Pharmacokinetics, Safety, and Intraocular Pressure-Lowering Profile of Omidenepag Isopropyl, a Selective, Nonprostaglandin, Prostanoid EP2 Receptor Agonist, in Healthy Japanese and Caucasian Volunteers (Phase I Study)

Abstract

Purpose: Omidenepag isopropyl (OMDI) is a prodrug of OMD, a selective, nonprostaglandin, prostanoid EP2 receptor agonist. This phase I study aimed to investigate the pharmacokinetic properties, safety, and intraocular pressure (IOP)-lowering efficacy of OMDI. Methods: Fourteen healthy male volunteers (7 Japanese and 7 Caucasian) 20-35 years of age received 1 drop of OMDI 0.0025% at 9:00 h in both eyes for 7 days. Blood samples were taken predose and up to 8 h postdose on days 1, 3, and 7. The plasma concentration of OMD was determined using high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters measured included the maximum plasma concentration (C max) and the half-life (t ½) of OMD. IOP, adverse events (AEs), ophthalmic examinations, vital signs, and laboratory values were assessed. Results: C max for all subjects was reached after 10-15 min and decreased with a t ½ of *30 min. Ad hoc statistical analyses found significant differences in some pharmacokinetic parameters between Japanese and Caucasian subjects, likely due to differences in body weight. These differences reduced over 7 days of dosing and were not thought to be clinically meaningful. There was no OMD accumulation after 7 days of repeated dosing. Mean IOP was reduced by *4-5 mmHg between baseline and 2 h postdose, remaining stable from day 3 onward. All AEs were mild and considered treatment related. Conclusions: Pharmacokinetic parameters of OMD were similar between Japanese and Caucasian subjects. There was no accumulation of OMD after 7 days of dosing. OMDI was well tolerated and demonstrated clinically significant IOP reductions.

Effects of a Novel Selective EP2 Receptor Agonist, Omidenepag Isopropyl, on Aqueous Humor Dynamics in Laser-Induced Ocular Hypertensive Monkeys

“…Dosing period and concentration of OMDI ophthalmic solution were determined on the basis of our previous animal 27 and clinical data. 28,34 On day 7, *4 h before measurements commenced, 10% fluorescein solution was applied to the cornea as 3 to 4 topical drops and then sedation was induced by intramuscular administration of ketamine HCl (15 mg/kg). A final dose of 0.002% OMDI ophthalmic solution or vehicle was applied topically to the eye at around 9:00 am.…”

Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma

“…The compound was reported to be very active in lowering IOP in various animal models of ocular hypertension and glaucoma (Kirihara et al ., ). DE‐117 was also shown to be sufficiently safe in healthy volunteers when administered to subjects at 0.002% to warrant further clinical evaluation (Aihara et al ., ). In a randomized, investigator‐masked, active‐controlled multicentre phase 3 trial in Japanese patients comparing DE‐117 versus latanoprost 0.005%, the compound wasshown to be similarly effective, although the IOP change from baseline in mean diurnal IOP for DE‐117 and latanoprost was 0.63 mmHg in favour of latanoprost (Lu et al ., ).…”

“…Somewhat interesting are also EP 2 receptor‐selective agonists, which have recently been reported to effectively lower IOP (Prasanna et al ., ; Schachar et al ., ; Aihara et al ., ). From this class, the most advanced is omidenepag isopropyl (DE‐117), which is being co‐developed by Santen and Ube Industries and is currently in phase 3 clinical trials.…”

A Highly Effective and Ultra-Long-Acting Anti-Glaucoma Drug, with a Novel Periorbital Delivery Method

“…14 Direct comparison of 0.1% doses of CP 533536-isopropyl ester and PGN 9856-isopropyl ester showed them essentially equieffective in reducing IOP at 24 h postdosing, but by 48 h, the activity of CP 533536-isopropyl ester had dissipated, whereas PGN 9856-isopropyl ester remained maximally efficacious. 11 Recently, preclinical and clinical information on a new selective EP 2 agonist prodrug, omidenepag, 15,16 have emerged. A once-daily dosing regimen was again employed 15,16 and it would appear to be a similar, but safer drug than taprenepag.…”

“…11 Recently, preclinical and clinical information on a new selective EP 2 agonist prodrug, omidenepag, 15,16 have emerged. A once-daily dosing regimen was again employed 15,16 and it would appear to be a similar, but safer drug than taprenepag.…”