Omidenepag Isopropyl

Absorption

The ophthalmic solution of omidenepag isopropyl is absorbed through the cornea, where it is hydrolyzed into its active metabolite, omidenepag. After the administration of one drop of omidenepag isopropyl 0.0025% eye drops to both eyes for 7 days, plasma concentration in humans reached Cmax at 10-15 minutes. There was no evidence of omidenepag isopropyl systemic accumulation, given that systemic exposure was similar between days 1 and 7. A study comparing the pharmacokinetic parameters of omidenepag in Japanese and Caucasian healthy subjects did not find significant differences. Japanese and Caucasian healthy subjects had a corresponding Cmax of 41.5 ± 20.1 and 27.2 ± 10.2 pg/mL, and a corresponding AUC0-8 h of 26.1 ± 5.7 and 15.3 ± 4.7 h·pg/mL (mean ± standard deviation).

Toxicity

Toxicity information regarding omidenepag isopropyl is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as ocular inflammation. Symptomatic and supportive measures are recommended. Lifetime studies evaluating the carcinogenic effects of omidenepag isopropyl or omidenepag have not been performed. In rats given omidenepag isopropyl subcutaneously for 26 weeks, nephroblastoma and a spermatic cord tumor were developed at 0.003 mg/kg/day (33 times the recommended human ophthalmic dose). At 0.03 mg/kg/day (319 times the recommended human ophthalmic dose), rats given omidenepag isopropyl developed mammary adenocarcinoma and pituitary pars distalis adenomas. Based on the results of the in vitro mouse lymphoma forward mutation assay, omidenepag isopropyl (no metabolic activation) was mutagenic and clastogenic. Its active metabolite, omidenepag, was not mutagenic in the in vivo mouse micronucleus and bacterial reverse mutation tests.

The Uses of Omidenepag Isopropyl

Omidenepag Isopropyl is a derivative of Omidenepag (O635205) which is a novel selective, non-prostanoid EP2 receptor agonist for the treatment of Glaucoma:

Indications

Omidenepag isopropyl ophthalmic solution (0.002%) is indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.

Background

Omidenepag isopropyl is a topical ocular hypotensive agent used to reduce intraocular pressure (IOP) in patients with glaucoma and ocular hypertension. Omidenepag isopropyl is quickly metabolized to its active metabolite, omidenepag, a molecule with high selectivity and agonistic activity towards the prostaglandin E2 (EP2) receptor. Prostanoid FP receptor agonists (FP agonists), such as latanoprost, are part of the first-line therapy for ocular hypertension and primary open-angle glaucoma; however, not all patients achieve adequate IOP reduction with FP agonists and require changes in treatment. The use of an EP2 receptor agonist such as omidenepag represents an alternative in these scenarios. Omidenepag IOP-lowering effect is comparable to the one observed with latanoprost. In 2018, omidenepag isopropyl was approved in Japan for the treatment of glaucoma and ocular hypertension. In September 2022, the FDA approved the use of omidenepag isopropyl.

Pharmacokinetics

Omidenepag isopropyl is rapidly hydrolyzed to its active metabolite, omidenepag. Omidenepag has a high affinity for the prostaglandin E2 (EP2) receptor and binds strongly with a Ki of 3.6 nM. Omidenepag also has high agonistic activity towards the EP2 receptor, with an EC50 of 8.3 nM, and has no effects over other receptors such as prostaglandin E1 (EP1) receptor and prostaglandin F receptor (FP). Unlike omidenepag, omidenepag isopropyl has weak or no affinity towards prostanoid receptors.
The use of omidenepag isopropyl may lead to pigmentation of the iris, periorbital tissue and eyelash. The pigmentation of the iris is likely to be permanent, while the pigmentation of the periorbital tissue and eyelash are reversible in most patients. Patients receiving omidenepag isopropyl may also experience eyelash changes and ocular inflammation. Also, in patients with pseudophakia, the use of omidenepag isopropyl may lead to macular edema.

Metabolism

Omidenepag isopropyl is rapidly metabolized after topical ocular administration by carboxylesterase-1 to its pharmacologically active form, omidenepag. In the liver, omidenepag is further metabolized through oxidation, N-dealkylation, glucuronidation, sulfate conjugation or taurine conjugation. CYP3A4 plas an important role in the liver metabolism of omidenepag.