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Simbrinza

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Simbrinza

CLINICAL PHARMACOLOGY

Mechanism of Action

SIMBRINZA™ is comprised of two components: brinzolamide (carbonic anhydrase inhibitor) and brimonidine tartrate (alpha 2 adrenergic receptor agonist). Each of these two components decreases elevated intraocular pressure. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous field loss and optic nerve damage.

Brinzolamide inhibits carbonic anhydrase in the ciliary processes of the eye to decrease aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. Brinzolamide has a peak ocular hypotensive effect occurring at 2 to 3 hours post-dosing. Fluorophotometric studies in animals and humans suggest that brimonidine tartrate has a dual mechanism of action by reducing aqueous humor production and increasing uveoscleral outflow. Brimonidine tartrate has a peak ocular hypotensive effect occurring at two hours post-dosing. The result is a reduction in intraocular pressure (IOP).

Pharmacokinetics

Following topical ocular administration, brinzolamide is absorbed into the systemic circulation. Due to its affinity for CA-II, brinzolamide distributes extensively into the RBCs and exhibits a long half-life in whole blood (approximately 111 days). In humans, the metabolite N-desethyl brinzolamide is formed, which also binds to CA and accumulates in RBCs. This metabolite binds mainly to CA-I in the presence of brinzolamide. In plasma, both parent brinzolamide and Ndesethyl brinzolamide concentrations are < 10 ng/mL. Binding to plasma proteins is approximately 60%. Brinzolamide is eliminated predominantly in the urine as unchanged drug. N-Desethyl brinzolamide is also found in the urine along with lower concentrations of the Ndesmethoxypropyl and O-desmethyl metabolites.

After ocular administration of a 0.2% solution of brimonidine tartrate, plasma concentrations peaked within 1 to 4 hours and declined with a systemic half-life of approximately 3 hours. In humans, systemic metabolism of brimonidine is extensive. It is metabolized primarily by the liver. Urinary excretion is the major route of elimination of the drug and its metabolites. Approximately 87% of an orally-administered radioactive dose was eliminated within 120 hours, with 74% found in the urine.

In humans, a study was conducted to evaluate the pharmacokinetics of the fixed combination of brinzolamide / brimonidine tartrate 1%/ 0.2% ophthalmic suspension. Healthy volunteers were randomly assigned to receive twice or three times a day either the fixed combination, or either of its individual components, brinzolamide or brimonidine. Subjects who were assigned to the brinzolamide alone or combination arms were administered oral brinzolamide capsules for two weeks prior to beginning dosing with the topical ocular suspension. The results demonstrate that the systemic plasma exposure (AUC and Cmax) to brinzolamide and brimonidine in humans is similar after dosing with the fixed combination to that observed following dosing with the individual components.

Clinical Studies

Two clinical trials of 3 months duration were conducted in patients with open-angle glaucoma or ocular hypertension to compare the IOP-lowering effect of SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2% dosed three times daily (TID) to individually administered 1% brinzolamide three times daily and 0.2% brimonidine tartrate three times daily. Mean IOP values at baseline are presented in Table 1.

Table 1: Mean (SD) IOP values at baseline

    SIMBRINZA™ Brinzolamide Brimonidine
Study 1 (n=209) (n=224) (n=216)
  8 AM 26.9 (2.63) 27.1 (2.64) 27.0 (2.56)
  10 AM 25.3 (2.76) 25.4 (2.74) 25.4 (2.78)
  3 PM 23.7 (2.98) 23.8 (3.24) 24.0 (3.27)
  5 PM 23.2 (3.08) 23.6 (3.39) 23.7 (3.30)
Study 2 (n=218) (n=229) (n=232)
  8 AM 27.2 (2.75) 27.2 (2.72) 27.3 (2.73)
  10 AM 25.8 (3.09) 26.0 (3.20) 25.8 (3.02)
  3 PM 24.4 (3.67) 24.4 (3.58) 24.0 (3.39)
  5 PM 24.1 (3.71) 24.2 (3.86) 23.7 (3.58)

The IOP-lowering effect of SIMBRINZA™ was 1 to 3 mmHg greater than monotherapy with either 1% brinzolamide or 0.2% brimonidine tartrate throughout the duration of the trials. Least Square Mean IOP (mmHg) and the results at Week 2, Week 6 and Month 3 for each study are provided in Table 2.

Table 2 : Mean IOP (mmHg) by Treatment Group and Treatment Difference in Mean IOP

Study 1 SIMBRINZA™
(N=209)
Brinzolamide
(N=224)
Brimonidine
(N=216)
Mean Mean Difference (95% CI)** Mean Difference (95% CI)**
Week 2
  8 AM 20.4 22.0 -1.6 (-2.3, -0.9) 22.4 -2.0 (-2.7, -1.3)
  10 AM 17.1 20.5 -3.4 (-4.1, -2.7) 19.4 -2.3 (-3.0, -1.6)
  3 PM 18.4 20.4 -1.9 (-2.6, -1.3) 20.6 -2.2 (-2.9, -1.5)
  5 PM 16.6 19.7 -3.2 (-3.9, -2.5) 18.4 -1.9 (-2.6, -1.2)
Week 6
  8 AM 20.4 21.9 -1.5 (-2.2, -0.8) 22.6 -2.3 (-3.0, -1.6)
  10 AM 17.5 20.2 -2.7 (-3.4, -2.0) 19.5 -2.0 (-2.7, -1.3)
  3 PM 18.9 20.2 -1.2 (-1.9, -0.5) 21.1 -2.1 (-2.8, -1.4)
  5 PM 17.0 19.7 -2.6 (-3.3, -1.9) 18.6 -1.5 (-2.2, -0.8)
Month 3
  8 AM 20.5 21.6 -1.1 (-1.8, -0.4) 23.3 -2.8 (-3.5, -2.1)
  10 AM 17.2 20.4 -3.2 (-3.9, -2.5) 19.7 -2.5 (-3.2, -1.8)
  3 PM 18.7 20.4 -1.8 (-2.5, -1.1) 21.3 -2.6 (-3.3, -1.9)
  5 PM 17.0 20.0 -3.0 (-3.7, -2.3) 18.8 -1.8 (-2.5, -1.1)
Study 2 (N=218) (N=229) (N=232)
Week 2
  8 AM 20.5 22.2 -1.7 (-2.4, -1.0) 22.8 -2.4 (-3.1, -1.7)
  10 AM 17.4 20.7 -3.3 (-4.0, -2.6) 19.2 -1.8 (-2.5, -1.2)
  3 PM 18.7 20.5 -1.7 (-2.4, -1.1) 21.1 -2.3 (-3.0, -1.6)
  5 PM 16.5 20.1 -3.6 (-4.3, -2.9) 18.3 -1.8 (-2.4, -1.1)
Week 6
  8 AM 20.7 21.9 -1.2 (-1.9, -0.5) 23.2 -2.5 (-3.2, -1.8)
  10 AM 17.4 20.5 -3.1 (-3.8, -2.4) 19.7 -2.3 (-3.0, -1.6)
  3 PM 19.3 20.2 -0.8 (-1.5, -0.2) 21.2 -1.9 (-2.6, -1.2)
  5 PM 16.9 19.9 -3.0 (-3.7, -2.3) 18.5 -1.7 (-2.4, -1.0)
Month 3
  8 AM 21.1 22.0 -1.0 (-1.7, -0.3) 23.2 -2.2 (-2.9, -1.5)
  10 AM 18.0 20.8 -2.8 (-3.5, -2.1) 19.9 -1.9 (-2.6, -1.2)
  3 PM 19.5 20.7 -1.2 (-1.9, -0.5) 21.5 -2.0 (-2.7, -1.3)
  5 PM 17.2 20.4 -3.2 (-3.9, -2.5) 18.9 -1.7 (-2.4, -1.0)
*Based on the Intent-to-Treat Population defined as all patients who received study drug and completed at least 1 on-therapy study visit.;
**The estimates are based on least square means derived from a linear mixed model that accounts for correlated IOP measurements within patient; Treatment difference is SIMBRINZA minus individual component. CI=95% Confidence Interval.

Figures 1 and 2 present the mean of individual subject IOP changes from baseline at Week 2, Week 6, and at Month 3 based on the observed data for the intent-to-treat population.

Figure 1: Mean IOP Change from Baseline (Study 1)

Mean IOP Change from Baseline (Study 1) - Illustration

Figure 2: Mean IOP Change from Baseline (Study 2)

Mean IOP Change from Baseline (Study 2) - Illustration

Last reviewed on RxList: 5/3/2013
This monograph has been modified to include the generic and brand name in many instances.

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