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

Abstract

Although ophthalmic timolol is generally well tolerated, a significant fraction of topically administered timolol can be systemically absorbed. We investigated the effect of the strong CYP2D6 inhibitor paroxetine on the pharmacokinetics of timolol after ophthalmic administration. In a four-phase crossover study, 12 healthy volunteers ingested either paroxetine (20 mg) or placebo daily for 3 days. In phases 1-2, timolol 0.1% gel, and in phases 3-4, timolol 0.5% drops were administered to both eyes. Paroxetine increased the plasma concentrations of timolol with both timolol formulations to a similar degree. The geometric mean ratio (95% confidence interval) of timolol peak concentration was 1.53-fold (1.23-1.91) with 0.1% timolol and 1.49-fold (0.94-2.36) with 0.5% timolol, and that of timolol area under the plasma concentration-time curve (AUC) from time 0 to 12 hours was 1.61-fold (1.26-to 2.06-fold) and 1.78-fold (1.21-2.62), respectively. During paroxetine administration, six subjects on 0.5% timolol drops, but none on 0.1% timolol gel, had plasma timolol concentrations exceeding 0.7 ng/ml, which can cause systemic adverse effects in patients at risk. There was a positive correlation between the AUC from time 0 to 13 hours of paroxetine and the placebo phase AUC from time 0 to infinity of timolol after timolol 0.5% drops (P < 0.05), and a nonsignificant trend after timolol 0.1% gel, consistent with the role of CYP2D6 in the metabolism of both agents. In the orthostatic test, heart rate immediately after upright standing was significantly lower (P < 0.05) during the paroxetine phase than during the placebo phase at 1 and 3 hours after 0.5% timolol dosing. In conclusion, paroxetine and other CYP2D6 inhibitors can have a clinically important interaction with ophthalmic timolol, particularly when patients are using 0.5% timolol formulations.

Systemic side effects of eye drops: a pharmacokinetic perspective

“…For this reason, this drug group is not recommended for asthmatics. Particular caution is recommended when ophthalmic timolol is coadministered with paroxetine or other strong cytochrome P450 (CYP)-2D6 inhibitors 64. These comedications increase the plasma concentrations of timolol and thereby increase the risk of adverse cardiovascular effects.…”

A Single Drop in the Eye – Effects on the Whole Body?

“…esterases, in the eye; which are important in that they metabolize prodrugs into their active form, as for example dipivefrin to adrenaline, latanoprost to prostaglandin F2alpha [ 6 ]. Orally administered drugs, which inhibit various drug- metabolizing CYP enzymes, can retard the metabolism of ophthalmic agents after their absorption into the eye, and on the other hand, can cause systemic adverse interactions after the topical drug has gained access to the circulation [ 10 ]. For this reason, patients who are poor metabolizers of CYP2D6 or are receiving drug treatment with potent inhibitors of this enzyme ( e.g.…”