Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Ophthalmologicals; Antiglaucoma preparations and miotics. ATC code: S01ED51.


Mechanism of action
DuoTrav contains two active substances: travoprost and timolol maleate. These two components lower intraocular pressure by complementary mechanisms of action and the combined effect results in additional IOP reduction compared to either compound alone.
Travoprost, a prostaglandin F2α analogue, is a full agonist which is highly selective and has a high affinity for the prostaglandin FP receptor, and reduces the intraocular pressure by increasing the outflow of aqueous humour via trabecular meshwork and uveoscleral pathways. Reduction of IOP in man starts within approximately 2 hours after administration and maximum effect is reached after 12 hours. Significant lowering of intraocular pressure can be maintained for periods exceeding 24 hours with a single dose.
Timolol is a non-selective adrenergic blocking agent that has no intrinsic sympathomimetic, direct myocardial depressant or membrane-stabilising activity. Tonography and fluorophotometry studies in man suggest that its predominant action is related to reduced aqueous humour formation and a slight increase in outflow facility.


Secondary pharmacology
Travoprost significantly increased optic nerve head blood flow in rabbits following 7 days of topical ocular administration (1.4 micrograms, once-daily).


Pharmacodynamic effects
Clinical effects
In a twelve-month, controlled clinical study in patients with open-angle glaucoma or ocular hypertension and baseline mean IOP of 25 to 27 mmHg, the mean IOP-lowering effect of DuoTrav dosed once-daily in the morning was 8 to 10 mmHg. The non-inferiority of DuoTrav as compared to latanoprost 50 micrograms/ml + timolol 5 mg/ml in the mean IOP reduction was demonstrated across all time-points at all visits.
In a three-month, controlled clinical study in patients with open-angle glaucoma or ocular hypertension and baseline mean IOP of 27 to 30 mmHg, the mean IOP-lowering effect of DuoTrav dosed once-daily in the morning was 9 to 12 mmHg, and was up to 2 mmHg greater than that of travoprost 40 micrograms/ml dosed once-daily in the evening and 2 to 3 mmHg greater than that of timolol 5 mg/ml dosed twice daily. A statistically superior reduction in morning mean IOP (8:00, 24 hours after the last dose of DuoTrav) was observed compared to travoprost at all visits throughout the study.


In two three-month, controlled clinical studies in patients with open-angle glaucoma or ocular DUO API DEC20 V3                                                                    EU SmPC Oct2020 hypertension and baseline mean IOP of 23 to 26 mmHg, the mean IOP-lowering effect of DuoTrav dosed once-daily in the morning was 7 to 9 mmHg. Mean IOP reductions were non-inferior, although numerically lower, to those achieved by concomitant therapy with travoprost 40 micrograms/ml dosed once-daily in the evening and timolol 5 mg/ml dosed once-daily in the morning.
In a 6-week, controlled clinical study in patients with open-angle glaucoma or ocular hypertension and baseline mean IOP of 24 to 26 mmHg, the mean IOP-lowering effect of DuoTrav (polyquaternium-1-preserved) dosed once-daily in the morning was 8 mmHg and equivalent to that of DuoTrav (benzalkonium chloride-preserved).


Inclusion criteria were common across the studies, with the exception of the IOP entry criteria and response to previous IOP therapy. The clinical development of DuoTrav included both patients naive and on therapy. Insufficient responsiveness to monotherapy was not an inclusion criterion.


Existing data suggest that evening dosing might have some advantages as regards mean IOP reduction. Consideration should be given to patient convenience and their likely compliance when recommending morning vs. evening dosing.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption
Travoprost and timolol are absorbed through the cornea. Travoprost is a prodrug that undergoes rapid ester hydrolysis in the cornea to the active free acid. Following once daily administration of DuoTrav PQ in healthy subjects (N= 22) for 5 days, travoprost free acid was not quantifiable in plasma samples from the majority of subjects (94.4%) and generally was not detectable one hour after dosing. When measurable (>0.01 ng/ml, the assay limit of quantitation), concentrations ranged from 0.01 to 0.03 ng/ml. The mean timolol steady- state Cmax was 1.34 ng/ml and Tmax was approximately 0.69 hours after once-daily administration of DuoTrav.


Distribution
Travoprost free acid can be measured in the aqueous humour during the first few hours in animals and in human plasma only during the first hour after ocular administration of DuoTrav. Timolol can be measured in human aqueous humour after ocular administration of timolol and in plasma for up to 12 hours after ocular administration of DuoTrav.


Biotransformation
Metabolism is the major route of elimination of both travoprost and the active free acid. The systemic metabolic pathways parallel those of endogenous prostaglandin F2α which are characterised by reduction of the 13-14 double bond, oxidation of the 15-hydroxyl and β-oxidative cleavages of the upper side chain.


Timolol is metabolised by two pathways. One route yields an ethanolamine side chain on the thiadiazole ring and the other gives an ethanolic side chain on the morpholine nitrogen and a second similar side chain with a carbonyl group adjacent to the nitrogen. The plasma t1/2 of timolol is 4 hours after ocular administration of DuoTrav.


Elimination
Travoprost free acid and its metabolites are mainly excreted by the kidneys. Less than 2% of an DUO API DEC20 V3                                                                     EU SmPC Oct2020 ocular dose of travoprost was recovered in urine as free acid. Timolol and its metabolites are primarily excreted by the kidneys. Approximately 20% of a timolol dose is excreted in the urine unchanged and the remainder excreted in urine as metabolites.