Effect of preservative removal from fixed-combination bimatoprost/timolol on intraocular pressure lowering: a potential timolol dose–response phenomenon

Abstract

PurposeMany patients with glaucoma require combination therapies to achieve target intraocular pressure (IOP) and preserve visual function. Ocular hypotensives often contain a preservative (eg, benzalkonium chloride [BAK]), but preservative-free (PF) formulations have been developed for patients with sensitivity. A Phase III study found the efficacy of bimatoprost 0.03%/timolol 0.5% (bim/tim, Ganfort®) PF to be equivalent to that of preserved bim/tim, although a trend favoring bim/tim PF was observed. As BAK is a corneal penetration enhancer, this literature review aims to explain these findings by exploring the relationship between timolol concentration and its IOP-lowering effect.MethodsSystematic searches were performed in Scopus and PubMed for clinical trials published in English between 1960 and July 2014 using the keywords “timolol”, “intraocular pressure”, and the concentrations “1%, 0.5%, OR 0.25%”. Articles that directly compared IOP-lowering effects of ≥2 concentrations of timolol were identified by manual screening, and cross-checked for duplication.ResultsSeventeen studies that included 10–371 patients were evaluated; the majority were randomized (16/17), double-masked (14/17), and enrolled patients with open-angle glaucoma or ocular hypertension (12/17). All studies investigated timolol in preserved formulations. Timolol concentrations tested ranged from 0.008% to 1.5%. Of 13 studies comparing timolol 0.25% versus 0.5%, two found the 0.25% dose to have greater IOP-lowering effects, and three reported the opposite; eight reported similar IOP lowering. Results also indicate that timolol 0.5% may be more effective than higher concentrations.ConclusionThe evidence suggests that timolol may have an inverted U-shaped dose–response curve, and that its optimal IOP-lowering concentration is between 0.25% and 0.5%. Compared with bim/tim, removal of the permeability enhancer BAK in bim/tim PF could have resulted in a lower timolol concentration at the target site, bringing the effective concentration within the 0.25%–0.5% range and enhancing the efficacy of bim/tim PF.

Role of CD4+ T Helper Cells in the Development of BAC-Induced Dry Eye Syndrome in Mice

“… 1 BAC is one of the most commonly used preservatives in ophthalmic solutions. 2 The toxicity of BAC has been validated in clinical and experimental research, 4 , 25 , 26 and it has been found that long-term use of eye drops with BAC causes redness, dryness, and foreign body sensation. BAC also induces tear film instability, cornea barrier dysfunction, and the loss of conjunctival goblet cells, 27 which are similar to the clinical manifestation of dry eye syndrome.…”

“…Benzalkonium chloride (BAC) is commonly used as a preservative in ophthalmic solutions due to its antimicrobial activities. 1 , 2 Studies have demonstrated, though, that long-term use of topical BAC induces toxic effects, including tear film instability, corneal barrier dysfunction, and the loss of conjunctival goblet cells, all of which cause dry-eye-like ocular surface damage, 1 , 3 , 4 However, the precise mechanism must be further explored.…”

Review of the Synthesis of Bimatoprost Drug Substance Used for the Treatment of Open-Angle Glaucoma

“…Bimatoprost ( 6 ), a PGF2 analogue, was first approved in US as Lumigan ophthalmic solution (0.01% and 0.03%). ,− Subsequently, bimatoprost ( 6 ) was also formulated differently either by itself or in combination with other classes of drug substances for eye care, such as Durysta implant, Ganfort and Tripligan fixed-combination ophthalmic solutions, − and Latisse applicator to treat hypotrichosis of the eyelashes by increasing their growth . It is evident from the bimatoprost ( 6 ) and related prostaglandin analogues (Figure , 7 – 12 ) that the common structural features in these drug substances are the presence cyclopentane moiety with four chiral centers (Figure ) and modifications in the upper and lower (α and ω) side chains.…”

Wireless theranostic smart contact lens for monitoring and control of intraocular pressure in glaucoma

“…The method and time of drug treatments as instructed have not been followed by many glaucoma patients 9 . Furthermore, each patient can have a different therapeutic effect of drugs, which necessitate a different drug dose for each person 10 . Accordingly, it is important to monitor continuous IOP changes in real-time and delivers drugs in response to the IOP profiles.…”