Proposed Pathway for Distribution of Nepafenac and Amfenac to Posterior Segment Tissues of Eye
Narrative Responses:
Purpose
The distribution pathway and extent of local delivery of the nonsteroidal anti-inflammatory drug nepafenac and its metabolite amfenac are not well characterized. We evaluated the ocular bioavailability and distribution of nepafenac and amfenac to the posterior segment of the eye, following topical ocular instillation in animal models.
Methods
Nepafenac ophthalmic suspension was delivered topically into the right eye of 36 New Zealand White rabbits (single-dose; 0.1%; one 30-µL drop) and 10 cynomolgus monkeys (multiple doses; 0.3%; one 30-µL drop, three-times daily for 7 days plus one additional drop on Day 8). The animals were euthanized and ocular tissues were harvested from both the dosed and undosed eyes. High-performance liquid chromatography mass spectrometry was used to measure nepafenac and amfenac concentrations. The difference in levels between dosed and undosed eyes in the same animal was used to determine locally-distributed concentrations of both compounds.
Results
In both animal models, higher locally-distributed peak drug concentrations were seen in dosed eye anterior sclera, choroid and retina (rabbit: nepafenac 92.1–714 nM, amfenac 10.9–469 nM; monkey: nepafenac 364–7140 nM, amfenac 17.6–887 nM), compared with corresponding posterior segments (rabbit: nepafenac 2.72–55.1 nM, amfenac 0.768–41.8 nM; monkey: nepafenac 292–1590 nM, amfenac 2.58–21.3 nM). A high-to-low concentration gradient and distribution of nepafenac and amfenac was observed from anterior to posterior ocular tissues and from the sclera inward. Distribution to the posterior segment was predominately via the local ocular versus systemic route.
Conclusion
Following topical administration, nepafenac and amfenac are readily bioavailable to the posterior segment of the eye via local distribution. The proposed pathway involves nepafenac and amfenac distribution to the sclera, choroid and retina via a local transconjunctival/scleral absorption route, with subsequent anterior-to-posterior movement and minimal vitreous humor involvement.