Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group:
Ophthalmological – betablocking agents – timolol, combinations
ATC code: S01ED51

Mechanism of action

Xalacom consists of two components: latanoprost and timolol maleate. These two components decrease elevated intraocular pressure (IOP) by different mechanisms of action and the combined effect results in additional IOP reduction compared to either compound administered alone.

Latanoprost, a prostaglandin F2α analogue, is a selective prostanoid FP receptor agonist that reduces the IOP by increasing the outflow of aqueous humour. The main mechanism of action is increased uveoscleral outflow.
Additionally, some increase in outflow facility (decrease in trabecular outflow resistance) has been reported in man. Latanoprost has no significant effect on the production of aqueous humour, the blood-aqueous barrier or the intraocular blood circulation. Chronic treatment with latanoprost in monkey eyes, which had undergone extracapsular lens extraction did not affect the retinal blood vessels as determined by fluorescein angiography.
Latanoprost has not induced fluorescein leakage in the posterior segment of pseudophakic human eyes during short term treatment.
Timolol is a beta-1 and beta-2 (non-selective) adrenergic receptor blocking agent that has no significant intrinsic sympathomimetic, direct myocardial depressant or membrane-stabilising activity. Timolol lowers IOP by decreasing the formation of aqueous in the ciliary epithelium.
The precise mechanism of action is not clearly established, but inhibition of the increased cyclic AMP synthesis caused by endogenous beta-adrenergic stimulation is probable. Timolol has not been found to significantly affect the permeability of the blood-aqueous barrier to plasma proteins. In rabbits, timolol was without effect on the regional ocular blood flow after chronic treatment.

Pharmacodynamic effects

Clinical efficacy and safety
In dose finding studies, Xalacom produced significantly greater decreases in mean diurnal IOP compared to latanoprost and timolol administered once daily as monotherapy. In two well controlled, double masked six- month clinical studies the IOP reducing effect of Xalacom was compared with latanoprost and timolol monotherapy in patients with an IOP of at least 25 mm Hg or greater. Following a 2-4 week run-in with timolol (mean decrease in IOP from enrollment of 5 mm Hg), additional decreases in mean diurnal IOP of 3.1, 2.0 and 0.6 mm Hg were observed after 6 months of treatment for Xalacom, latanoprost and timolol (twice daily), respectively. The IOP lowering effect of Xalacom was maintained in 6 month open label extension of these studies.

Existing data suggest that evening dosing may be more effective in IOP lowering than morning dosing.
However, when considering a recommendation of either morning or evening dosing, sufficient consideration should be given to the lifestyle of the patient and their likely compliance.

It should be kept in mind that in case of insufficient efficacy of the fixed combination, results from studies indicate that the use of unfixed administration of Timolol bid and latanoprost once a day might be still efficient.

Onset of action of Xalacom is within one hour and maximal effect occurs within six to eight hours. Adequate IOP reducing effect has been shown to be present up to 24 hours post dosage after multiple treatments.

Pharmacokinetic Properties

5.2. Pharmacokinetic properties

Latanoprost
Absorption
Latanoprost is an isopropyl ester prodrug, which per se is inactive but after hydrolysis by esterases in the cornea to the acid of latanoprost, becomes biologically active. The prodrug is well absorbed through the cornea and all drug that enters the aqueous humor is hydrolysed during the passage through the cornea.


Distribution
Studies in man indicate that the maximum concentration in the aqueous humour, approximately 15-30 ng/mL, is reached about 2 hours after topical administration of latanoprost alone.After topical application in monkeys latanoprost is distributed primarily in the anterior segment, the conjunctiva and the eye lids.

The acid of latanoprost has a plasma clearance of 0.40 l/h/kg and a small volume of distribution, 0.16 l/kg, resulting in a rapid half life in plasma, 17 minutes. After topical ocular administration the systemic bioavailability of the acid of latanoprost is 45%. The acid of latanoprost has a plasma protein binding of 87%.

Biotransformation and elimination
There is practically no metabolism of the acid of latanoprost in the eye. The main metabolism occurs in the liver. The main metabolites, the 1,2-dinor and 1,2,3,4- tetranor metabolites, exert no or only weak biological activity in animal studies and are excreted primarily in the urine.

Timolol

Absorption and distribution
The maximum concentration of timolol in the aqueous humour is reached about 1 hour after topical administration of eye drops. Part of the dose is absorbed systemically and a maximum plasma concentration of 1 ng/mL is reached 10-20 minutes after topical administration of one eye drop to each eye once daily (300 micrograms/day).

Biotransformation
The half life of timolol in plasma is about 6 hours. Timolol is extensively metabolised in the liver.

Elimination
The metabolites are excreted in the urine together with some unchanged timolol.
Xalacom

Pharmacokinetic/pharmacodynamic relationship
No pharmacokinetic interactions between latanoprost and timolol were observed, although there was an approximate 2-fold increased concentration of the acid of latanoprost in aqueous humour 1-4 hours after administration of Xalacom compared to monotherapy.