Transdermal timolol: beta blockade and plasma concentrations after application for 48 hours and 7 days

An effective and well-tolerated transdermal beta-adrenergic blocker that could be applied once weekly would facilitate compliance. The pharmacokinetics and pharmacodynamics of a once-weekly formulation of transdermal timolol, a beta-blocker, were evaluated in healthy males. One (n = 6), two (n = 5), and three (n = 5) patches (97.5 mg base/12.58 cm2 patch) were applied at weekly intervals to the subjects' inner arm for 48 hours (part A) and two patches were applied for 7 days (part B). In part A, mean exercise (bicycle ergometry) heart rate (beats/min, bpm) was suppressed from baseline at 48 hours after the patch (p less than 0.05) in each case (1 patch 167 vs 131 bpm; 2 patches 165 vs 120 bpm; 3 patches 159 vs 120 bpm). Mean plasma timolol concentrations at 48 hours after the patch for one, two, and three patches were 5, 11, and 14 ng/ml, respectively. For part B, mean exercise heart rate at baseline, 24, and 168 hours was 161, 113, and 130 bpm (p less than 0.05), and mean plasma timolol concentrations at these times were 0, 23, and 4 ng/ml. The relationship between suppression of exercise heart rate and plasma timolol concentrations within subjects was well described by an inhibitory EMAX model, where EMAX ranged from a suppression of 42-65 bpm associated with a 50% inhibitory (IC50) concentration that ranged from 2-4 ng/ml. Transdermal timolol was associated with significant beta blockade for up to 7 days, and caused only minimal skin irritation.