Brinzolamide

Summary

Abstract

Brinzolamide is a highly specific carbonic anhydrase (CA) inhibitor which lowers intraocular pressure (IOP) by reducing the rate of aqueous humour formation. Formulated as a 1 % ophthalmic suspension (Azopt®) and administered twice or three times daily, brinzolamide is indicated for the topical management of primary open-angle glaucoma (POAG) and ocular hypertension (OH) as either monotherapy or adjunctive therapy with topical β-blockers.

As monotherapy in patients with POAG or OH, brinzolamide 1% demonstrated IOP-lowering efficacy that was significantly greater than placebo, equivalent to three-times-daily dorzolamide 2% but significantly lower than twice-daily timolol 0.5%. Brinzolamide 1% was equally effective in twice- and three-times—daily regimens producing diurnal mean IOP reductions from baseline in the range of 13.2–21.8%. When used adjunctively twice daily with timolol 0.5%, brinzolamide 1% was as effective as dorzolamide 2% and superior to placebo in lowering IOP in patients with POAG or OH.

In clinical trials, brinzolamide 1% was well tolerated causing only nonserious adverse effects that were generally local, transient and mild to moderate in severity. The incidence of the most common adverse events associated with the use of brinzolamide 1 % was either similar to (blurred vision and abnormal taste) or significantly lower than (ocular discomfort) with dorzolamide 2%. Topical brinzolamide 1% does not appear to produce the acid-base or electrolyte disturbances and severe systemic adverse effects characteristic of oral CA inhibitors. It can be used in patients unresponsive to β-blockers or in whom β-blockers are contraindicated.

Brinzolamide 1% administered twice daily is among the least costly alternatives and adjuncts to β-blocker therapy for glaucoma and is generally associated with less direct medical cost than dorzolamide.

Conclusion: Brinzolamide 1% ophthalmic suspension administered twice or three times daily, as monotherapy or adjunctive therapy with topical β-blockers, has good IOP-lowering efficacy in patients with POAG or OH that is equivalent to that of dorzolamide 2% (three times daily as monotherapy, twice daily as adjunctive therapy). Brinzolamide is generally well tolerated and does not produce the systemic adverse effects associated with oral CA inhibitors. It can be used in patients who are unresponsive to, intolerant of, or unable to receive, ophthalmic β-blockers. Thus, brinzolamide, either as monotherapy or adjunctive therapy with topical β-blockers, should be regarded as a good second-line option in the pharmacological management of POAG and OH, and may be preferred over dorzolamide because of significantly less ocular discomfort.

Overview of Pharmacodynamic Properties

Brinzolamide is a nonbacteriostatic sulfonamide derivative with higher lipophilicity and lower aqueous solubility than dorzolamide or acetazolamide at physiological pH. As a consequence, brinzolamide forms a suspension at pH 7.4 which is more comfortable to the eye than the acidic pH of dorzolamide solution (pH 5.6).

Brinzolamide is a highly specific, noncompetitive and reversible carbonic anhydrase (CA)-II inhibitor with an ≈4-fold greater in vitro binding affinity for CA-II than dorzolamide. The main local ocular effect of brinzolamide is produced predominantly by inhibition of CA-II in the secretory cells of ciliary processes inside the eye. Inhibition of this isoenzyme reduces the rate of aqueous humour formation, consequently lowering intraocular pressure (IOP).

Following topical instillation, brinzolamide enters the blood circulation but systemic adverse effects with its use do not occur mainly because of incomplete saturation and inhibition of CA-II in erythrocytes and kidneys, and the low affinity of brinzolamide for other CA isoforms in the human body.

Brinzolamide has been shown to produce significant reduction in IOP compared with placebo in the eyes of healthy volunteers and patients with glaucoma (see also Therapeutic Efficacy summary). Significantly greater reductions in both daytime and night-time rates of aqueous humour flow were obtained with brinzolamide compared with both placebo (p < 0.001) and dorzolamide (p < 0.05) in healthy volunteers. However, in the same study, the effects on IOP reduction at both trough and peak times were similar with both drugs.

CA-II is also present in corneal endothelium, where it plays a role in the mechanism responsible for maintaining corneal stroma in a relatively dehydrated state. Inhibition of this mechanism can potentially lead to corneal decompensation and impaired vision. Brinzolamide 1% appears to have no adverse effect on corneal endothelial cell function in patients with normal corneas; no clinically relevant or statistically significant changes from baseline in corneal thickness and corneal endothelial cell density occurred in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OH) during an 18-month clinical trial.

Topically applied brinzolamide significantly (p-values not reported) reduced the optic nerve head blood flow to normal levels in the eyes with hypertensive and preperimetric POAG, but caused no change in the eyes with advanced, perimetric glaucoma compared with normal eyes, in a 1-month clinical trial.

Overview of Pharmacokinetic Properties

Published data relating to the pharmacokinetic properties of brinzolamide in humans are limited. After topical ocular instillation in rabbits, brinzolamide 1% was readily absorbed in the conjunctiva, cornea, iris, ciliary body, aqueous humour, lens, choroid and retina, reaching peak concentrations in the anterior eye segment tissues within 0.5–2 hours. Systemic absorption of brinzolamide does occur, but plasma concentrations in healthy human volunteers are generally below quantitation levels because of the drug’s preferential distribution to erythrocytes. Extensive but saturable binding to CA-II in erythrocytes is the cause of nonlinear whole-blood pharmacokinetics of brinzolamide in rats. Concentration-independent plasma protein binding of brinzolamide in the range of 59–63% has been reported in an in vitro study in human plasma.

Metabolic inactivation of brinzolamide is carried out predominantly in the liver through oxidative O- and N-dealkylation by cytochrome P450 isoenzymes. N-desethyl-brinzolamide binds predominantly to CA-I in erythrocytes and is the major metabolite found in whole human blood (but not in plasma). N-desmethox-ypropyl- and O-desmethyl-brinzolamide have been detected as minor metabolites in urine but not in the whole blood of humans.

In humans, brinzolamide is predominantly excreted in the urine (≈60% unchanged and 20% as the N-desethyl metabolite) and has a long whole-blood half-life (111 days following topical administration of brinzolamide 3% ophthalmic suspension three times daily for 14 days in 15 healthy male volunteers).

Therapeutic Efficacy

The efficacy of brinzolamide 1% ophthalmic suspension administered twice or three times daily as monotherapy or adjunctive therapy with twice-daily timolol 0.5% ophthalmic solution has been evaluated in six randomised, double-blind, multicentre, comparative clinical trials of 2 weeks to 18 months duration in a total of 1735 evaluable patients (previously pharmacologically treated) with POAG or OH. The trials compared the IOP-lowering efficacy of brinzolamide 1% with that of dorzolamide 2% (twice daily in monotherapy, three times daily in adjunctive therapy trials), timolol 0.5% (twice daily) or placebo. The primary efficacy endpoint in most trials was the diurnally corrected (i.e. for trough and peak times) mean IOP reduction from baseline; the longest duration trial reported only the mean reduction from baseline in trough IOP (measured at 8am). In all trials, IOP measurements were performed using Goldmann applanation tonometry. All trials were also preceded by appropriate washout periods, which, in two trials evaluating adjunctive use of brinzolamide 1%, also served as run-in phases for nonblind timolol administration.

As Monotherapy: Overall, in four monotherapy trials in a total of 1414 patients, brinzolamide 1% demonstrated IOP-lowering efficacy that was significantly greater than that of placebo (all p < 0.005), similar to dorzolamide 2%, but significantly lower than timolol 0.5% (p < 0.0002, where reported).

In a placebo-controlled, parallel-group trial in 142 patients with POAG or OH, brinzolamide 1–3% produced clinically relevant and statistically significant reductions in mean baseline IOP (p-values not reported). Brinzolamide 1%, 2% and 3% were equally effective in reducing diurnally corrected mean IOP from baseline and more effective than brinzolamide 0.3% (p < 0.036). The study found brinzolamide 1 % to be the optimal concentration for lowering the elevated IOP in patients with glaucoma when administered twice daily.

The short-term efficacy of brinzolamide 1% administered twice and three times daily was equivalent to that of three-times-daily dorzolamide 2%; mean daily IOP reduction from baseline was in the range of 13.2–21.8% for twice-daily and 13.2–21.5% for three-times-daily brinzolamide 1%, and 15.7–22.9% for dorzolamide 2% in two 3-month clinical trials in a total of 921 patients with POAG or OH (all p < 0.001). Clinically relevant reductions from baseline of the morning trough IOP were maintained long term with brinzolamide 1% throughout an 18-month trial involving 351 patients with POAG or OH (13.2% and 12.6%, respectively, in twice- and three-times-daily regimens; both p < 0.0001 vs baseline), although the effect was significantly lower than with twice-daily timolol 0.5% ophthalmic solution (20.5%; p < 0.0002).

After 3 months of treatment in two monotherapy trials, brinzolamide 1% administered twice or three times daily, respectively, produced IOP response (i.e. an IOP reduction ≥5mm Hg) or control (i.e. IOP of ≤21mm Hg) in up to 75.7% and 80.1% of patients, compared with up to 80.0% of patients who received dorzolamide 2% three times daily and up to 82.0% of patients who received timolol 0.5% twice daily.

As Adjunctive Therapy: Brinzolamide 1% was as effective as dorzolamide 2% (14.1–22.0% vs 14.0–21.2%) and superior to placebo (13.2–16.6% vs 4.4–10.4%; all p ≤ 0.03) in lowering IOP in patients with POAG or OH (n = 321) when used adjunctively with timolol 0.5% ophthalmic solution in twice- and three-times-daily regimens, respectively, at all timepoints during two 3-month trials. Furthermore, in the active-controlled trial (n = 213), a similar proportion of patients achieved IOP reduction or control with brinzolamide plus timolol and dorzolamide plus timolol (50.0–89.3% vs 43.9–85.4%, respectively).

Tolerability

Brinzolamide 1% ophthalmic suspension administered twice or three times daily was well tolerated in randomised, double-blind, multicentre, comparative, mono-therapy clinical trials in a total of 1626 patients with POAG or OH; brinzolamide-related adverse events were nonserious and generally mild to moderate in severity, occurring mostly at the time of eyedrop instillation and usually resolving without treatment.

In the only long-term (18-month) clinical trial, adverse events and inadequate IOP control were the most common reasons for treatment discontinuation and accounted, respectively, for 39% and 17% of discontinuations in the twice-, and 27% and 21% in the three-times-daily brinzolamide groups, and for 30% and 4% in the timolol group.

In all clinical trials, the most common ocular adverse events related to brinzolamide treatment were transient blurring of vision and ocular discomfort (i.e. stinging and burning ocular sensations). The incidence of blurred vision in 3- and 18-month trials was relatively low (3–8% with twice-daily, and 3.6–5.2% with three-times-daily regimens) and not statistically significantly greater than that reported in patients receiving three-times-daily dorzolamide 2% (0.6% and 0.8%) or placebo (1.5%), or twice-daily timolol 0.5% (0% and 5.3%). In clinical trials of up to 18 months duration, ocular discomfort at the time of instillation occurred ≈3–9 times less frequently with brinzolamide 1% than with dorzolamide 2% (p < 0.05). In addition, burning and/or stinging sensation was significantly less intense with brinzolamide 1% compared with dorzolamide 2% (p < 0.0001) in two weekly comfort studies in a total of 198 patients with POAG or OH.

Results of a prospective, nonblind, noncomparative, crossover, multicentre clinical study in 447 evaluable patients with glaucoma indicate that substituting dorzolamide 2% with brinzolamide 1% for mono- or adjunctive therapy may provide improved ocular comfort. One to 3 months after the switch, 69%, 26% and 5% of patients, respectively, reported improvement, no change, and worsening in ocular comfort. Consequently, more than twice as many patients preferred brinzolamide over dorzolamide for their glaucoma therapy (59% vs 26%; p-value not reported).

Brinzolamide did not affect visual acuity, visual fields, cup-to-disc ratio and other ocular signs, and corneal endothelial cell function (see Overview of Pharmacodynamic Properties summary) in patients with POAG or OH receiving treatment for up to 18 months during clinical trials.

Abnormal (i.e. bitter or sour) taste was the only local, nonocular adverse event associated with brinzolamide 1%, which occurred in ≥3% of patients across monotherapy and adjunctive therapy trials. The incidence of abnormal taste with brinzolamide use was dose- and frequency-related (6.8–12.1% with brinzolamide 1% three times daily), and was not statistically significantly different than that with dorzolamide 2%.

Topical brinzolamide 1% does not appear to produce acid-base or electrolyte disturbances and was not associated with clinically significant systemic adverse effects, generally observed with oral CA inhibitors, in clinical trials of up to 18 months duration.

Pharmacoeconomic Analyses

Thus far, pharmacoeconomic analyses relating to the use of brinzolamide in the treatment of POAG and OH have been limited to a cost-minimisation study and two cost analyses.

The European cost-minimisation study showed that initiating medical glaucoma therapy with brinzolamide 1% in patients with POAG or OH was associated with lower (in Italy, Spain and Portugal) or similar (in France) total direct medical costs per patient over 3 months compared with dorzolamide 2%. The analysis was conducted from the perspective of healthcare payers from each country and in the context of second-line use of topical CA inhibitors, and was based on similar week 4 responder rates between brinzolamide and dorzolamide regimens from four randomised, double-blind, comparative brinzolamide clinical trials. The cost benefit of short-term brinzolamide versus dorzolamide therapy was explained by the lower administration rate of brinzolamide (twice daily) with equal efficacy to dorzolamide (three times daily) [see Therapeutic Efficacy summary] and lower rate of therapy discontinuation with brinzolamide than with dorzolamide due to better local tolerability (see Tolerability summary).

Two US cost analyses conducted from a payer’s perspective and covering similar periods (1999 and 1998–2000) both showed that twice-daily therapy with brinzolamide 1% incurred less cost than with dorzolamide 2%. Both studies also found that glaucoma monotherapy was less costly with twice-daily brinzolamide 1% than with brimonidine 2% (twice daily) or latanoprost 0.005% (once daily), but more costly than with generic timolol maleate 0.5% (twice daily).

Dosage and Administration

Brinzolamide 1 % ophthalmic suspension is indicated for the treatment of elevated IOP in patients with POAG or OH. The recommended dosage of brinzolamide in Europe is one drop instilled in the conjunctival sac of the affected eye(s) twice daily (for use as either monotherapy or adjunctive therapy with topical ophthalmic β-blockers). In Europe, brinzolamide monotherapy is also indicated in patients unresponsive to β-blockers or in whom β-blockers are contraindicated. In the US, the recommended administration regimen for brinzolamide as monotherapy is three times daily; formal US recommendations for the use of brinzolamide in combination with other topical antiglaucoma drugs have not been made.

Brinzolamide is not recommended in the US and is contraindicated in Europe for the treatment of patients with severe renal impairment (creatinine clearance <30 mL/min), as brinzolamide and its metabolites are excreted predominantly by the kidney (see Overview of Pharmacokinetic Properties summary). In patients with hepatic impairment, either the use of brinzolamide is not recommended (US) or the drug should be used with caution (Europe). It appears prudent to avoid the use of brinzolamide in patients with previous hypersensitivity reactions to sulfonamides.

Wearers of soft contact lenses should allow a period of at least 15 minutes to elapse between instillation of brinzolamide and the re-insertion of lenses.