Travoprost

Travoprost, a prostaglandin F_2α 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.

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/mL of the free acid in aqueous humour one to two hours after topical dosing of travoprost. Aqueous humour concentrations declined with a half-life of approximately 1.5 hours.

Distribution

Following topical ocular administration of travoprost 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 F_2α which are characterised by reduction of the 13-14 double bond, 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 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.

Paediatric population

A pharmacokinetic study in paediatric patients aged 2 months to <18 years demonstrated very low plasma exposure to travoprost free acid, with concentrations ranging from below the 10 pg/mL assay limt of quantitation (BLQ) to 54.5 pg/mL. In 4 previous systemic pharmacokinetic studies in adult populations, travoprost free acid plasma concentrations ranged from BLQ to 52.0 pg/mL. While most of the plasma data across all studies was non-quantifiable, making statistical comparisons of systemic exposure across age groups unfeasible, the overall trend shows that plasma exposure to travoprost free acid following topical administration is extremely low across all age groups evaluated.

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.

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).