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Tomoko Kirihara, Ryo Iwamura, Kenji Yoneda, Noriko Kawabata-Odani, Atsushi Shimazaki, Kouichi Kawazu; DE-117, a selective EP2 agonist, lowered intraocular pressure in animal models. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5709.
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© ARVO (1962-2015); The Authors (2016-present)
Controlling intraocular pressure (IOP) is only treatment method which clinical efficacy for preventing glaucomatous visual field loss has been proven. The objective of this study is to investigate the ocular hypotensive efficacy of DE-117 in animal models.
Binding activities of DE-117, a hydrolyzed from of DE-117 (hDE-117), and PGE2 to receptors EP2 and EP4 were evaluated by using human recombinant receptors. Metabolism of DE-117 after topical administration was confirmed in rabbits by measurement of the amounts of both DE-117 and hDE-117 in the aqueous humor. Ocular hypotensive efficacy of DE-117 was evaluated in ocular normotensive rabbits, dogs, and monkeys and in ocular hypertensive monkeys. Dosing frequency was as follows: single, in rabbits and ocular hypertensive monkeys; once a day for 28 days, in dogs; once a day for 7 days, in ocular normotensive monkeys. Efficacy in monkeys was compared with 0.005% latanoprost.
IC50 of hDE-117 to EP2 and EP4 were 10 nmol/L and 5.48 mmol/L, respectively. Binding activity of hDE-117 was stronger than that of DE-117, and more selective to EP2 than that of PGE2. After topical administration of 0.1% DE-117, Cmax of hDE-117 was 108 ± 23 ng/mL (mean ± SD), and the amount of DE-117 was not detectable. Single administration of DE-117 at 0.001%, 0.01%, and 0.03% significantly lowered IOP in rabbits. Repeated dosing of DE-117 at 0.0006% lowered IOP at every measurement point significantly in dogs. Maximal reductions in IOP from baseline of DE-117 at 0.0001%, 0.001% and 0.01% and latanoprost in ocular normotensive monkeys with repeated dosing for 7 days were 2.4 ± 0.6 mmHg, 7.6 ± 1.7 mmHg (p < 0.01), 13.3 ± 1.2 mmHg (p < 0.01), and 2.5 ± 0.4 mmHg (p < 0.01) (mean ± SE), respectively. Maximal reductions of IOP from baseline of single administration of 0.01% DE-117 and latanoprost in ocular hypertensive monkeys were 19.9 ± 3.0 mmHg and 9.7 ± 1.8 mmHg (mean ± SE, both p < 0.01), respectively.
These studies demonstrated that DE-117 has significant ocular hypotensive efficacy in both ocular normotensive and hypertensive animal models. The efficacy of DE-117 at certain concentration was greater than that of 0.005% latanoprost in monkeys.
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