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General Description:

Omidenepag isopropyl, identified by CAS number 1187451-19-9, is a notable compound with significant therapeutic applications. 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 , 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 . 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.

Indications:

This drug is primarily indicated for: 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. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Omidenepag isopropyl undergoes metabolic processing primarily in: 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. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Omidenepag isopropyl are crucial for its therapeutic efficacy: 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 C_max 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 C_max of 41.5 ± 20.1 and 27.2 ± 10.2 pg/mL, and a corresponding AUC_{0-8 h} of 26.1 ± 5.7 and 15.3 ± 4.7 h·pg/mL (mean ± standard deviation). The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Omidenepag isopropyl is an important consideration for its dosing schedule: The half-life of omidenepag isopropyl is not available. The mean terminal half-life of its active metabolite, omidenepag, is approximately 30 minutes. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Omidenepag isopropyl exhibits a strong affinity for binding with plasma proteins: The protein binding of omidenepag isopropyl is not available. The protein binding of its active metabolite, omidenepag, is 97.8%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Omidenepag isopropyl from the body primarily occurs through: In rats given 0.03% omidenepag isopropyl in both eyes as a single dose (5 mcL/eye, 3 mcg/animal), 89% of the administered dose was excreted 168 hours after ocular instillation. Omidenepag was eliminated in feces (83%) and urine (4%). Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Omidenepag isopropyl is distributed throughout the body with a volume of distribution of: Not available. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Omidenepag isopropyl is a critical factor in determining its safe and effective dosage: Not available. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Omidenepag isopropyl exerts its therapeutic effects through: 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 K_i 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. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Omidenepag isopropyl functions by: Omidenepag isopropyl is a prodrug of omidenepag, a relatively selective prostaglandin E2 (EP2) receptor agonist that decreases intraocular pressure (IOP). Elevated IOP is associated with glaucomatous field loss risk, and the higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss. The exact mechanism by which omidenepag lowers IOP is not fully elucidated; however, it has been suggested that by binding to the EP2 receptor, omidenepag causes an increase in aqueous humor outflow through the conventional and uveoscleral pathways. The EP2 receptor is present in different types of ocular tissues associated with aqueous humor dynamics, such as the ciliary muscle (CM) and trabecular meshwork (TM). The stimulation of EP2 receptors may lead to an increase in intracellular cyclic adenosine monophosphate (cAMP) and result in the relaxation of tissues in the CM and TM. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Omidenepag isopropyl is categorized under the following therapeutic classes: Antiglaucoma Agents, Hypotensive Agents, Ophthalmic Solutions, Ophthalmics, Prodrugs, Pyrazoles, Pyridines, Receptors, Prostaglandin E, EP2 Subtype, agonists, Sulfonamides. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Omidenepag isopropyl include:

• Water Solubility: Practically insoluble