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S. Saati, J. Russell, R. Varma, E. Meng, S. Louie, M. S. Humayun; Pharmacokinetics and Intraocular Pressure Lowering Effect of Timolol 0.5% (Ocudose) and Travoprost 0.004%(Travatan-z) in Rabbit Eyes. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3164.
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© ARVO (1962-2015); The Authors (2016-present)
To compare the pharmacokinetics and intraocular pressure (IOP) lowering effect of glaucoma drops (Timolol vs.Travoprost) in rabbits
This study compares the absorption profile and IOP lowering effect of 0.5% Timolol (Ocudose) and 0.004% Travoprost (Travatan-z) following a single instillation into the right eye of pigmented rabbits. Twelve rabbits were assigned to four groups of three each. A single drop (50 µL) of Timolol and Travoprost was administered in the middle of the lower conjunctival sac in groups (A, B) and (C, D), respectively. IOP value was measured in groups A and C before and 0.5, 1, 2, 4 and 6 hours after instillation. Aqueous humor samples (100 µL) were collected from groups B and D at the same time points for total of 2 and 6 hours, respectively, after drug application. Drug concentrations were analyzed, using LC-MS.
Travoprost displayed a Cmax of 30.1 ± 1.56 ng/ml of free acid at 1 hour after instillation and tapered off to 6.15 ± 0.46 ng/ml by 6 hours. Timolol reached a mean peak concentration of 854.66 ± 85 ng/ml at 0.5 hour after application and fell to 259.66±31.02 ng/ml by 2 hours. The pharmacokinetics of Timolol appears to be linear elimination, where the half-life was calculated to be 0.88 ± 0.23 hours. Travoprost elimination follows a two-compartment model, where an initial elimination phase is followed by a slower beta elimination phase. A Travoprost half-life of 2.14 ± 0.13 hours was calculated. The time of maximum IOP reduction after Timolol application (at 0.5 hour) was correlated to that of maximum concentration. IOP values gradually returned to baseline after 2 hours, which is parallel to tapering off the drug concentration in anterior chamber (AC). The time of maximum IOP reduction (at 2 hours) after Travoprost application was obviously later than mean peak concentration (at 1 hour). The IOP values increased slightly after 2 hours and still remained lower than baseline.
Timolol and Travoprost free acid concentration in the AC were minimal compared to the original concentration administered yet ng/ml can lead to an IOP reduction. The higher Cmax for Timolol is consistent with a higher corneal permeability. Timolol was shown to absorb faster with higher concentration over the 6 hour study. This profile is consistent with earlier reduction of IOP following Timolol administration compared to Travoprost adminstration.
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