1521-009X/42/12/2068–2076$25.00 http://dx.doi.org/10.1124/dmd.114.059576 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 42:2068–2076, December 2014 Copyright ª 2014 by The American Society for Pharmacology and Experimental Therapeutics Paroxetine Markedly Increases Plasma Concentrations of Ophthalmic Timolol; CYP2D6 Inhibitors May Increase the Risk of Cardiovascular Adverse Effects of 0.5% Timolol Eye Drops s Jukka Mäenpää, 1 Marjo Volotinen-Maja, 2 Hannu Kautiainen, Mikko Neuvonen, Mikko Niemi, Pertti J. Neuvonen, and Janne T. Backman Santen Oy, Tampere, Finland (J.M., M.V.-M.); Medcare Oy, Äänekoski, Finland (H.K.); and Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (M.Ne., M.Ni., P.J.N., J.T.B.) Received June 17, 2014; accepted September 26, 2014 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 volun- teers 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. Introduction Glaucoma affects about 60 million people globally (Quigley, 2011). Timolol is a nonselective b-adrenoceptor blocking agent that is widely used as an ophthalmic preparation for the treatment of glaucoma (Brooks and Gillies, 1992). Although ophthalmic administration of timolol is generally well tolerated, even 80% of a topically administered timolol dose can be systemically absorbed (Shell, 1982; Korte et al., 2002). This can lead to systemic adverse effects affecting the cardiac, pulmonary, and central nervous systems (Van Buskirk, 1980; Van Buskirk and Fraunfelder, 1984). Timolol is contraindicated in patients with sinus bradycardia, second- or third-degree atrio-ventricular block, overt cardiac failure, cardiogenic shock, cerebrovascular insufficiency, and asthma (Taniguchi and Kitazawa, 1997; Frishman et al., 2001). Systemically absorbed timolol may cause severe respiratory problems in patients who have bronchial hyper-reactivity or asthma. These adverse effects have been recognized for decades (Nelson et al., 1986). However, since ophthalmic timolol is applied topically, the systemic effects may be overlooked in clinical use. In fact, several case reports of severe systemic adverse effects of ophthalmic timolol have been published to alarm physicians of the risks (Minish and Herd, 2002; van der Velde et al., 2004; Carey, 2006; Müller et al., 2006; Calenda and Tourrel, 2007; Patane’ et al., 2008; Schweitzer et al., 2008; Walia et al., 2011; Canpolat et al., 2013). In glaucoma patients, there is a significant correlation between plasma concentrations of timolol and suppression of heart rate, particularly during exercise. Plasma timolol concentrations over 0.7 ng/ml are regularly associated with a heart rate reduction of 10 beats per minute or more at the maximal load in exercise tests (Nieminen et al., 2005b; Uusitalo et al., 2006). To minimize systemic effects caused by timolol eye drops, their viscosity has been increased, so that the mean residence time of timolol on the ocular surface has increased. Accordingly, once-daily Part of this work was previously presented as an abstract and poster: Mäenpää J, Volotinen-Maja M, Kautiainen H, Neuvonen M, Niemi M, Neuvonen PJ, Backman JT (2014) Paroxetine raises the plasma concentrations of ophthalmic timolol; CYP2D6 inhibitors may increase the risk of systemic effects with 0.5% timolol eye drops. 20th International Syposium on Microsomes and Drug Oxidations; 2014 May 18–22; Stuttgart, Germany. 1 Current affiliation: AstraZeneca, Research and Development, Patient Safety, Mölndal, Sweden. 2 Current affiliation: Vitabalans Oy, Hämeenlinna, Finland. Financial support for this study was provided by the Finnish Funding Agency for Technology and Innovation [Project number 353 /31 /08], and by Santen Oy, Tampere, Finland. dx.doi.org/10.1124/dmd.114.059576. s This article has supplemental material available at dmd.aspetjournals.org. ABBREVIATIONS: AUC, area under the plasma concentration–time curve; AUC 0-‘ , AUC from time 0 to infinity; AUC 0-12h , AUC from time 0 to 12 hours; AUC 0-13h , AUC from time 0 to 13 hours; C max , peak concentration; CV, coefficient of variation; EM, extensive metabolizer; PM, poor metabolizer; t 1/2 , elimination half-life; t max , time to peak concentration; UM, ultra-rapid metabolizer. 2068 http://dmd.aspetjournals.org/content/suppl/2014/09/26/dmd.114.059576.DC1 Supplemental material to this article can be found at: at ASPET Journals on June 22, 2017 dmd.aspetjournals.org Downloaded from