Timolol Concentrations Research Articles

Effect of preservative removal from fixed-combination bimatoprost/timolol on intraocular pressure lowering: a potential timolol dose-response phenomenon.

PurposeMany patients with glaucoma require combination therapies to achieve target intraocular pressure (IOP) and preserve visual function. Ocular hypotensives often contain a preservative (eg, benzalkonium chloride [BAK]), but preservative-free (PF) formulations have been developed for patients with sensitivity. A Phase III study found the efficacy of bimatoprost 0.03%/timolol 0.5% (bim/tim, Ganfort®) PF to be equivalent to that of preserved bim/tim, although a trend favoring bim/tim PF was observed. As BAK is a corneal penetration enhancer, this literature review aims to explain these findings by exploring the relationship between timolol concentration and its IOP-lowering effect.MethodsSystematic searches were performed in Scopus and PubMed for clinical trials published in English between 1960 and July 2014 using the keywords “timolol”, “intraocular pressure”, and the concentrations “1%, 0.5%, OR 0.25%”. Articles that directly compared IOP-lowering effects of ≥2 concentrations of timolol were identified by manual screening, and cross-checked for duplication.ResultsSeventeen studies that included 10–371 patients were evaluated; the majority were randomized (16/17), double-masked (14/17), and enrolled patients with open-angle glaucoma or ocular hypertension (12/17). All studies investigated timolol in preserved formulations. Timolol concentrations tested ranged from 0.008% to 1.5%. Of 13 studies comparing timolol 0.25% versus 0.5%, two found the 0.25% dose to have greater IOP-lowering effects, and three reported the opposite; eight reported similar IOP lowering. Results also indicate that timolol 0.5% may be more effective than higher concentrations.ConclusionThe evidence suggests that timolol may have an inverted U-shaped dose–response curve, and that its optimal IOP-lowering concentration is between 0.25% and 0.5%. Compared with bim/tim, removal of the permeability enhancer BAK in bim/tim PF could have resulted in a lower timolol concentration at the target site, bringing the effective concentration within the 0.25%–0.5% range and enhancing the efficacy of bim/tim PF.

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 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.

In vivo evaluation and in-depth pharmaceutical characterization of a rapidly dissolving solid ocular matrix for the topical delivery of timolol maleate in the rabbit eye model

The purpose of this study was to investigate the in-depth pharmaceutical properties and in vivo behavior of a novel lyophilized rapidly dissolving solid ocular matrix (RD-SOM) as a 'solid eye drop' formulation comprising timolol maleate as the model drug. Thermal and molecular transition analysis displayed similar findings with no incompatibility between formulation components. Porositometric studies confirmed the presence of interconnecting pores across the matrix surface. The HETCAM test indicated an irritation score of 0 with the inference of good tolerability for the RD-SOM in the New Zealand White albino rabbit eye model. Ex vivo permeation across excised rabbit cornea showed an improved steady state drug flux (0.00052 mg cm(-2)min(-1)) and permeability co-efficient (1.7 × 10(-4)cmmin(-1)) for the RD-SOM compared to pure drug and a marketed eye drop preparation. UPLC analysis quantitatively separated timolol maleate and the internal standard (diclofenac sodium) and gamma irradiation was used as a terminal sterilization procedure. In vivo results revealed a peak concentration of timolol was reached at 104.9 min. In the case of a typical eye drop formulation a lower Cmax was obtained (1.97 ug/mL). Level A point-to-point IVIVC plots via the Wagner-Nelson method revealed a satisfactory R(2) value of 0.84. In addition, the biodegradability and ocular compatibility of the RD-SOM was confirmed by histopathological toxicity studies.

Fractional Carbon Dioxide Laser–Assisted Drug Delivery of Topical Timolol Solution for the Treatment of Deep Infantile Hemangioma: A Pilot Study

Infantile hemangiomas (IHs) are benign vascular tumors of infancy. Topical timolol has recently been reported to be an effective treatment for superficial IHs, although it failed to have an effect on deep IHs. This prospective study was aimed at evaluating the feasibility of ablative fractional laser-assisted drug delivery for enhancing topical timolol permeation into deep IHs. Nine patients ages 1 to 6 months with deep IHs were enrolled. A fractional carbon dioxide (CO2 ) laser system was applied to the skin surface of deep IHs using the DeepFx mode (25-30 mJ/pulse, 5% density, single pulse) at 1-week intervals. Topical timolol maleate 0.5% ophthalmic solution was applied under occlusion for 30 minutes four to five times per day for an average treatment duration of 14.2 weeks. Clinical improvement was evaluated according to a global score and the Hemangioma Activity Score (HAS). Four patients (44.4%) demonstrated excellent regression, four (44.4%) showed good response, and one (11.1%) experienced moderate regression. The HAS declined from 4.1 ± 0.7 at baseline to 1.7 ± 0.7 at 1 week (p < 0.001) and 1.4 ± 0.7 at 3 months (p = 0.03) after the last treatment procedure. Plasma timolol concentration was not detected in any of the patients after the first administration of topical timolol. No systemic complication or skin side effects were observed in any of the patients. Ablative fractional laser-assisted transdermal delivery of topical timolol is a safe and effective method for the treatment of deep IHs.

Removal of preservative from Ganfort improves intraocular pressure (IOP) lowering in patients – A timolol dose‐response phenomenon

AbstractPurpose A benzalkonium chloride (BAK)‐free fixed‐combination formulation of bimatoprost and timolol (Ganfort) has been developed for patients who are sensitive to preservatives. A randomized controlled study in 561 patients compared the IOP‐lowering efficacy of the BAK‐free formulation versus the preserved Ganfort. At all timepoints, IOP lowering, numerically, consistently favoured the BAK‐free formulation. This finding contradicted expectations that the removal of BAK would result in lower ocular bioavailability of both bimatoprost and timolol, resulting in less efficacy. Research was conducted to explore possible explanation for the clinical observation.Methods Literature search on timolol dose response was performed, focusing on IOP lowering following topical dosing of 0.1%, 0.25%, and 0.5% timolol ophthalmic solutions.Results A U‐shaped dose‐response curve exists for timolol, and available data suggest that the dose that elicits maximal IOP lowering lies between 0.25% and 0.5%.Conclusion Removal of BAK from the fixed combination product Ganfort, which contains 0.5% timolol, may have resulted in a lower, but optimal, ocular concentration of timolol, leading to improved IOP‐lowering efficacy with the preservative‐free formulation. Commercial interest

Topical Timolol for Small Hemangiomas of Infancy

Propranolol has become the treatment of choice of large and complicated infantile hemangiomas. There is a controversy concerning the safety of systemic propranolol. Here we show that topical use of the beta-blocker timolol can also inhibit the growth and promote regression of infantile hemangiomas. In this case series we treated 11 infantile hemangiomas in nine children including six preterm babies with the nonselective betablocker timolol. A timolol containing gel was manufactured from an ophthalmic formulation of timolol 0.5% eyedrops. This gel was applied using a standardized occlusive dressing (Finn-Chambers) containing approximately 0.25 mg of timolol. In all infants topical timolol was associated with growth arrest, a reduction in redness and thickness within the first 2 weeks. Seven hemangiomas showed almost complete resolution, and four became much paler and thinner. No data are available on the transdermal absorption of timolol. Even supposing complete absorption of timolol from the occlusive dressing, a maximum dose of 0.25 mg of timolol would result per day and hemangioma. Regression of infantile hemangiomas treated using 0.5% timolol gel in this case series occurred earlier than spontaneous regression which is generally not observed before the age of 9-12 months. The promising results need to be verified in prospective randomized trials on topical beta blocker administration for infantile hemangiomas which should address dose, duration, and mode of application.

Timolol Maleate 0.5% or 0.1% Gel‐Forming Solution for Infantile Hemangiomas: A Retrospective, Multicenter, Cohort Study

Therapeutic options for superficial infantile hemangiomas (IH) are limited. Recently, timolol maleate gel, a topical nonselective beta-blocker, has been reported as a potentially effective treatment for superficial IH. This study is an extension of a previously published pilot study designed to further investigate the efficacy and safety and to identify predictors of good response of topical 0.5% or 0.1% timolol maleate gel-forming solution. This was a retrospective cohort study including patients enrolled from five centers. Patients were included if they were treated with timolol maleate 0.1% or 0.5% gel-forming solution and had photographic documentation of the IH and at least one follow-up visit. Patients with concomitant active treatment using other IH treatments were excluded. The primary endpoint was change in the appearance of IH as evaluated using a visual analog scale (VAS). Data from 73 subjects were available for final analysis. Timolol maleate gel-forming solution 0.5% was used in 85% (62/73) of patients, the remainder being treated with 0.1%. The median age at treatment initiation was 4.27 months (interquartile range [IQR] 2.63-7.21 mos), and patients were treated for a mean of 3.4 ± 2.7 months. All patients except one improved, with a mean improvement of 45 ± 29.5%. Predictors of better response were superficial type of hemangioma (p = 0.01), 0.5% timolol concentration (p = 0.01), and duration of use longer than 3 months (p = 0.04). Sleeping disturbance was noted in one patient. This study further demonstrates the efficacy and tolerability of topical timolol maleate and gradual improvement with longer treatment in patients with superficial IH.

Plasma levels and systemic safety of 0.1% unpreserved Timolol maleate gel, 0.5% Timolol aqueous solution and 0.5% Timolol maleate gel

To compare systemic absorption of three formulations of timolol eye drops: 0.1% timolol maleate gel, 0.5% timolol aqueous solution, and 0.5% timolol maleate gel. This was a double cross-over phase I study. Cross-over 1: two weeks of 0.1% timolol gel once daily, followed by a 3-week wash-out period and then two weeks of 0.5% timolol aqueous solution twice a day (group 1) or the reverse (group 2). Cross-over 2: two weeks of 0.1% timolol gel once daily, followed by a 3-week wash-out period, and then two weeks of 0.5% timolol gel once daily (group 3) or the reverse (group 4). Subjects underwent tonometry, blood sampling, and heart rate and blood pressure assessments (during bicycle exercise and head-up tilt tests) before and after instillation at the beginning and end of each treatment period. Forty-three healthy volunteers were randomized: 11 subjects in groups 1, 2, and 3, and 10 subjects in group 4. Areas under the concentration-time curve (AUC) values after administration of timolol 0.5% formulations were 15- to 38-fold higher than those seen after administration of timolol 0.1% gel. Maximum timolol concentrations after instillation of 0.1% gel are reduced by almost 90% compared to concentrations obtained after both 0.5% aqueous solution and 0.5% gel instillation. The AUC between 0 and 12 h post-administration were also reduced by up to 93 to 98%. After treatment with a timolol 0.1% gel formulation, systemic concentrations found were considerably lower than after administration of timolol 0.5% gel or in aqueous solution.

Metabolism of Ophthalmic Timolol: New Aspects of an Old Drug

Glaucoma is a common eye disease that can cause irreversible blindness if not diagnosed and treated in the early stages of progression. This disease is often, albeit not always, associated with increased intraocular pressure, which is also the most important risk factor for glaucoma. Currently, the only treatment option of glaucoma is reduction of intraocular pressure. A β-adrenergic antagonist, timolol, has been used for the treatment of glaucoma and increased intraocular pressure for more than 30 years and still remains the drug of choice. Locally, timolol is well tolerated. However, it has been reported that approximately 80% of a topically administered eye drop is systemically absorbed. Thus, ophthalmic timolol may cause severe adverse cardiovascular and respiratory effects. On the basis of the aforementioned situation, it is somewhat surprising to notice that the metabolism of timolol has only recently been studied in detail even though the drug has been used for decades. Earlier clinical studies have suggested that timolol is metabolized by CYP2D6, an important member of the cytochrome P450 family. Our recent in vitro studies demonstrated convincingly that CYP2D6 is the main enzyme contributing to timolol metabolism, although also CYP2C19 may have a minor role. Liver is the principal site of timolol metabolism, because - according to our recent findings - only negligible amounts of CYP2D6 are expressed in human ocular tissues. After topical administration, systemic timolol concentrations may be high enough to cause cardiovascular and respiratory adverse effects especially in patients who are CYP2D6 poor metabolizers or use concomitant CYP2D6 inhibitors.

Stripping Voltammetric Determination of Timolol Drug in Pharmaceuticals and Biological Fluids

A sensitive and reliable stripping voltammetric method was developed to determine timolol drug. This method is based on the adsorptive accumulation of the drug at a hanging mercury drop electrode (HMDE) and then a negative sweep was initiated, which yield a well defined cathodic peak at –850 mV versus (Ag/AgCl) silver reference electrode. To achieve high sensitivity, various experimental and instrumental variables were investigated such as supporting electrolyte, pH, accumulation time and potential, scan rate, frequency, pulse amplitude, convection rate and working electrode area. The monitored adsorptive current was directly proportional to the concentration of timolol and it shows a linear response in the range from 1 × 10–7 to 1.5 × 10–6 mol●l–1 of this drug (correlation coefficient = 0.998) and the detection limit (S/N = 3) is 1.26 × 10–9 mol●l–1 at an accumulation time of 30 sec. The developed adsorptive stripping voltammetry (AdSV) procedure shows a good reproducibility, the relative standard deviation RSD% (n = 8) at a concentration level of 1 × 10–6 mol●l–1 of timolol was 0.13%, whereas the method accuracy was indicated via the mean recovery of 110% ± 1.414%. Possible interferences by several substances usually present in the pharmaceutical formulations have been also evaluated. The applicability of this approach was illustrated by the determination of the drug in pharmaceutical preparation and biological fluids such as serum and urine.

Ophthalmic timolol in a hydrogel vehicle leads to minor inter-individual variation in timolol concentration in aqueous humor

Ophthalmic timolol has been used for decades in the treatment of glaucoma and ocular hypertension, traditionally in aqueous 0.5% eye drops. Recently a timolol 0.1% hydrogel has been developed to improve systemic safety. The aim of the present study was to compare aqueous humor timolol concentrations after administration of 0.1% hydrogel and aqueous 0.5% timolol in patients scheduled for a cataract operation. The concentration in the aqueous humor was 210±175ng/ml (mean±S.D.) 2h after administration of timolol 0.1% hydrogel and 538±304ng/ml after aqueous 0.5% timolol. In the aqueous 0.5% timolol group more patients had unnecessarily high concentrations of timolol in the aqueous humor. β1-receptors and β2-receptors were practically 100% occupied after administration of both products. The hydrogel proved to be an excellent formulation in giving smaller inter-individual variation in penetration of timolol into the aqueous humor. Only a weak correlation was seen between corneal thickness and the aqueous humor concentration of timolol in the aqeuous 0.5% timolol group. In conclusion, in contrast to the conventional aqueous 0.5% timolol, 0.1% timolol hydrogel caused only slight inter-individual variation in timolol concentration in the aqueous humor.

Evaluation of Aqueous Humor Concentrations of Istalol® and Betimol® Following a Single Ocular Instillation in Rabbit Eyes

The aim of this study was to evaluate the pharmacokinetic absorption profiles of two commercially available ophthalmic solutions following a single instillation into each eye of New Zealand white rabbit eyes. A single dose of either timolol maleate with potassium sorbate (TLA) or timolol hemihydrate (THH) was instilled into each eye of New Zealand white rabbits (15 rabbits/drug preparation, 50-microL dose). Animals were euthanized 15, 30, 60, 120, and 180 min after instillation, with 3 animals/drug/time intervals. Aqueous humor from both eyes of each animal was pooled and analyzed for timolol concentration, using the high-performance liquid chromatography method. TLA reached a mean peak concentration of 3.705 +/- 0.3012 microg/mL at 15 min, tapering to 0.539 +/- 0.1431 microg/mL by 180 min. THH reached a mean peak concentration of 2.239 +/- 0.1430 microg/mL at 15 min postinstillation, tapering to 0.148 +/- 0.0282 microg/mL by 180 min. TLA containing potassium sorbate demonstrated an absorption profile of more rapid absorption (1.7 fold greater at 15 minutes) and longer residences time (3.6 fold greater at 180 minutes) than the THH. At every time point throughout the study, TLA demonstrated greater drug concentration than THH.

Ophthalmic timolol in a hydrogel vehicle leads to minor interindividual variation in timolol concentration in aqueous humor

Abstract Purpose Ophthalmic timolol has been used for decades in the treatment of glaucoma and ocular hypertension, traditionally in aqueous 0.5% eye drops. Recently a timolol 0.1% hydrogel has been developed to improve systemic safety. The aim of the present study was to compare aqueous humor timolol concentrations after administration of 0.1% hydrogel and aqueous 0.5% timolol in patients scheduled for a cataract operation. Results The concentration in the aqueous humor was 210 ± 175 ng/ml (mean ± SD) two hours after administration of timolol 0.1% hydrogel and 538 ± 304 ng/ml after aqueous 0.5% timolol. In the aqueous 0.5% timolol group more patients had unnecessarily high concentrations of timolol in the aqueous humor. Beta 1‐receptors and Beta 2‐receptors were practically 100% occupied after administration of both products. The hydrogel proved to be an excellent formulation in giving smaller inter‐individual variation in penetration of timolol into the aqueous humor. Only a weak correlation was seen between corneal thickness and the aqueous humor concentration of timolol in the aqeuous 0.5% timolol group. A similar correlation was observed between age and concentration of timolol in the aqeuous 0.5% timolol group. Conclusion In contrast to the conventional aqueous 0.5% timolol, 0.1% timolol hydrogel caused only slight inter‐individual variation in timolol concentration in the aqueous humor.

Ophthalmic timolol in a hydrogel vehicle leads to minor interindividual variation in timolol concentration in aqueous humor

Ophthalmic timolol in a hydrogel vehicle leads to minor interindividual variation in timolol concentration in aqueous humor

Timolol Concentrations in Breast Milk of a Woman Treated for Glaucoma: Calculation of Neonatal Exposure

Timolol Concentrations in Breast Milk of a Woman Treated for Glaucoma: Calculation of Neonatal Exposure

Timolol Concentrations in Breast Milk of a Woman Treated for Glaucoma: Calculation of Neonatal Exposure

Timolol Concentrations in Breast Milk of a Woman Treated for Glaucoma: Calculation of Neonatal Exposure

Timolol Concentrations in Breast Milk of a Woman Treated for Glaucoma

A 32-year-old lactating woman with open-angle glaucoma used timolol maleate 0.5% eye drops twice daily to her right eye for 6 months. Four milk samples were collected over a span of 6 days. Timolol maleate milk levels were examined by liquid chromatography tandem mass spectrometry and found to be at a mean of 0.12 ng/mL (range, 0 to 0.37 ng/mL). At this level, the theoretical maximum relative infant dose expressed as a percentage of the weight-adjusted maternal dose was 0.012%. As most glaucoma patients administer drops to both eyes, the dosage was duplicated to reflect the more pertinent calculated theoretical relative infant dose of 0.024%. This dose of timolol is unlikely to cause systemic side effects to the healthy breastfed infant.

Ocular Pharmacokinetic/Pharmacodynamic Modeling for Timolol in Rabbits Using a Telemetry System

We have established an ocular pharmacokinetic/pharmacodynamic (PK/PD) model for a beta-adrenergic antagonist, timolol, after instillation into rabbits. Timolol concentrations were determined by HPLC in the tear fluid, aqueous humor, cornea, and iris-ciliary body after instillation or ocular injection into the anterior chamber of the eye in rabbits. In addition, intraocular pressure (IOP) measurement was performed after instillation of timolol by a telemetry system, which was able to obtain detailed IOP data automatically. The PK/PD parameters were estimated by fitting the concentration-time profiles and the ocular hypotensive effect-time profiles using MULTI (RUNGE) program. The PK model consisted of six compartments and the PD model included aqueous humor dynamics based on an action mechanism of timolol, which causes lowering of IOP by suppressing aqueous humor production. The PK/PD model described well the concentration-time profiles and the ocular hypotensive effect-time profiles after instillation of timolol. This study is the first trial to develop an ocular PK/PD model for timolol after instillation. This model can predict both the drug concentrations in various ocular tissues and the ocular hypotensive effect after instillation of timolol.

Ocular Pharmacokinetic/Pharmacodynamic Modeling for Multiple Anti-glaucoma Drugs

We have constructed a new ocular pharmacokinetic pharmacodynamic (PK/PD) model for anti-glaucoma drugs to describe ocular hypotensive effects on intraocular pressure (IOP) after instillation of a combination of an alpha(1)-adrenergic antagonist, bunazosin, and a beta-adrenergic antagonist, timolol, into rabbits. This model was constructed by the combination of two ocular PK/PD models for bunazosin and timolol by including aqueous humor dynamics based on both action mechanisms. We also verified the reliability of this model by confirming the drug concentrations in aqueous humor and ocular hypotensive effects after instillation of the drug combination. The aqueous humor concentrations of timolol and bunazosin were determined by an HPLC, and ocular hypotensive effect-time profiles were measured using a telemetry system, which was able to record automatically detailed effects. The combined model could simulate the aqueous humor concentrations of both drugs and the additive IOP-lowering effect after instillation of the combination using the MULTI (RUNGE) program and PK/PD parameters which were obtained from ocular hypotensive effects after instillation of bunazosin alone or timolol alone. The theoretical concentration curves of both drugs in the aqueous humor and the theoretical ocular hypotensive effect curves almost agreed with both the observed concentrations and ocular hypotensive effects after instillation of the drug combination. These results indicate the reliability and usefulness of PK/PD modeling considering aqueous humor dynamics to predict IOP in multidrug therapy. This is the first study to develop a PK/PD model for multidrug therapy for the eye.

Effects of Timolol on MYOC, OPTN, and WDR36 RNA Levels

To evaluate if timolol affects expression of 3 open-angle glaucoma genes and to study its ability to modulate dexamethasone-induced up-regulation of MYOC. We used quantitative polymerase chain reaction assay of glaucoma gene transcript levels from human trabecular meshwork (HTM) cultures exposed to 3 different doses of timolol. Three HTM cell cultures were grown with or without 1 of 3 timolol doses in the presence or absence of dexamethasone. All 3 concentrations of timolol reduced MYOC RNA levels in 1 HTM culture compared with an untreated control and showed negligible effects in the other 2 cultures. Timolol had no effect on dexamethasone-induced MYOC transcript levels in any of the 3 cultures. Timolol, dexamethasone, and dexamethasone plus timolol had a negligible effect on OPTN and WDR36 RNA levels. Timolol can reduce MYOC RNA levels in HTM cultures from some individuals. Timolol does not alter OPTN or WDR36 levels or ameliorate MYOC induction by dexamethasone in vitro. It remains to be determined whether timolol could reduce production of misfolded myocilin protein by HTM cells in individuals with MYOC missense mutations. A broader survey of interindividual variation in response to timolol as well as mechanistic studies are still needed before potential therapeutic implications can be explored.