Improved systemic safety and risk-benefit ratio of topical 0.1% timolol hydrogel compared with 0.5% timolol aqueous solution in the treatment of glaucoma.
OBJECTIVE
The purpose of the study was to compare the systemic safety and risk-benefit ratio of 0.1% timolol hydrogel and 0.5% aqueous timolol eye drops in the treatment of glaucoma.


METHODS
An 8-week randomised, double-blind, cross-over, multicentre study. A total of 25 patients with primary open-angle glaucoma, exfoliation glaucoma, or ocular hypertension was enrolled. After completing a wash-out period, patients were randomly chosen to receive either 0.1% timolol hydrogel once daily or 0.5% aqueous timolol eye drops twice daily. Intraocular pressure and heart rate during rest and exercise, head-up tilt test results, spirometry readings, and plasma concentrations of timolol were recorded. The risk-benefit ratio was determined by calculating the ratio between several heart rate endpoints and the change in intraocular pressure (IOP).


RESULTS
The mean drug-induced change in the peak heart rate during exercise was -13.5 beats/min (SD 7.6) in the 0.5% aqueous timolol group and -5.1 beats/min (SD 6.7) in the 0.1% timolol hydrogel group (P<0.001; 95% CI 4.06-12.18). There was no significant difference in the IOP-reducing efficacy between these compounds. The risk-benefit ratio was significantly improved when 0.1% timolol hydrogel was used, compared with 0.5% aqueous timolol in the exercise test. In the head-up tilt test the risk-benefit ratio was significantly improved at rest (P<0.05), at 1 min (P<0.05) and at 5 min (P<0.001) after patients had received 0.1% timolol hydrogel. There were, however, no differences in spirometry readings. After patients had been treated with 0.1% timolol hydrogel, plasma concentrations of timolol were 1/6 (at peak) and 1/50 (at trough) of those of 0.5% aqueous timolol.


CONCLUSIONS
Drug-induced changes in the peak heart rate, and head-up tilt test results as well as plasma concentrations of timolol, were significantly more pronounced after treatment with 0.5% aqueous timolol than with 0.1% timolol hydrogel. Because of the statistically similar IOP-reducing efficacy of these formulations the risk-benefit ratio was significantly improved when patients used 0.1% timolol hydrogel instead of 0.5% aqueous timolol.
Uusitalo
Hannu
H
Department of Ophthalmology, University of Kuopio and Kuopio University Hospital, P.O. Box 1777, 70211 Kuopio, Finland. hannu.uusitalo@uku.fi
Kähönen
Mika
M
Ropo
Auli
A
Mäenpää
Jukka
J
Bjärnhall
Gunilla
G
Hedenström
Hans
H
Turjanmaa
Väinö
V
D000287:Administration, Topical; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001682:Biological Availability; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005080:Exercise Test; D005260:Female; D005902:Glaucoma, Open-Angle / Q000188:drug therapy*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009798:Ocular Hypertension / Q000188:drug therapy; D009883:Ophthalmic Solutions / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D018570:Risk Assessment; D013147:Spirometry; D018667:Tilt-Table Test; D013999:Timolol / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014792:Visual Acuity / Q000187:drug effects
D000959:Antihypertensive Agents; D009883:Ophthalmic Solutions; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D013999:Timolol