Pharmacotherapeutic Group: Prostaglandin F2a analogue. Glaucoma and ocular hypertension treatment agent.
Pharmacology: Pharmacodynamics: The active substance latanoprost, a prostaglandin F2α analogue, is a selective prostanoid FP receptor agonist that reduces the IOP by increasing the outflow of aqueous humor, primarily through the uveoscleral route and also through the trabecular meshwork. Reduction of the intraocular pressure in man starts about three to four hours after administration and maximum effect is reached after eight to twelve hours. Pressure reduction is maintained for at least 24 hours. Pivotal studies have demonstrated that Xalatan is effective as a monotherapy. In addition clinical trials investigating combination use have been performed. These include studies that show that latanoprost is effective in combination with beta-adrenergic antagonists (timolol). Short term (1 or 2 weeks) studies suggest that the effect of latanoprost is additive in combination with adrenergic agonists (dipivalyl epinephrine, oral carbonic anhydrase inhibitors (acetazolamide) and at least partly additive with cholinergic agonists (pilocarpine).
Clinical trials have shown that latanoprost has no significant effect on the production of aqueous humor. Latanoprost has not been found to have any effect on the blood-aqueous barrier.
Clinical studies of latanoprost in primary chronic angle closure glaucoma have been limited to 12 weeks. Clinical efficacy and safety in patients with primary chronic angle glaucoma have not been established beyond 12 weeks.
Latanoprost has not induced fluorescein leakage in the posterior segment of pseudophakic human eyes during short-term treatment.
Latanoprost in clinical doses has not been found to have any significant pharmacological effects on the cardiovascular or respiratory system.
Pharmacokinetics: Absorption: Latanoprost is absorbed through the cornea where the isopropyl ester prodrug is hydrolyzed to the acid form to become biologically active. Studies in man indicate that the peak concentration in the aqueous humor is reached about two hours after topical administration.
Distribution: The distribution volume in humans is 0.16 ± 0.02 L/kg. The acid of latanoprost can be measured in aqueous humor during the first four hours, and in plasma only during the first hour after local administration.
Metabolism: Latanoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to the biologically active acid. The active acid of latanoprost reaching the systemic circulation is primarily metabolized by the liver to the 1,2-dinor and 1,2,3,4-tetranor metabolites via fatty acid β-oxidation.
Excretion: The elimination of the acid of latanoprost from human plasma is rapid (t1/2=17 min) after both intravenous and topical administration. Systemic clearance is approximately 7 mL/min/kg. Following hepatic β-oxidation, the metabolites are mainly eliminated via the kidneys. Approximately 88% and 98% of the administered dose is recovered in the urine after topical and intravenous dosing, respectively.
Toxicology: Preclinical safety data: Systemic/Ocular Effects: The ocular as well as systemic toxicity of latanoprost has been investigated in several animal species. Generally, latanoprost is well tolerated with a safety margin between clinical ocular dose and systemic toxicity of at least 1000 times. High doses of latanoprost, approximately 100 times the clinical dose/kg body weight, administered intravenously to unanesthetized monkeys have been shown to increase the respiration rate probably reflecting bronchoconstriction of short duration. In monkeys, latanoprost has been infused intravenously in doses of up to 500 mcg/kg without major effects on the cardiovascular system. In animal studies, latanoprost has not been found to have sensitizing properties. In the eye, no toxic effects have been detected with doses of up to 100 micrograms/eye/day in rabbits or monkeys (clinical dose is approximately 1.5 micrograms/eye/day). Latanoprost has no or negligible effects on the intraocular blood circulation when used at the clinical dose and studied in monkeys.
In chronic ocular toxicity studies, administration of latanoprost 6 micrograms/eye/day has also been shown to induce increased palpebral fissure. This effect is reversible and occurs at doses above the clinical dose level. The effect has not been seen in humans.
Carcinogenesis: Carcinogenicity studies in mice and rats were negative.
Mutagenesis: Latanoprost was found negative in reverse mutation tests in bacteria, gene mutation in mouse lymphoma and mouse micronucleus test. Chromosome aberrations were observed in vitro with human lymphocytes. Similar effects were observed with prostaglandin F2α, a naturally occurring prostaglandin, and indicate that this is a class effect.
Additional mutagenicity studies on in vitro/in vivo unscheduled DNA synthesis in rats were negative and indicate that latanoprost does not have mutagenic potency.
Impairment of Fertility: Latanoprost has not been found to have any effect on male or female fertility in animal studies. In the embryotoxicity study in rats, no embryotoxicity was observed at intravenous doses (5, 50 and 250 micrograms/kg/day) of latanoprost. However, latanoprost induced embryolethal effects in rabbits at doses of 5 micrograms/kg/day and above. Latanoprost has been shown to cause embryofetal toxicity in rabbits characterized by increased incidences of late resorption and abortion and reduced fetal weight when given in intravenous doses approximately 100 times the human dose.
Teratogenesis: No teratogenic potential has been detected.