VYZULTA Οphthalmic solution Ref.[10112] Active ingredients: Latanoprostene bunod

Reduction of the intraocular pressure starts approximately 1 to 3 hours after the first administration with the maximum effect reached after 11-13 hours in eyes with elevated intraocular pressure.

Absorption

The systemic exposure of latanoprostene bunod and its metabolites latanoprost acid and butanediol mononitrate were evaluated in one study with 22 healthy subjects after topical ocular administration of VYZULTA 0.024% once daily (one drop bilaterally in the morning) for 28 days. There were no quantifiable plasma concentrations of latanoprostene bunod (lower limit of quantitation, LLOQ, of 10.0 pg/mL) or butanediol mononitrate (LLOQ of 200 pg/mL) post-dose on Day 1 and Day 28. The mean maximal plasma concentrations (C_max) of latanoprost acid (LLOQ of 30 pg/mL) were 59.1 pg/mL and 51.1 pg/mL on Day 1 and Day 28, respectively. The mean time of maximal plasma concentration (T_max) for latanoprost acid was approximately 5 minutes post-administration on both Day 1 and Day 28.

Distribution

There were no ocular distribution studies performed in humans.

Metabolism

After topical ocular administration, latanoprostene bunod is rapidly metabolized in the eye to latanoprost acid (active moiety), an F2α prostaglandin analog, and butanediol mononitrate. After latanoprost acid reaches the systemic circulation, it is primarily metabolized by the liver to the 1,2-dinor and 1,2,3,4-tetranor metabolites via fatty acid β-oxidation.

Butanediol mononitrate is metabolized to 1,4-butanediol and nitric oxide. The metabolite 1,4-butanediol is further oxidized to succinic acid and enters the tricarboxylic acid (TCA) cycle.

Elimination

The elimination of latanoprost acid from human plasma is rapid as latanoprost acid plasma concentration dropped below the LLOQ (30 pg/mL) in the majority of subjects by 15 minutes following ocular administration of VYZULTA 0.024% in humans.

Latanoprostene bunod was not mutagenic in bacteria and did not induce micronuclei formation in the in vivo rat bone marrow micronucleus assay. Chromosomal aberrations were observed in vitro with human lymphocytes in the absence of metabolic activation.

Latanoprostene bunod has not been tested for carcinogenic activity in long-term animal studies. Latanoprost acid is a main metabolite of latanoprostene bunod. Exposure of rats and mice to latanoprost acid, resulting from oral dosing with latanoprost in lifetime rodent bioassays, was not carcinogenic.

Fertility studies have not been conducted with latanoprostene bunod. The potential to impact fertility can be partially characterized by exposure to latanoprost acid, a common metabolite of both latanoprostene bunod and latanoprost. Latanoprost acid has not been found to have any effect on male or female fertility in animal studies.

A 9-month toxicology study administered topical ocular doses of latanoprostene bunod to one eye of cynomolgus monkeys: control (vehicle only), one drop of 0.024% bid, one drop of 0.04% bid and two drops of 0.04% per dose, bid. The systemic exposures are equivalent to 4.2-fold, 7.9-fold, and 13.5-fold the clinical dose, respectively, on a body surface area basis (assuming 100% absorption). Microscopic evaluation of the lungs after 9 months observed pleural/subpleural chronic fibrosis/inflammation in the 0.04% dose male groups, with increasing incidence and severity compared to controls. Lung toxicity was not observed at the 0.024% dose.

In clinical studies up to 12 months duration, patients with open-angle glaucoma or ocular hypertension with average baseline intraocular pressures (IOPs) of 26.7 mmHg, the IOP-lowering effect of VYZULTA (latanoprostene bunod ophthalmic solution) 0.024% once daily (in the evening) was up to 7 to 9 mmHg.