generic ocular implants.

Public Health Relevance

Generic drug products reduce the cost of health care and economic burden. However, it is not always straightforward to develop generic drug products that perform similar to the brand name or reference products. This is particularly the case for ocular implants, which are drug products that are either injected or surgically placed in the eye. A key hurdle in the development of generic ocular implants is a clear understanding of the relationship between in vitro performance of the implants and their in vivo performance. Such an understanding would enable the design of implants to meet in vivo requirements. Filling the above knowledge gaps to expedite development of generic ocular implants is the primary objective of this project.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZFD1-SRC (99))
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University of Colorado Denver
Schools of Pharmacy
United States
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