Advantages of Efficacy and Safety of Fixed-Dose Tafluprost/Timolol Combination Over Fixed-Dose Latanoprost/Timolol Combination

• Published in: PloS one Vol. 11; no. 7; p. e0158797
• Main Authors: Fuwa, Masahiro, Ueda, Kenji, Akaishi, Takahiro, Yamashita, Naoko, Kirihara, Tomoko, Shimazaki, Atsushi, Mano, Hidetoshi, Kawazu, Kouichi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.07.2016; Public Library of Science (PLoS)
• Subjects: Acids; Animals; Antihypertensive Agents - pharmacokinetics; Antihypertensive Agents - pharmacology; Area Under Curve; Bioavailability; Biology and Life Sciences; Cell Line; Chromatography; Chromatography, Liquid; Complications and side effects; Cornea; Cytotoxicity; Dilution; Disease Models, Animal; Dosage and administration; Drug Combinations; Drug dosages; Epithelial cells; Female; Glaucoma; Glaucoma - drug therapy; Glaucoma - metabolism; Glaucoma - physiopathology; Humans; Hypertension; Intraocular pressure; Intraocular Pressure - drug effects; Intraocular Pressure - physiology; Laboratories; Latanoprost; Liquid chromatography; Macaca fascicularis; Male; Mass spectrometry; Mass spectroscopy; Measurement; Medicine and Health Sciences; Metabolic Clearance Rate; Monkeys; Ocular Hypertension - drug therapy; Ocular Hypertension - metabolism; Ocular Hypertension - physiopathology; Ophthalmology; Patients; Pharmaceutical sciences; Pharmacokinetics; Pharmacology; Physiological aspects; Pressure effects; Prostaglandins F - pharmacokinetics; Prostaglandins F - pharmacology; Prostaglandins F, Synthetic - pharmacokinetics; Prostaglandins F, Synthetic - pharmacology; R&D; Rats, Sprague-Dawley; Research & development; Research and analysis methods; Safety; Tafluprost; Tandem Mass Spectrometry; Time Factors; Timolol; Timolol - pharmacokinetics; Timolol - pharmacology; Toxicity; Treatment Outcome; Japan; New York
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0158797

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. 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. 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. Taf/T-FDC provides increased IOP-lowering effect duration and lower potential ocular surface toxicity than Lat/T-FDC.