Paroxetine Markedly Increases Plasma Concentrations of Ophthalmic Timolol; CYP2D6 Inhibitors May Increase the Risk of Cardiovascular Adverse Effects of 0.5% Timolol Eye Drops

Although ophthalmic timololis generally well tolerated, a significant fraction of topically administered timololcan be systemically absorbed. We investigated the effect of the strong CYP2D6inhibitor paroxetineon the pharmacokinetics of timololafter ophthalmicadminisration. In a 4-phase crossover study, 12 healthy volunteers ingested either paroxetine20 mg or placebo daily for 3 days. In phases 1-2, timolol0.1% gel, and in phases 3-4, timolol0.5% drop was given on both eyes. Paroxetineincreased the plasma concentrations of timololwith both timololformulations to a similar degree. The geometric mean ratio (95% CI) of timololCmax was 1.53-fold (1.23-1.91) with 0.1% timololand 1.49-fold (0.94-2.36) with 0.5% timolol, and that of timololAUC0-12h was 1.61-fold (1.26-2.06-fold) and 1.78-fold (1.21-2.62), respectively. During paroxetine, 6 subjects on 0.5% timololdrop but none on 0.1% timololgel had plasma timololconcentrations exceeding 0.7 ng/ml, which can cause systemic adverse effects in patients at risk. There was a positive correlation between the AUC0-13h of paroxetineand the placebo phase AUC0-∞ of timololafter timolol0.5% drops (P<0.05), and a nonsignificant trend after timolol0.1% gel, consistent with the role of CYP2D6in the metabolism of both agents. In orthostatic test, heart rate immediately after upright standing was significantly lower (P<0.05) during the paroxetinephase than during the placebo phase at 1 h and 3 h after 0.5% timololdosing. In conclusion, paroxetineand other CYP2D6inhibitors can have a clinically important interaction with ophthalmic timolol, particularly when patients are using 0.5% timololformulations.