Benefits of Tafluprost and Timolol Fixed-Dose Combination for the Treatment of Glaucoma Are Confirmed by Studies on Experimental Animal Models.
OBJECTIVE
To assess the usefulness of 0.0015% tafluprost and 0.5% timolol fixed-dose combination (TT-FDC) for glaucoma, the ocular hypotensive effect of TT-FDC and concentration of tafluprost and timolol in the aqueous humor were compared with those of the concomitant administration of 0.0015% tafluprost and 0.5% timolol with or without an appropriate administration interval.


METHODS
The ocular hypotensive effect was assessed by intraocular pressure (IOP) measurement in cynomolgus monkeys. Drug penetration into the aqueous humor was estimated by the concentrations of tafluprost acid (active metabolic form of tafluprost) and timolol, which were measured using liquid chromatography-tandem mass spectrometry after administration of tafluprost and timolol to Sprague Dawley rats.


RESULTS
The ocular hypotensive effect of TT-FDC was equivalent to that of the concomitant administration of timolol and tafluprost at a more than 5-min interval in monkeys. However, the ocular hypotensive effect of the concomitant administration of timolol and tafluprost without an interval (-2.8 ± 0.2 mmHg at peak IOP reduction) was significantly weaker compared with TT-FDC (-4.3 ± 0.5 mmHg at peak IOP reduction, P = 0.008 vs. concomitant administration of timolol and tafluprost) in monkeys. The aqueous humor concentration of the second administered drug (tafluprost) was not affected by the dosing conditions, whereas the concentration of the first instilled drug (timolol) without the interval was lower than that with a 5-min interval (1,200 ng · h/mL vs. 1,890 ng · h/mL in AUC0-4) in rats.


CONCLUSIONS
TT-FDC demonstrates a clear benefit by preventing efficacy loss without an appropriate interval in experimental animal models.
Research and Development Division, Santen Pharmaceutical Co., Ltd. , Osaka, Japan .
Takahiro
T
Akaishi
Research and Development Division, Santen Pharmaceutical Co., Ltd. , Osaka, Japan .
Atsushi
A
Shimazaki
Research and Development Division, Santen Pharmaceutical Co., Ltd. , Osaka, Japan .
Asaka
A
Tonouchi
Research and Development Division, Santen Pharmaceutical Co., Ltd. , Osaka, Japan .
Kenji
K
Ueda
Research and Development Division, Santen Pharmaceutical Co., Ltd. , Osaka, Japan .
Nobuaki
N
Miyawaki
Research and Development Division, Santen Pharmaceutical Co., Ltd. , Osaka, Japan .
Kouichi
K
Kawazu
D060433:Administration, Ophthalmic; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001082:Aqueous Humor / Q000378:metabolism; D002853:Chromatography, Liquid / Q000379:methods; D004195:Disease Models, Animal; D004338:Drug Combinations; D005260:Female; D005901:Glaucoma / Q000188:drug therapy* / Q000473:pathology; D007429:Intraocular Pressure / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D009798:Ocular Hypertension / Q000188:drug therapy; D011460:Prostaglandins F / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry / Q000379:methods; D013999:Timolol / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D000959:Antihypertensive Agents; D004338:Drug Combinations; D011460:Prostaglandins F; C485333:tafluprost; D013999:Timolol