Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Antiglaucoma preparations and miotics, carbonic anhydrase inhibitors, ATC code: S01EC04

Mechanism of action

Carbonic anhydrase (CA) is an enzyme found in many tissues of the body, including the eye.
Carbonic anhydrase catalyses the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid.

Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humour secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. The result is a reduction in intraocular pressure (IOP) which is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss.
Brinzolamide, an inhibitor of carbonic anhydrase II (CA-II), the predominant iso-enzyme in the eye, with an in vitro IC50 of 3.2 nM and a Ki of 0.13 nM against CA-II.

Clinical efficacy and safety

The IOP-reducing effect of Azopt 1% as adjunctive therapy to the prostaglandin analogue travoprost was studied. Following a 4 week run-in with travoprost, patients with an IOP ≥19 mmHg were randomized to receive added treatment with brinzolamide or timolol. An additional decrease in mean diurnal IOP of 3.2 to 3.4 mmHg for the brinzolamide group and 3.2 to 4.2 mmHg for the timolol group were observed. There was an overall higher incidence of non-serious ocular adverse reactions, mainly related to signs of local irritation, in the brinzolamide/travoprost groups. The events were mild and did not affect the overall discontinuation rates in the studies (see also section 4.8).

A clinical trial was conducted with A Azopt 1% ZOPT in 32 paediatric patients less than 6 years of age, diagnosed with glaucoma or ocular hypertension. Some patients were naive to IOP therapy whilst others were on other IOP-lowering medicinal product(s). Those who had been on previous IOP medicinal product(s) were not required to discontinue their IOP medicinal product(s) until initiation of monotherapy with Azopt 1%.

Among patients who were naive to IOP therapy (10 patients), the efficacy of Azopt 1% was similar to that seen previously in adults, with mean IOP reductions from baseline ranging up to 5 mmHg.
Among patients who were on topical IOP-lowering medicinal product(s) (22 patients), mean IOP increased slightly from baseline in the Azopt 1% group.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Following topical ocular administration, brinzolamide is absorbed into the systemic circulation. Due to its high affinity for CA-II, brinzolamide distributes extensively into the red blood cells (RBCs) and exhibits a long half-life in whole blood (mean of approximately 24 weeks). In humans, the metabolite N-desethylbrinzolamide 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 brinzolamide and N-desethylbrinzolamide concentrations are low and generally below assay quantitation limits (<7.5 ng/ml).

Binding to plasma proteins is not extensive (about 60%). Brinzolamide is eliminated primarily by renal excretion (approximately 60%). About 20% of the dose has been accounted for in urine as metabolite. Brinzolamide and N-desethylbrinzolamide are the predominant components in the urine along with trace levels (<1%) of the N-desmethoxypropyl and O-desmethyl metabolites.
In an oral pharmacokinetic study, healthy volunteers received 1 mg capsules of brinzolamide twice daily for up to 32 weeks and RBC CA activity was measured to assess the degree of systemic CA inhibition.

Brinzolamide saturation of RBC CA-II was achieved within 4 weeks (RBC concentrations of approximately 20 µM). N-Desethylbrinzolamide accumulated in RBCs to steady state within 20-28 weeks reaching concentrations ranging from 6-30 µM. The inhibition of total RBC CA activity at steady state was approximately 70-75%.

Subjects with moderate renal impairment (creatinine clearance of 30-60 ml/minute) were administered 1 mg of brinzolamide twice daily orally for up to 54 weeks. Brinzolamide RBC concentration ranged from about 20 to 40 µM by week 4 of treatment. At steady-state, brinzolamide and its metabolite RBC concentrations ranged from 22.0 to 46.1 and 17.1 to 88.6 µM, respectively.

N-desethylbrinzolamide RBC concentrations increased and total RBC CA activity decreased with decreasing creatinine clearance but brinzolamide RBC concentrations and CA-II activity remained unchanged. In subjects with the highest degree of renal impairment inhibition of total CA activity was greater although it was inferior to 90% at steady-state.

In a topical ocular study, at steady-state, brinzolamide RBC concentrations were similar to those found in the oral study, but levels of N-desethylbrinzolamide were lower. Carbonic anhydrase activity was approximately 40-70% of predose levels.