Pharmacotherapeutic group: Antiglaucoma preparations and miotics, prostaglandin analogues. ATC code: S01EE04.
Pharmacology: Pharmacodynamics: Mechanism of action: Travoprost, a prostaglandin F2 analogue, is a highly selective full agonist which has a high affinity for the prostaglandin FP receptor, and reduces the intraocular pressure by increasing the outflow of aqueous humour via trabecular meshwork and uveoscleral pathways. Reduction of the intraocular pressure in man starts about 2 hours after administration and maximum effect is reached after 12 hours. Significant lowering of intraocular pressure can be maintained for periods exceeding 24 hours with a single dose.
Clinical efficacy and safety: In a clinical trial, patients with open-angle glaucoma or ocular hypertension treated with IZBA eye drops dosed once-daily in the evening, demonstrated intraocular pressure lowering equivalent to Travoprost 40 μg/ml eye drops, solution at all on-therapy visits and time points (95 % CI within ±1.0 mmHg). The mean reduction from baseline in IOP ranged from 7.1 to 8.2 mmHg as summarised in Table 1. The mean percent reductions in IOP from baseline to each study visit and assessment time point ranged from 28.4 % to 30.7 %. (See Table 1.)
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An improved safety profile has been observed for IZBA eye drops when compared to the marketed Travoprost 40 μg/ml eye drops, solution (benzalkonium chloride preserved or polyquaternium-1 preserved). The most common adverse reaction associated with both IZBA eye drops and Travoprost 40 μg/ml eye drops, solution is hyperaemia. Hyperaemia (ocular or conjunctival) was observed in 11.8 % of patients (N = 442) exposed to IZBA eye drops compared with 14.5 % observed for patients exposed to Travoprost 40 μg/ml eye drops, solution, benzalkonium chloride preserved.
Secondary pharmacology: Travoprost significantly increased optic nerve head blood flow in rabbits following 7 days of topical ocular administration (1.4 micrograms, once-daily).
Travoprost 40 μg/ml eye drops, solution 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.
Pharmacokinetics: Absorption: Travoprost is an ester prodrug. It is absorbed through the cornea where the isopropyl ester is hydrolysed to the active free acid. Studies in rabbits have shown peak concentrations of 20 ng/g of the free acid in aqueous humour one to two hours after topical dosing of Travoprost 40 μg/ml eye drops, solution. Aqueous humour concentrations declined with a half-life of approximately 1.5 hours.
Distribution: Following topical ocular administration of Travoprost 40 μg/ml eye drops, solution to healthy volunteers, low systemic exposure to active free acid was demonstrated. Peak active free acid plasma concentrations of 25 pg/ml or less were observed between 10 and 30 minutes post-dose. Thereafter, plasma levels declined rapidly to below the 10 pg/ml assay quantitation limit before 1 hour post-administration. Due to the low plasma concentrations and rapid elimination following topical dosing, the elimination half-life of active free acid in man could not be determined.
Biotransformation: Metabolism is the major route of elimination of both travoprost and the active free acid. The systemic metabolic pathways parallel those of endogenous prostaglandin F2 which are characterised by reduction of the double bond in position C13-C14, oxidation of the 15-hydroxyl and -oxidative cleavages of the upper side chain.
Elimination: Travoprost free acid and its metabolites are mainly excreted by the kidneys. Travoprost 40 μg/ml eye drops, solution has been studied in patients with mild to severe hepatic impairment and in patients with mild to severe renal impairment (creatinine clearance as low as 14 ml/min). No dosage adjustment is necessary in these patients.
Toxicology: Preclinical safety data: In ocular toxicity studies in monkeys, administration of travoprost at a dose of 0.45 microgram, twice a day, was shown to induce increased palpebral fissure. Topical ocular administration of travoprost to monkeys at concentrations of up to 0.012 % to the right eye, twice daily for one year resulted in no systemic toxicity.
Increased palpebral fissure observed in monkeys were not seen in rabbits or in the clinical trials with travoprost products and is considered to be species specific.
Reproduction toxicity studies have been undertaken in rat, mice and rabbit by systemic route. Findings are related to FP receptor agonist activity in uterus with early embryolethality, post-implantation loss, foetotoxicity. In pregnant rat, systemic administration of travoprost at doses more than 200 times the clinical dose during the period of organogenesis resulted in an increased incidence of malformations. Low levels of radioactivity were measured in amniotic fluid and foetal tissues of pregnant rats administered 3H-travoprost. Reproduction and development studies have demonstrated a potent effect on foetal loss with a high rate observed in rats and mice (180 pg/ml and 30 pg/ml plasma, respectively) at exposures 1.2 to 6 times the clinical exposure (up to 25 pg/ml).
Data to evaluate a potential effect on the environment are currently limited.