Gunfort® [Bimatoprost, Timolol]

Pharmacological properties

Gunfort - a combined drug, which includes bimatoprost and timolol maleate, which reduce high intraocular pressure (IOP) due to the combined effect, which allows to achieve a more pronounced effect compared to the effect of each drug separately.

Bimatoprost - an ophthalmic agent that reduces IOP, belongs to the group of synthetic prostamide, and according to its chemical structure - to prostaglandin F_2α (PGF_2α), bimatoprost does not affect any of the known types of prostaglandin receptors. The mechanism for reducing IOP of bimatoprost includes an increase in the outflow of intraocular fluid through the trabecular network and from the uveoscleral parts of the eye.

Timolol is a non-selective blocker of β-adrenergic receptors, without internal sympathomimetic and membrane-stabilizing activity.

Timolol reduces IOP by reducing the production of intraocular fluid. The exact mechanism of action of timolol has not been established, perhaps it is associated with inhibition of cAMP synthesis and is caused by endogenous stimulation of β-adrenergic receptors.

Bimatoprost reduces IOP with a peak hypotensive effect, noticeable about 12 hours after application; timolol reaches its peak antihypertensive effect after about 1–2 hours. Both drugs, both bimatoprost and timolol, significantly reduce IOP after the first instillation.

The hypotensive effect of the drug Gunfort is not inferior to the effect that is achieved with the help of adjuvant therapy with bimatoprost (1 time per day) and timolol (2 times per day).

Given the results of clinical trials conducted by Allergan, it is recommended to use the drug in the morning. However, if it is necessary for the patient, you can consider an additional dose of the drug in the evening. The results of bimatoprost studies show comparable indicators of IOP control, regardless of morning or evening dosing.

Pharmacokinetics Systemic absorption of the drug is minimal and does not differ both with combined treatment and with the administration of each of the components of the drug separately.

In two studies lasting 12 months, during which the absorption of the drug was studied, there is no systemic cumulation of any of the active substances.

Bimatoprost. In in vitro studies, bimatoprost penetrates well into the iris and sclera. The average coefficient of permeability in the cornea was 3.24 · 10^-6 cm / s. Bimatoprost penetrated into the sclera tissue better than into the corneal tissue, with an average permeability coefficient of 14.510^-6 cm / s. With topical application of eye drops of bimatoprost, the combined systemic effect is very low, without accumulation. When instillation of 0.03% bimatoprost solution, 1 drop in both eyes of a healthy person 1 time per day for 2 weeks, C_max bimatoprost in blood plasma was achieved within 10 minutes after administration, and within 1.5 hours its concentration in blood plasma decreased below the level of determination (0.025 ng / ml). The average values ​​of C_max and AUC_0-24 bimatoprost were close on the 7th and 14th day of administration and amounted to 0.08 ng / ml and 0.09 ng · h / ml, respectively, indicating that a balanced concentration of bimatoprost was achieved during the 1st week of local application.

In two three-phase studies of safety and efficacy, bimatoprost concentrations were measured in the blood of patients with glaucoma and ocular hypertension (n = 88, application - 1 time per day and n = 89 - 2 times per day). Samples were taken approximately 5 minutes after the evening intake on the 0th, 3rd, 6th and 12th month. Concentrations of bimatoprost in the blood were similar to those detected in healthy subjects, and there was no significant systemic accumulation of the substance for a long time. The C-1 acid metabolite (AGN 191522) was generally not detected in the blood during these studies.

Bimatoprost is evenly distributed in the tissues, the volume of the systemic distribution in humans upon reaching a balanced concentration of the substance was 0.67 l / kg. Bimatoprost is located mainly in blood plasma.

The relationship between bimatoprost and plasma proteins is about 88% at concentrations ranging from 1 to 250 ng / ml, regardless of concentration. (Note: when calculating the safety profile, the concentration of free substance in biological species was used). Up to 20% of bimatoprost entered into feedback with synthetic melanin at concentrations in the range of 0.2–100 μg / ml, which was also independent of concentration.

Bimotoprost is not intensively metabolized in the human eye and is one of the main circulating substances in the blood when it enters the systemic circulation after topical application. After that, bimatoprost undergoes glucuronidation, oxidation, N-diethylation and deamidation with the formation of various metabolites. Bimatoprost glucuronide conjugates are the most common metabolites that are excreted through the kidneys and gastrointestinal tract. It was established that hydrolysis of bimatoprost to free acid is not a necessary condition for its hypotensive effect.

Average c_max total radioactivity in the blood, determined after iv administration of radioactively labeled bimatoprost at a dose of 3.12 μg / kg to 6 healthy individuals, was 14.5 ng-eq / ml. Total radioactivity was excreted within a short T_½ 1.74 hours. The concentration of intact bimatoprost in the blood was a maximum of 12.2 ng / ml and rapidly decreased with T_½ at 0.771 hours (about 45 minutes). The concentrations of AGN 191522 and the metabolite C-1 acid in the blood were much lower than the concentrations of bimatoprost, since its C_max amounted to 0.12 ng / ml. The total clearance in the blood of unchanged bimatoprost is 1.50 l / h / kg.

About 67% of the administered dose of bimatoprost was excreted in the urine, with only a small fraction excreted as unchanged substance. 25% of the dose was excreted through the gastrointestinal tract, with 15–40% in the form of an unchanged substance.

Significant systemic accumulation of bimatoprost after application 2 times a day for 7 days was not observed in the age category of 18–44 years (mean value = 28.5) and in elderly patients 65–80 years (mean value = 71.0). Bimatoprost quickly entered the bloodstream in both age groups, and its concentration was below the detection limit after 1.5 hours in most patients. Systemic exposure was higher in the elderly than in the young, both after a single dose and after repeated use (124 and 213%, respectively). Average AUC_0-24 amounted to 0.0634 ng · h / ml in elderly patients and was statistically significantly higher than in young subjects (0.0218 ng · h / ml), which allowed the presence of an age factor. Nevertheless, this phenomenon is not considered clinically significant, since bimatoprost shows the same effectiveness and safety in both young patients and elderly people.

Timolol Timolol to a small extent binds to plasma proteins (~ 60%).

The systemic effect of timolol was well characterized after oral administration in humans. When administered orally in humans, timolol is rapidly and almost completely absorbed (~ 90%). Its plasma concentration can be determined within half an hour after administration, and C_max achieved approximately 1–2 hours after administration. T_½ timolol in plasma is 4 hours T_½ is essentially unchanged in patients with moderate renal failure.

Timolol is partially metabolized in the liver and excreted along with the metabolites through the kidneys. After oral administration, timolol undergoes a pre-systemic moderate metabolism (~ 50%), and only a small amount of unchanged substance is excreted in the urine along with metabolites.

In patients who underwent surgical treatment of cataracts, after instillation of eye drops in the form of 0.5% solution C_max timolol in the intraocular fluid after 1 h was 898 ng / ml. A certain amount of the drugs substance enters the systemic circulation. The half-life of timolol in blood plasma is about 4-6 hours.

A randomized cross-sectional pharmacokinetic study (192024-503T) involving 17 healthy subjects determined whether a combination of the individual components in the Gunfort drug could affect the systemic absorption of each individual component compared to absorption with monotherapy. The study participants received Gunfort, 0.03% bimatoprost and 0.5% timolol once a day, in the morning, for 7 days.

The mean values ​​of the pharmacokinetic parameters and the associated variables were very similar for bimatoprost during monotherapy and when using combination therapy, which indicates the absence of substance-substance interaction for bimatoprost.

The average value of C_max for timolol was lower (29%) when using the combined drug (p0.05) compared with timolol monotherapy. Given the systemic side effects associated with timolol, this reduction may be an advantage for combination therapy in terms of overall safety. No significant differences in AUC_0-24 and T_½ timolol between the use of a combination drug and monotherapy.

According to the results of two three-phase studies of safety and efficacy, blood bimatoprost concentrations measured in patients with glaucoma and ocular hypertension were similar to those found in healthy subjects, and there was no significant systemic accumulation of the drug for 12 months.

Indications

IOP reduction in patients with open-angle glaucoma and intraocular hypertension with insufficient effectiveness of monotherapy with drugs of the group of β-adrenergic receptor blockers and prostaglandin analogues for topical application.

Application

Gunfort is applied topically to the eye.

1 drop is instilled into the conjunctival sac of the affected eye 1 time per day in the morning.

If the drug is missed 1 time, the drug can be administered the next day. It is not recommended to exceed the dose - 1 introduction 1 time per day.

As in the case of other eye drops, in order to reduce possible systemic absorption, it is recommended to lightly press with your finger the inner edge of the lower eyelid near the nose for at least 1 minute immediately after instillation.

Use in elderly patients. Data on the safety and efficacy of the drug in elderly patients are similar to those of other adult patients.

Children. The safety and effectiveness of the use of the drug Gunfort in children have not been investigated.

The drug should not be prescribed to patients under the age of 18 years.

Contraindications

Hypersensitivity to timolol, bimatoprost and excipients that are part of the drug. Syndrome of increased reactivity of the respiratory tract, including acute stage BA and past episodes in history, severe hobl. sinus bradycardia, sinus node weakness syndrome, sinoatrial block, grade II and III av block, which is not controlled by a pacemaker, clinically expressed heart failure, cardiogenic shock.

Side effects

When using, the following adverse reactions may occur (in each group, adverse reactions are presented in order of decreasing severity).

The frequency of adverse reactions that are listed below is defined as follows:

Additional adverse reactions listed below were recorded with the active substances bimatoprost and timolol, and are possible with the use of Gunforta.

Bimatoprost

Timolol As with topical administration of other ophthalmic preparations, a systemic absorption of the active substances of the Hanfort drug (bimatoprost and timolol) is possible. Given the presence of the β-adrenergic component of timolol, adverse reactions typical of systemic β-adrenergic blockers may occur.

The incidence of systemic adverse reactions after topical application is lower than after systemic use. To reduce systemic absorption, see APPLICATION.

Additional adverse reactions that have been reported with topical use of β-adrenergic receptor blockers and may occur with the use of Gunfort are listed below.