DuoTrav

DuoTrav Mechanism of Action

travoprost + timolol

Manufacturer:

Novartis

Distributor:

Zuellig
/
Firma Chun Cheong
Full Prescribing Info
Action
Pharmacotherapeutic group: Ophthalmologicals; Antiglaucoma preparations and miotics. ATC code: S01ED51.
Pharmacology: Pharmacodynamics: Mechanism of action: DuoTrav eye drops contain 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 F 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 eye drops dosed once-daily in the morning was 8 to 10 mmHg. The non-inferiority of DuoTrav eye drops 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 eye drops 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 (08:00, 24 hours after the last dose of DuoTrav eye drops) 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 hypertension and baseline mean IOP of 23 to 26 mmHg, the mean IOP-lowering effect of DuoTrav eye drops 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 eye drops (polyquaternium-1-preserved) dosed once-daily in the morning was 8 mmHg and equivalent to that of DuoTrav eye drops (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 eye drops 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.
Pharmacokinetics: 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 eye drops 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 eye drops.
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 eye drops. 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 eye drops.
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 F 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 eye drops.
Elimination: Travoprost free acid and its metabolites are mainly excreted by the kidneys. Less than 2% of an 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.
Toxicology: Preclinical safety data: In monkeys, administration of DuoTrav eye drops twice-daily was shown to induce increased palpebral fissure and to increase iris pigmentation similar to that observed with ocular administration of prostanoids.
DuoTrav eye drops preserved with polyquaternium-1 induced minimal ocular surface toxicity, compared to eye drops preserved with benzalkonium chloride, on cultured human corneal cells and following topical ocular administration in rabbits.
Travoprost: Topical ocular administration of travoprost to monkeys at concentrations of up to 0.012% to the right eye, twice daily for one year resulted in no systemic toxicity.
Reproduction toxicity studies with travoprost have been undertaken in rats, mice and rabbits using the systemic route. Findings are related to FP receptor agonist activity in uterus with early embryolethality, post-implantation loss and foetotoxicity. In pregnant rats, systemic administration of travoprost at doses more than 200 times the clinical dose during the period of organogenesis resulted in an increased incidence of malformations. Low levels of radioactivity were measured in amniotic fluid and foetal tissues of pregnant rats administered 3H-travoprost.
Reproduction and development studies have demonstrated a potent effect on foetal loss with a high rate observed in rats and mice (180 pg/mL and 30 pg/mL plasma, respectively) at exposures 1.2 to 6 times the clinical exposure (up to 25 pg/mL).
Timolol: Non-clinical data revealed no special hazard for humans with timolol based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential. Reproduction toxicity studies with timolol showed delayed foetal ossification in rats with no adverse effects on postnatal development (7000 times the clinical dose) and increased foetal resorptions in rabbits (14000 times the clinical dose).
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