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Pharmacotherapeutic group: Ophthalmologicals, antiglaucoma preparations and miotics. ATC code: S01ED51.
Pharmacology: Mechanism of action (MOA): DuoTrav contains two active ingredients: travoprost and timolol maleate. These two agents reduce IOP by complementary mechanisms of action with a combined effect greater than that of either compound administered alone (synergistic effect).
Travoprost, a prostaglandin F2alpha analogue, is a full agonist which is highly selective and has a high affinity for the prostaglandin FP receptor, and reduces IOP by increasing the outflow of aqueous humor via trabecular meshwork and uveoscleral pathways. Reduction of IOP in humans starts within approximately 2 hours of administration and maximum effect is achieved within 12 hours. Significant IOP reduction can be maintained for periods exceeding 24 hours following a single dose.
Timolol is a non-selective beta-adrenergic blocking agent that has no intrinsic sympathomimetic, direct myocardial depressant or membrane-stabilizing activity. Its predominant ocular mechanism of action is to reduce aqueous humor formation and a slight increase in outflow activity.
Pharmacodynamics: In addition to reducing IOP, travoprost has been shown to increase optic nerve head blood flow based on data in rabbits following 7 days of topical ocular administration (1.4 micrograms, once daily (QD)).
Clinical studies: In a 12-month, controlled clinical study in patients with open-angle glaucoma or ocular hypertension and a mean baseline IOP range of 25 to 27 mmHg, the mean IOP-lowering of DuoTrav dosed QD in the morning was 8 to 10 mmHg. The non-inferiority of DuoTrav as compared with latanoprost 0.005% plus timolol 0.5% in mean IOP reduction was demonstrated across all time points at all visits.
In a 3-month, controlled clinical study in patients with open-angle glaucoma or ocular hypertension and a mean baseline IOP range of 27 to 30 mmHg, the mean IOP-lowering effect of DuoTrav dosed QD in the morning was up to 2 mmHg greater than that of travoprost 0.004% dosed QD in the evening and 2 to 3 mmHg greater than that of timolol 0.5% dosed b.i.d. A statistically significant superior reduction in mean morning IOP (8 AM - 24 hours after the previous DuoTrav dose) was observed compared with travoprost 0.004% at all visits throughout the study.
In two 3-month, controlled clinical studies in patients with open-angle glaucoma or ocular hypertension and a mean baseline IOP range of 23 to 26 mmHg, the mean IOP-lowering effect of DuoTrav dosed QD in the morning was 7 to 9 mmHg. Mean IOP reductions were non-inferior, although numerically lower, compared with those achieved by concomitant therapy with travoprost 0.004% dosed QD in the evening and timolol 0.5% dosed QD in the morning.
In a 6-week, controlled clinical study in patients with open-angle glaucoma or ocular hypertension and a mean baseline IOP range of 24 to 26 mmHg, the mean IOP-lowering effect of DuoTrav (polyquaternium
1-preserved) dosed QD in the morning was 8 mmHg and equivalent to that of DuoTrav (benzalkonium chloride-preserved).
Inclusion criteria were similar across the previously mentioned clinical studies, with the exception of the IOP entry criteria and response to previous IOP-lowering therapy. The clinical development of DuoTrav included both treatment-naïve patients and patients on therapy. Insufficient responsiveness to monotherapy was not an inclusion criterion. DuoTrav was well tolerated with no serious adverse events observed.
Additional randomized, double- or observer-masked, active-controlled studies have been performed in which over 500 subjects with open-angle glaucoma or ocular hypertension were treated with Travoprost 0.004%/Timolol 0.5%.
Many of these studies measured the IOP-lowering effects Travoprost 0.004%/Timolol 0.5% after a wash-out period and these demonstrated an IOP-lowering effect from baseline that is consistent with that shown in the pivotal studies described previously.
Pharmacokinetics: Absorption: Travoprost and timolol are absorbed through the cornea. Travoprost is an isopropyl ester prodrug which undergoes rapid hydrolysis in the cornea to produce the active free acid. Following QD administration of DuoTrav (polyquaternium-1-preserved) to healthy subjects for 5 days, travoprost free acid plasma concentrations were below the 0.010 ng/mL assay quantitation limit in the majority of samples. Quantifiable free acid concentrations were observable in some cases within 1 hour post-dose, ranging from 0.010 to 0.030 ng/mL. The mean timolol steady-state Cmax was 1.34 ng/mL and Tmax was approximately 0.69 hours after QD administration of DuoTrav. Timolol has a plasma elimination half-life of about 4 hours.
Distribution: Travoprost free acid can be measured in aqueous humor for several hours in animals and in human plasma up to 1 hour post-dose. Timolol can be measured in human aqueous humor after topical ocular administration of timolol and in plasma for up to 12 hours following topical ocular administration of DuoTrav.
Biotransformation/metabolism: Metabolism is the primary clearance mechanism for both travoprost and its free acid. The systemic metabolic pathways for travoprost free acid parallel those of endogenous prostaglandin F2alpha, which are characterized by reduction of the 13 to 14 double bond, oxidation of the 15-hydroxyl to form a ketone, and beta-oxidative cleavages of the carboxylic acid side chain.
Timolol is primarily metabolized by CYP2D6 via two pathways. One route yields an ethanolamine side chain on the thiadiazole ring and the other generates an ethanolic side chain on the morpholine nitrogen and a second similar side chain with a carbonyl function adjacent to the nitrogen. No timolol metabolism occurs within the eye.
Elimination: Both travoprost free acid and timolol, along with their respective metabolites, are primarily excreted in urine. Less than 2% of an ocular dose of travoprost was recovered in urine as travoprost free acid. Approximately 20% of a timolol dose was found in urine as parent drug with the remainder excreted as metabolites.
Due to the very low concentrations and rapid disappearance of travoprost free acid from plasma, elimination half-life could not be determined. Timolol has a plasma elimination half-life of about 4 hours.
Linearity/non-linearity: Both travoprost and timolol exhibit linear pharmacokinetics following topical administration, either alone or in combination.
Pediatric patients (below 18 years): The pharmacokinetics of DuoTrav in pediatric patients has not been studied.
Pharmacogenomics: Higher plasma concentrations were detected in CYP2D6 poor metabolizers (PMs) compared with extensive metabolizers (EMs). Similar results have been obtained after the administration of ophthalmic timolol.
Toxicology: Non-clinical safety data: Non-clinical data for travoprost and timolol reveal no special hazard for humans based on conventional studies of single dose toxicity, repeated-dose toxicity, genotoxicity, carcinogenicity and topical ocular irritation studies. Ocular irritation studies were also conducted with travoprost plus timolol, and no adverse effects were observed with the exception of widened palpebral fissure and increased iris pigmentation in monkeys, which is consistent with the topical ocular administration of prostaglandins in humans. For details on reproductive studies, see Use in Pregnancy & Lactation.
Fertility studies in rats dosed with travoprost subcutaneously resulted in significant reductions in the number of corpora lutea, viable fetuses, and an increased early post-implantation loss as well as resorption rate at 10 micrograms/kg/day (34 times the MROHD based on BSA). The no effect level was set at 3 micrograms/kg/day (10 times the MROHD based on BSA). In contrast, fertility studies with timolol in rats showed no effects at oral doses up to 150 mg/kg/day (4,050 times the MROHD based on BSA).
