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Travatan Z (Travoprost Ophthalmic) - Description and Clinical Pharmacology



Travoprost is a synthetic prostaglandin F analogue. Its chemical name is [1R-[1α(Z),2β(1E,3R*),3α,5α]]-7-[3,5-Dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl) phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethylester. It has a molecular formula of C26H35F3O6 and a molecular weight of 500.55. The chemical structure of travoprost is:

Travoprost is a clear, colorless to slightly yellow oil that is very soluble in acetonitrile, methanol, octanol, and chloroform. It is practically insoluble in water.

TRAVATAN Z® (travoprost ophthalmic solution) 0.004% is supplied as sterile, buffered aqueous solution of travoprost with a pH of approximately 5.7 and an osmolality of approximately 290 mOsmol/kg.

TRAVATAN Z® contains Active: travoprost 0.04 mg/mL; Inactives: polyoxyl 40 hydrogenated castor oil, sofZia® (boric acid, propylene glycol, sorbitol, zinc chloride), sodium hydroxide and/or hydrochloric acid (to adjust pH) and purified water, USP. Preserved in the bottle with an ionic buffered system, sofZia®.


Mechanism of Action

Travoprost free acid, a prostaglandin analog is a selective FP prostanoid receptor agonist which is believed to reduce intraocular pressure by increasing uveoscleral outflow. The exact mechanism of action is unknown at this time.


Travoprost is absorbed through the cornea and is hydrolyzed to the active free acid. Data from four multiple dose pharmacokinetic studies (totaling 107 subjects) have shown that plasma concentrations of the free acid are below 0.01 ng/ml (the quantitation limit of the assay) in two-thirds of the subjects. In those individuals with quantifiable plasma concentrations (N=38), the mean plasma Cmax was 0.018 ± 0.007 ng/ml (ranged 0.01 to 0.052 ng/mL) and was reached within 30 minutes. From these studies, travoprost is estimated to have a plasma half-life of 45 minutes. There was no difference in plasma concentrations between Days 1 and 7, indicating steady-state was reached early and that there was no significant accumulation.

Travoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to its biologically active free acid. Systemically, travoprost free acid is metabolized to inactive metabolites via beta-oxidation of the α(carboxylic acid) chain to give the 1,2-dinor and 1,2,3,4-tetranor analogs, via oxidation of the 15-hydroxyl moiety, as well as via reduction of the 13,14 double bond.

The elimination of travoprost free acid from plasma was rapid and levels were generally below the limit of quantification within one hour after dosing. The terminal elimination half-life of travoprost free acid was estimated from fourteen subjects and ranged from 17 minutes to 86 minutes with the mean half-life of 45 minutes. Less than 2% of the topical ocular dose of travoprost was excreted in the urine within 4 hours as the travoprost free acid.


Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies in mice and rats at subcutaneous doses of 10, 30, or 100 mcg/kg/day did not show any evidence of carcinogenic potential. However, at 100 mcg/kg/day, male rats were only treated for 82 weeks, and the maximum tolerated dose (MTD) was not reached in the mouse study. The high dose (100 mcg/kg) corresponds to exposure levels over 400 times the human exposure at the maximum recommended human ocular dose (MRHOD) of 0.04 mcg/kg, based on plasma active drug levels.

Travoprost was not mutagenic in the Ames test, mouse micronucleus test or rat chromosome aberration assay. A slight increase in the mutant frequency was observed in one of two mouse lymphoma assays in the presence of rat S-9 activation enzymes.

Travoprost did not affect mating or fertility indices in male or female rats at subcutaneous doses up to 10 mcg/kg/day [250 times the maximum recommended human ocular dose of 0.04 mcg/kg/day on a mcg/kg basis (MRHOD)]. At 10 mcg/kg/day, the mean number of corpora lutea was reduced, and the post-implantation losses were increased. These effects were not observed at 3 mcg/kg/day (75 times the MRHOD).


In clinical studies, patients with open-angle glaucoma or ocular hypertension and baseline pressure of 25-27 mmHg who were treated with TRAVATAN® (travoprost ophthalmic solution) 0.004% or TRAVATAN Z® (travoprost ophthalmic solution) 0.004% dosed once-daily in the evening demonstrated 7-8 mmHg reductions in intraocular pressure. In subgroup analyses of these studies, mean IOP reduction in black patients was up to 1.8 mmHg greater than in non-black patients. It is not known at this time whether this difference is attributed to race or to heavily pigmented irides.

In a multi-center, randomized, controlled trial, patients with mean baseline intraocular pressure of 24-26 mmHg on TIMOPTIC* 0.5% BID who were treated with TRAVATAN® (travoprost ophthalmic solution) 0.004% dosed QD adjunctively to TIMOPTIC* 0.5% BID demonstrated 6-7 mmHg reductions in intraocular pressure.

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