Long-term ocular safety and systemic exposure of doxycycline hyclate ophthalmic solution in juvenile rabbits: a 270-day preclinical GLP study

PURPOSE: Pediatric myopia is associated with scleral extracellular matrix remodeling. Doxycycline hyclate, a tetracycline-class matrix metalloproteinase inhibitor at sub-antimicrobial doses, is being investigated for long-term myopia treatment. This study evaluated the chronic ocular safety and systemic exposure of a doxycycline hyclate ophthalmic solution following repeated topical administration in a juvenile model. METHODS: A 9-month Good Laboratory Practice (GLP) repeat-dose study was conducted in juvenile Dutch Belted rabbits. Animals received bilateral topical ocular administration of doxycycline hyclate ophthalmic solution at 0.1, 1.0, or 5.0 mg/mL (0.005, 0.05, or 0.25 mg/eye), or vehicle control, twice daily for 270 days, followed by a 14-day recovery. Assessments included clinical signs, body weights, ophthalmic examinations, intraocular pressure (IOP), clinical pathology, toxicokinetic evaluation, and gross/microscopic pathology. RESULTS: generally observed 1-12 hours post-dose on Days 1, 180, and 270. Exposure demonstrated low accumulation and was independent of sex. No test article-related macroscopic observations, organ weight changes, or microscopic pathological findings were identified. CONCLUSION: Twice-daily topical doxycycline hyclate ophthalmic solution was well tolerated in juvenile rabbits for 9 months. No systemic or ocular toxicity was identified, establishing the No-Observed-Adverse-Effect Level (NOAEL) at 0.25 mg/eye (1 mg/day). These findings support the safety of long-term ocular exposure to doxycycline hyclate for chronic applications.