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

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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.

Section: Introductionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

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)

Aihara

Kawata

et al. 2019

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“…OMDI is hydrolyzed by esterases to omidenepag (OMD) during corneal penetration, and the IOP-lowering effects of this drug are associated with increased outflow facility and uveoscleral outflow. 19 In a previous clinical study, topical applications of 0.002% OMDI significantly reduced IOP in patients with glaucoma, and all of the associated ocular AEs were mild in severity. 20 FP agonists, including latanoprost, inhibit adipogenesis by stimulating FP receptor in 3T3-L1 cells.…”

Section: Introductionmentioning

confidence: 85%

Effects of the Selective EP2 Receptor Agonist Omidenepag on Adipocyte Differentiation in 3T3-L1 Cells

Yamamoto

Taniguchi

Inazumi

et al. 2020

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Purpose: We aimed at comparing the effects of omidenepag (OMD) with those of prostaglandin F (FP) receptor agonists (FP agonists) on adipogenesis in mouse 3T3-L1 cells. Methods: To evaluate the agonistic activities of OMD against the mouse EP2 (mEP2) receptor, we determined cAMP contents in mEP2 receptor-expressing CHO cells by using radioimmunoassays. Overall, 3T3-L1 cells were cultured in differentiation medium for 10 days and adipocyte differentiation was assessed according to Oil Red O-stained cell areas. Changes in expression levels of the adipogenic transcription factors Pparg, Cebpa, and Cebpb were determined by using real-time polymerase chain reaction (PCR). OMD at 0.1, 1, 10, and 40 mmol/L, latanoprost free acid (LAT-A) at 0.1 mmol/L, or prostaglandin F 2a (PGF 2a ), at 0.1 mmol/L were added to cell culture media during adipogenesis. Oil Red O-stained areas and expression patterns of transcription factor targets of OMD or FP agonists were compared with those of untreated controls. Results: The 50% effective concentration (EC 50 ) of OMD against the mEP2 receptor was 3.9 nmol/L. Accumulations of Oil Red O-stained lipid droplets were observed inside control cells on day 10. LAT-A and PGF 2a significantly inhibited the accumulation of lipid droplets; however, OMD had no effect on this process even at concentrations up to 40 mmol/L. LAT-A and PGF 2a significantly suppressed Pparg, Cebpa, and Cebpb gene expression levels during adipocyte differentiation. Conversely, OMD had no obvious effects on the expression levels of these genes. Conclusions: A selective EP2 receptor agonist, OMD, did not affect the adipocyte differentiation in 3T3-L1 cells, whereas FP agonists significantly inhibited this process.

“…Differing from butaprost, 17 PGN 9856-isopropyl ester decreased aqueous humor secretion. Further discrepancies among EP 2 agonist effects on aqueous humor dynamics have been provided by a recent study on omidenepag, which increased outflow facility, 18 in addition to improving uveoscleral outflow and leaving aqueous flow unchanged. 18 In contrast to butaprost and PGN 9856-isopropyl ester, aqueous humor dynamics studies on omidenepag were performed on laser-induced ocular hypertensive monkeys.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Further discrepancies among EP 2 agonist effects on aqueous humor dynamics have been provided by a recent study on omidenepag, which increased outflow facility, 18 in addition to improving uveoscleral outflow and leaving aqueous flow unchanged. 18 In contrast to butaprost and PGN 9856-isopropyl ester, aqueous humor dynamics studies on omidenepag were performed on laser-induced ocular hypertensive monkeys. 18 Since the trabecular meshwork is the site of laser-induced photocoagulation in the ''glaucomatous'' monkey model and the resultant effect on aqueous dynamics is a reduction in fluorophotometric outflow facility and an increase in uveoscleral outflow, 19 direct comparison of drugs in the ocular hypertensive and normotensive models may be prudent.…”

Section: Pharmacokineticsmentioning

confidence: 99%

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

Woodward

Wang²,

Coleman³

et al. 2019

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Purpose: Two features define the future of glaucoma therapeutics: (1) greatly improved ocular hypotensive efficacy and (2) a delivery method that improves patient convenience and compliance. A highly efficacious and extraordinarily long-acting ocular hypotensive agent PGN 9856-isopropyl ester represents a potential nextgeneration anti-glaucoma drug. A new periorbital drug delivery route was also investigated. Methods: PGN 9856-isopropyl ester pharmacology was determined by employing human cells, including prostanoid receptor transfectants, and FLIPr or cellular dielectric spectroscopy technology. Intraocular pressure (IOP) was measured in conscious cynomolgus monkeys trained to accept pneumatonometry when under gentle restraint. For periorbital application, the compound was applied radially using a roller-ball device connected to a cylindrical reservoir. Pharmacokinetic data were obtained using LC/MS/MS instrumentation. Results: Single doses of PGN 9856-isopropyl ester, administered over a 0.001%-0.01% dose range, produced profound decreases in monkey IOP that persisted for at least 5 days, which was long after the drug was detectable in ocular tissues. It was not uncommon for a single eye drop to reduce IOP to the level of 4-7 mm Hg. Drug application to the periorbital dermis of ocular normotensive monkeys produced a similarly profound reduction in IOP, which was well maintained. Conclusions: PGN 9856-isopropyl ester appears to possess efficacy and duration of action properties unmatched by currently prescribed anti-glaucoma agents and by those currently undergoing clinical evaluation. In addition, application to the periorbital skin using a roller-ball device offers a more convenient method of ophthalmic drug delivery than eye drops and is noninvasive, unlike other ''dropless'' technologies.