Omidenepag

Omidenepag is a relatively selective EP2 receptor agonist which decreases intraocular pressure (IOP). The exact mechanism of action is unknown at this time. Elevated IOP represents a major risk factor for glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss.

Absorption

Omidenepag is absorbed through the cornea where prodrug omidenepag isopropyl is hydrolyzed to become biologically active metabolite, omidenepag. After once daily ocular administration of one drop of omidenepag isopropyl 0.0025% eye drops to both eyes in humans for 7 days, plasma concentrations of omidenepag reached C_max at 10-15 minutes. Systemic exposure was similar between days 1 and 7, indicating no systemic accumulation.

Elimination

Metabolism

After topical ocular administration, omidenepag isopropyl is rapidly metabolized in the eye to omidenepag (active moiety) by carboxylesterase-1. The pharmacologically active form, omidenepag is further metabolized by liver through oxidation, N-dealkylation, glucuronidation, sulfate conjugation or taurine conjugation.

Excretion

In rats, 0.03% ¹⁴C-omidenepag was instilled in both eyes as a single dose (5 mcL/eye, 3 mcg/animal). By 168 hours after ocular instillation, 89% of the administered radioactive dose had been excreted. Specifically, 83% and 4% of the administered radioactive dose were excreted in the feces and urine, respectively, and radioactivity in expired air was below the lower limit of quantitation.

Nasal cavity respiratory epithelium metaplasia was observed in cynomolgus monkeys receiving unilateral topical ocular instillations of omidenepag isopropyl at 0.003% (0.9 mcg/eye) [1.07 fold the MRHOD, based on ocular dose comparison]. In a 13-week monkey study, the 0.9 mcg/eye dose was associated with nasal cavity respiratory epithelial metaplasia, and increased nasal cavity goblet cell respiratory epithelium mucosa. In a 39-week monkey study, the 0.9 mcg/eye dose was associated with increased incidence and severity of nasal cavity respiratory epithelium metaplasia. These findings were present in both the treated side and untreated contralateral side, and they were also observed in the vehicle group.