Eybelis Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: The mechanism of IOP-lowering effect of Omidenepag isopropyl (Eybelis) ophthalmic solution is considered to increase aqueous outflow via both trabecular and uveoscleral outflow pathways by stimulating EP2 receptor.
Omidenepag (active metabolite) selectively bound to EP2 receptor (Ki=3.6 nM), and showed potent agonistic activity to EP2 receptor (EC₅₀=8.3 nM).
Aqueous humor dynamics in monkeys with laser-induced ocular hypertension was determined by using a fluorophotometry method when 0.002% omidenepag isopropyl ophthalmic solution was instilled into the monkey eyes once daily for 7 days: No change was observed in aqueous humor production while significant increases were observed in outflow facility (assumed to be via the trabecular outflow pathway) and in uveoscleral outflow.
Clinical efficacy and safety: By using Omidenepag isopropyl (Eybelis) (once daily administration) and the comparator (0.005% latanoprost ophthalmic solution, once daily administration), Phase II/III clinical study was conducted in 189 patients with primary open angle glaucoma or ocular hypertension in Japan. Intraocular pressure (IOP) lowering effect was observed from week 1 at first scheduled visit. The results demonstrated that change in IOP levels (Mean±SD) of this product was -5.96±2.45 mmHg at Week 4, and verified that the product was non-inferior to the comparator. (See Figure and Table 1.)

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Pharmacokinetics: Plasma concentrations: Plasma concentrations of omidenepag (active metabolite) were determined when 0.0025% omidenepag isopropyl ophthalmic solution was instilled into both eyes of 14 healthy adult volunteers (7 Japanese and 7 Caucasian subjects) one drop a time, once daily for 7 days. The concentrations reached the peak of about 34 pg/mL at 10 minutes after the instillation (Day 1), and that of about 35 pg/mL at 15 minutes after instillation (Day 7), respectively. The half-life was about 30 minutes (Days 1 and 7). (Note: The concentration of Omidenepag isopropyl (Eybelis) is 0.002%).
Ocular tissue distribution in animals: (Monkeys): Concentrations in the ocular tissues reached the maximum between 15 minutes to 4 hours after a single ocular instillation of 0.03% ¹⁴C-omidenepag isopropyl ophthalmic solution into monkey eyes. High concentrations were observed especially in the cornea, conjunctiva and trabecular meshwork. In these tissues, the concentrations reached the peak level at 15 minutes after instillation, and ¹⁴C-omidenepag isopropyl was eliminated thereafter.