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XALACOM (latanoprost and timolol ophthalmic solution (as timolol maleate) Action And Clinical Pharmacology

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Action And Clinical Pharmacology

Mechanism of Action

XALACOM (latanoprost and timolol maleate) consists of two components: latanoprost and timolol maleate. Each mL of XALACOM contains latanoprost 50 micrograms and timolol maleate 6.8 mg equivalent to 5 mg timolol. These two components decrease elevated intraocular pressure (IOP) by different mechanisms of action.

Latanoprost is a prostanoid selective FP receptor agonist which reduces the IOP by increasing the outflow of aqueous humor. The main mechanism of action is increased uveoscleral outflow. In addition, some increase in outflow facility (decrease in trabecular outflow resistance) has been reported in man. Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity. Timolol lowers the IOP by decreasing the formation of aqueous humor in the ciliary epithelium. The precise mechanism of action is not clearly established. The combined effect of these two agents administered as XALACOM once daily results in additional intraocular pressure reduction compared to either component administered alone separately. For details of information obtained from Clinical Trials with XALACOM, please refer to CLINICAL TRIALS section.

Pharmacokinetics

Latanoprost: Latanoprost is an isopropyl ester prodrug which is inactive but becomes biologically active after hydrolysis to the acid of latanoprost. The prodrug is well absorbed through the cornea and all drug that enters the aqueous humor is hydrolysed by esterases during the passage through the cornea. Studies in man indicate that the maximum concentration in the aqueous humor, approximately 30 ng/mL, is reached about 2 hours after topical administration of latanoprost alone. 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%. The main metabolism occurs in the liver. There is practically no metabolism of the acid of latanoprost in the eye. The main metabolites, 1,2-dinor and 1,2,3,4- tetranor metabolites, exert no or weak biological activity in animal studies and are excreted primarily in the urine.

Timolol: The maximum concentration of timolol in the aqueous humor is reached about one hour after topical ocular administration. Part of the dose is absorbed systemically and a maximum plasma concentration of 1 ng/mL is reached 10-20 minutes after topical ocular administration of one drop to each eye once daily (300mcg/day). The half-life of timolol in plasma is about 6 hours. Timolol is extensively metabolized in the liver. The metabolites, and unchanged timolol, are excreted in the urine.

XALACOM: No pharmacokinetic interactions between latanoprost and timolol have been observed although the aqueous humor concentrations of the acid of latanoprost tended to be higher 1 to 4 hours after administration of the combination product compared to monotherapy with either latanoprost or timolol.

Special Populations and Conditions

Elderly, Gender, Pediatric and Race: Differences in the pharmacokinetics of XALACOM in these populations has not been investigated.

Diseases and Demographic Characteristics: No studies have been performed to investigate the influence of other diseases or demographic characteristics on the pharmacokinetics of XALACOM due to the inherit difficulties in measuring the drug concentrations after topical administration on the eyes.

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