Travatan Mechanism of Action

Pharmacotherapeutic Group: Ophthalmologicals-antiglaucoma preparations and miotics-prostaglandin analogues. ATC code: S01E E04.
Pharmacology: Pharmacodynamics: Mechanism of action: Travoprost, a prostaglandin F2α analogue, is a highly selective full agonist which has a high affinity for the prostaglandin FP receptor, and is believe to reduce IOP by increasing the outflow of aqueous humour via trabecular meshwork and uveoscleral pathways. Reduction of IOP in human starts about 2 hours after administration and maximum IOP reduction is reached within 12 hours. Significant lowering of IOP can be maintained for periods exceeding 24 hours with a single dose.
As primary therapy, TRAVATAN eye drops, dosed once daily, reduced IOP 7 to 9 mmHg. Stable diurnal IOP reductions were achieved as early as 2 weeks after initiation of therapy and were maintained over 6 to 12 month treatment periods in 3 well-controlled studies.
Pharmacodynamic effects: In addition to reducing IOP, travoprost has been shown to increase optic nerve head blood flow, and decrease tear film stability and tear secretion. Travoprost does not affect respiration rate/volume or systolic blood pressure during exercise and recovery. Prostaglandin F2α analogs can induce the anagen phase in hair follicles and stimulate melanogenesis in the skin.
Travoprost 0.004% eye drops preserved with polyquaternium-1 induced minimal ocular surface toxicity, compared to eye drops preserved with benzalkonium chloride, on cultured human corneal cells and following topical ocular administration in rabbits.
Pharmacodynamic/Pharmacokinetic relationship: See Pharmacology: Pharmacokinetics under Actions.
Data from clinical trials: In a clinical trial, patients with open-angle glaucoma or ocular hypertension who were treated with Travoprost 0.004% eye drops (polyquaternium-preserved) dosed QD in the evening demonstrated 8-9 mmHg reductions (approximately 33%) in IOP from a baseline range of 24-36 mmHg. Data on adjunctive administration of Travoprost 0.004% eye drops with timolol 0.5% and limited data with brimonidine 0.2% collected during clinical trials showed an additive effect of Travoprost 0.004% eye drops with these concomitant medications. No clinical data are available on adjunctive use with other ocular hypotensive medications. Travoprost 0.004% eye drops is generally well-tolerated and safe. The most common side effect is hyperemia, as observed with other ophthalmic prostaglandin analogs.
Pediatric population: See Dosage & Administration.
Pharmacokinetics: Absorption: Travoprost is an isopropyl ester prodrug. It is absorbed through the cornea where the isopropyl ester is hydrolysed to the active free acid. Studies in rabbits have shown maximum concentrations of approximately 20 ng/g of travoprost free acid in aqueous humour were achieved within 1-2 hours of topical ocular dosing. Aqueous humour concentrations of travoprost free acid declined with a half-life of approximately 1.5 hours. Low concentrations of travoprost free acid are also found in plasma following topical dosing.
Distribution: Following topical ocular administration to humans, low systemic exposure to active free acid was observed, with peak plasma concentrations of 20 pg/ml or less observed between 10 and 20 minutes post-dose. Plasma concentrations declined rapidly to below the 10 pg/ml assay quantitation limit within 1 hour of administration. Trace plasma concentrations of travaprost may be present immediately following dosing in some subjects.
Biotransformation: Metabolism is the major route of clearance for both travoprost and its free acid in nonclinical species. The systemic metabolic pathways parallel those of endogenous prostaglandin F2α which are characterised by reduction of the 13-14 double bond, oxidation of the 15-hydroxyl to a ketone and β-oxidative cleavages of the carboxylic acid side chain.
Elimination: Following administration of radiolabelled travoprost to rats, approximately 95% of the dose was eliminated within 24 hours. Approximately, 75% of the dose was eliminated in the feces and the remainder was excreted in urine.
Linear/non-linear pharmacokinetics: Travoprost exhibits linear pharmacokinetics in both ocular tissues and plasma after topical ocular administration.
Pharmacokinetic/pharmacodynamic relationship(s): Pharmacokinetic and pharmacodynamics relationship has not been established for travaprost after topical ocular administration.
Pharmacokinetics in special populations: The systemic pharmacokinetics of Travoprost 0.004% eye drops has been studied in patients with mild to severe hepatic impairment as well as in patients with mild to severe renal impairment (creatine clearance as low as 14 mL/minute). No dose adjustment is required in these populations.
Pediatric pharmacokinetics: The systemic pharmacokinetics of travoprost after topical ocular administration in patients between the ages of 2 months to less than 18 years of age showed a similar concentration range to that of adults, with most plasma samples below the limit of quantitation of 10 pg/mL.
Toxicology: Preclinical Safety Data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, and carcinogenic potential. Adverse reproductive and developmental toxicity was observed in animals at exposure levels of travoprost similar to clinical exposure levels and is possibly relevant to clinical use.