title: Advantages of Efficacy and Safety of Fixed-Dose Tafluprost/Timolol Combination Over Fixed-Dose Latanoprost/Timolol Combination.
abstract: OBJECTIVE
  To compare the safety and efficacy of fixed-dose tafluprost/timolol combination (Taf/T-FDC) with those of fixed-dose latanoprost/timolol combination (Lat/T-FDC) by measuring the intraocular pressure (IOP)-lowering effect, ocular pharmacokinetics, and ocular surface toxicity.
  
  
  METHODS
  The IOP-lowering effect of Taf/T-FDC and Lat/T-FDC in ocular normotensive monkeys was evaluated at 4 and 8 h after instillation in study A, at 12, 14, 16, and 18 h after instillation in study B, and at 24, 26, 28, and 30 h after instillation in study C. Drug penetration into the eye was evaluated by measuring the concentrations of timolol, tafluprost acid (active metabolic form of tafluprost), and latanoprost acid (active metabolic form of latanoprost) using liquid chromatography coupled with tandem mass spectrometry after single instillation of Taf/T-FDC or Lat/T-FDC to Sprague Dawley rats. Cytotoxicity following 1-30 min exposure of SV40-transformed human corneal epithelial cells to Taf/T-FDC or Lat/T-FDC was analyzed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assays. Undiluted and 10-fold diluted solutions of each FDC were evaluated.
  
  
  RESULTS
  The IOP-lowering effect of Taf/T-FDC was almost equivalent to that of Lat/T-FDC at 4-8 h after instillation. The peak IOP reduction of Taf/T-FDC and Lat/T-FDC was observed at 8 h after instillation, and there is no difference between the two. The difference between them was observed at 24-30 h after instillation, and Taf/T-FDC demonstrated a significantly greater IOP-lowering effect than Lat/T-FDC at 24-30 h after instillation. The IOP-lowering effect of Taf/T-FDC was sustained up to 30 h after instillation, while that of Lat/T-FDC had almost disappeared at 28 h after instillation. Timolol concentrations in aqueous humor after Taf/T-FDC instillation were higher than those after Lat/T-FDC instillation (Cmax, 3870 ng/mL vs 1330 ng/mL; AUCinf, 3970 ng·h/mL vs 1250 ng·h/mL). The concentrations of tafluprost acid and latanoprost acid in aqueous humor after instillation of Taf/T-FDC and Lat/T-FDC, respectively, were similar to those after instillation of mono-preparations of tafluprost and latanoprost, respectively. The cytotoxic effect of Taf/T-FDC to the human corneal epithelial cells was significantly lower than that of Lat/T-FDC at all evaluated time points in both undiluted and 10-fold diluted FDCs.
  
  
  CONCLUSIONS
  Taf/T-FDC provides increased IOP-lowering effect duration and lower potential ocular surface toxicity than Lat/T-FDC.
authors.affiliation: Global Research and Development, Santen Pharmaceutical Co., Ltd., Ikoma-shi, Nara, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fuwa
authors.affiliation: Global Research and Development, Santen Pharmaceutical Co., Ltd., Ikoma-shi, Nara, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ueda
authors.affiliation: Global Research and Development, Santen Pharmaceutical Co., Ltd., Ikoma-shi, Nara, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Akaishi
authors.affiliation: Global Research and Development, Santen Pharmaceutical Co., Ltd., Ikoma-shi, Nara, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Yamashita
authors.affiliation: Global Research and Development, Santen Pharmaceutical Co., Ltd., Ikoma-shi, Nara, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kirihara
authors.affiliation: Global Research and Development, Santen Pharmaceutical Co., Ltd., Ikoma-shi, Nara, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shimazaki
authors.affiliation: Global Research and Development, Santen Pharmaceutical Co., Ltd., Ikoma-shi, Nara, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Mano
authors.affiliation: Global Research and Development, Santen Pharmaceutical Co., Ltd., Ikoma-shi, Nara, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Kawazu
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D002460:Cell Line; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D004338:Drug Combinations; D005260:Female; D005901:Glaucoma / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects* / Q000502:physiology; D000077338:Latanoprost; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D009798:Ocular Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D011460:Prostaglandins F / Q000493:pharmacokinetics / Q000494:pharmacology*; D011461:Prostaglandins F, Synthetic / Q000493:pharmacokinetics / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D013999:Timolol / Q000493:pharmacokinetics / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D004338:Drug Combinations; D011460:Prostaglandins F; D011461:Prostaglandins F, Synthetic; C485333:tafluprost; D000077338:Latanoprost; D013999:Timolol