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Takafumi Ouchi, Cheryl Rowe-Rendleman, Douglas Ross, Fumitaka Suto, Andrew Wood; Single dose pharmacokinetics of ONO-9054 in healthy volunteers. Invest. Ophthalmol. Vis. Sci. 2013;54(15):441. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
ONO-9054 (Ono Pharmaceuticals, Osaka Japan) is a novel prodrug compound with ocular hypotensive activity. ONO-9054 is an isopropyl ester derivative of the free acid ONO-AG-367 that has been classified as a dual FP/EP3 agonist that may be effective in lowering intraocular pressure in humans. The serum levels of the parent compound and its active metabolite were measured after instillation of a single dose to the eyes of healthy volunteers.
A randomized, double-masked, placebo controlled clinical trial (NCT01508988) was conducted with 48 healthy volunteers who received a single dose of ONO-9054 ranging in concentration from 0.3-30 ug/mL q.d. in the morning. Blood samples were collected by venipuncture at predose, 5, 10, 20, 30, and 45 minutes; 1, 1.5, 2, 4, 6, 8, and 12 hours following dose. All samples were centrifuged within 30 minutes of blood collection and the plasma samples were stored at -70°C. The pharmacokinetic parameters of Cmax, Tmax, T1/2, and AUClast were calculated.
The plasma concentration of ONO-9054 was below the limit of quantitation in all but 1 volunteer. The plasma concentration of ONO-AG-367 reached Cmax at a median range Tmax of 10 to 15 minutes for all doses. The mean T1/2 ranged from 0.48 to 0.83h. At 6 h and later time points, the plasma concentration of ONO-AG-367 was below the limit of quantification. Cmax and AUClast of ONO-AG-367 generally increased with dose.
The active compound ONO-AG-367 was almost completely metabolized within the first hour after dosing. Pharmacokinetic modeling based upon these single dose pharmacokinetic results suggests that the systemic concentrations of ONO-AG-367 disappear rapidly but there is a possibility that q.d. dosing may maintain the drug at clinically effective levels which could lower IOP in the eye. Additionally, this pharmacokinetic modeling could be useful to evaluate the relationship between plasma concentration of ONO-AG-367 and the systemic safety. Based upon this rationale, these results support the need for additional clinical trials to demonstrate efficacy, safety and pharmacokinetics of multiple doses of ONO-9054 ophthalmic solution to manage patients with elevated pressures as a result of glaucoma.
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