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Pharmacology: Pharmacodynamics: Mechanism of action: The mechanism of IOP-lowering effect of omidenepag isopropyl 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 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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Click on icon to see table/diagram/imagePharmacokinetics: 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 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.
Toxicology: Preclinical safety data: Single dose toxicity: Single dose ocular irritation was evaluated with 0.1% omidenepag isopropyl ophthalmic solution in cynomolgus monkeys. There were no mortalities and no test article-related changes in clinical signs. Slight conjunctival hyperemia was observed just after the instillation and recovered until 6 hours after the instillation.
Single dose toxicity was evaluated with 0.4, 1.3, 4 mg/kg omidenepag isopropyl in Sprague Dawley rats by SC route. Rats received once SC doses of omidenepag isopropyl solution. There were no mortalities in any group. Loose stool was transiently observed from 1 to 5 hours after the dosing in all groups.
Repeated dose toxicity: The ocular and systemic toxicity of omidenepag isopropyl ophthalmic solution (0.003%-0.03%) administered by ocular route once or twice daily (equivalent to 0.0009-0.036 mg/body/day) were investigated in male and female cynomolgus monkeys for 13 weeks. There were no mortalities or any test article-related changes in body weight, food consumption, ophthalmology (except for corneal thickness and miosis), electrocardiogram (ECG), blood pressure, urinalysis, hematology, serum biochemistry, necropsy, organ weight, or histopathology in any group. Clinical signs of anisocoria were seen in all animals after twice daily (BID) administration of 0.03% omidenepag isopropyl. It is postulated that this effect was the result of miosis in the treated eye due to the pharmacological action of omidenepag isopropyl. The miosis is considered not to be toxicologically significant because it was reversible after a 4-week recovery period and function of light reflex was normal. A mild increase in corneal thickness was observed at all doses of omidenepag isopropyl ophthalmic solution at week 4 and appeared to be dose-dependent. The degree of the increase in corneal thickness at omidenepag isopropyl doses of 0.003% QD, 0.01% QD, 0.03% QD, and two drops of 0.03% BID was 3.4%, 3.1%, 3.9%, 8.1% for males, and 4.4%, 5.7%, 5.1%, and 8.4% for females, respectively, compared with the pre-dosing baseline. The effect on corneal thickness was reversible after a 4-week recovery period and there was no additional deterioration of corneal thickness from 4 weeks to 13 weeks. In addition, no corneal endothelial cell loss was observed in specular microscopy and no structural change of cornea was observed in histopathology. Therefore, the mild increase in corneal thickness is also considered not to be toxicologically significant. In this study, the no-systemic-toxicity dose level and the no-local-irritation dose level was more than 0.03% BID (0.036 mg/body/day).
The ocular and systemic toxicity of omidenepag isopropyl ophthalmic solution (0.003%, 0.01%) administered by ocular route once daily (equivalent to 0.0009, 0.003 mg/body/day) were investigated in male and female cynomolgus monkeys for 39 weeks. There were no mortalities or any test article-related changes in body weight, food consumption, ophthalmology, electrocardiogram (ECG), blood pressure, urinalysis, hematology, serum biochemistry, necropsy, organ weight, or histopathology in any group. Clinical signs of anisocoria were seen in all omidenepag isopropyl groups. They are considered not to be toxicologically significant same as the 13-week study. A mild increase in corneal thickness was observed in 0.01% omidenepag isopropyl group but the increase of corneal thickness was also observed in non-treated eyes. In addition, no corneal endothelial cell loss was observed in specular microscopy and no structural change of cornea was observed in histopathology. Therefore, the mild increase in corneal thickness is considered to be incidental and not to be toxicologically significant. In this study, the no-systemic-toxicity dose level and the no-local-irritation dose level was more than 0.01% QD (0.003 mg/body/day).
Carcinogenesis: Carcinogenicity studies have not been conducted with omidenepag isopropyl.
Mutagenesis: There was no genotoxicity associated with omidenepag isopropyl in clinical dose.
Reproductive and Developmental Toxicity: Fertility: Omidenepag isopropyl have not been found to have any effect on fertility and early embryonic development in rats at doses approximately 50,000 times the indicated dose in human.
Pregnancy: Reproduction studies have been performed in rats and rabbits. In rats, omidenepag isopropyl have not been found to have any effect on embryo-fetal development in rats at doses approximately 50,000 times the indicated dose in human. In rabbits, it has not been found to have any effect on embryo-fetal development at doses approximately 4,000 times the indicated dose in human, but a high number of embryo-fetal deaths, percentage post-implantation loss, and a low number of live fetuses and percentage fetal viability were noted at doses approximately 40,000 times the indicated dose in humans.
