title: Effect of preservative removal from fixed-combination bimatoprost/timolol on intraocular pressure lowering: a potential timolol dose-response phenomenon.
abstract: OBJECTIVE
  Many 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.
  
  
  METHODS
  Systematic 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.
  
  
  RESULTS
  Seventeen 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Department of Translational Sciences, Allergan plc, Irvine, CA, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Ophthalmology Clinical Development, Allergan plc, Irvine, CA, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Bejanian
keywords: bimatoprost; dose–response; glaucoma; intraocular pressure; preservative; timolol