Topical Bimatoprost

Summary

Abstract

Bimatoprost, a synthetic prostamide analogue, is a new ocular hypotensive agent indicated for the second-line treatment of open-angle glaucoma and ocular hypertension. The drug is formulated as a 0.03% ophthalmic solution. Bimatoprost lowers intraocular pressure (IOP) by increasing aqueous humour outflow.

When applied topically once daily in patients with ocular hypertension or glaucoma, bimatoprost 0.03% significantly reduced IOP. Mean IOP was reduced by approximately 7.5 to 9.2mm Hg 12 hours after drug administration in randomised clinical trials. The reduction in IOP was maintained throughout the 24-hour dosage interval. Once-daily treatment with bimatoprost 0.03% was found to be significantly more effective than timolol 0.5% (administered twice daily as an ophthalmic solution or once daily as a gel-forming solution) in randomised comparative trials in patients with ocular hypertension and glaucoma. Furthermore, after 1 to 6 months’ treatment, the percentage of patients reaching a target IOP of ≤17mm Hg was significantly greater in the bimatoprost-treated groups than in those receiving timolol.

Bimatoprost 0.03% ophthalmic solution was found to be at least as effective as topical latanoprost 0.005% administered once daily in two clinical trials. Reductions in IOP 16 and 20 hours postdose were greater in patients treated with bimatoprost, indicating superior control of IOP at timepoints throughout the dosage interval. In patients refractory to β-blocker therapy, treatment with bimatoprost 0.03% produced greater reductions in diurnal IOP measurements than combination therapy with topical dorzolamide 2%/timolol 0.5%; approximately twice as many bimatoprost 0.03% recipients achieved an IOP of ≤16mm Hg.

The most commonly reported adverse effect during clinical trials of once-daily bimatoprost 0.03% was conjunctival hyperaemia which occurred in 42 to 46% of patients treated. However, most cases were mild and only 1 to 4% of patients withdrew from treatment as a result. Overall withdrawal rates as a result of adverse events during clinical trials ranged from 2.6 to 7%. Bimatoprost has been reported to cause changes in the pigmentation of the periorbital skin, eyelashes and iris, and increase eyelash growth. The long-term consequences of these effects are unknown. Cardiopulmonary adverse effects, which have been associated with the use of β-blockers such as timolol, were not reported in clinical trials of bimatoprost.

Thus, in clinical trials of up to 1-year duration, bimatoprost 0.03% has been found to be effective in significantly lowering IOP and is generally well tolerated. It provides an alternative treatment option for patients in whom β-blockers are contraindicated. Furthermore, bimatoprost provides an effective second-line treatment option in patients who do not achieve target IOP with other topical ocular hypotensive agents, or who experience unacceptable adverse effects. Wider clinical use of this drug will establish the place of bimatoprost in the treatment of open-angle glaucoma and ocular hypertension.

Pharmacodynamic Profile

Bimatoprost is a fatty acid amide chemically related to endogenous prostamide F_2α. The mechanism of action of bimatoprost has not been fully elucidated. Receptor binding studies have found the drug to be essentially inactive at adrenergic, cholinergic, cannabinoid and dopaminergic receptors. One study found that bimatoprost did not interact with prostaglandin receptors; however, a second in vitro study demonstrated that prostaglandin F_2α was dissociated from the prostaglandin F (FP) receptor by bimatoprost with an apparent dissociation constant of 4390 nmol/L. Furthermore, stimulation of the receptor was demonstrated by the mobilisation of calcium ions following the addition of high concentrations of bimatoprost to Swiss 3T3 mouse fibroblasts and human embryonic kidney cells transfected with the human ocular FP receptor.

A trial in 25 healthy volunteers demonstrated that the intraocular pressure (IOP)-lowering effects of topical bimatoprost administered as a 0.03% ophthalmic solution resulted from an increased outflow of aqueous humour. The increased humour flow appeared to be primarily due to a reduction in tonographic resistance to outflow (the pressure-sensitive pathway) and possibly through an increase in uveoscleral outflow (the pressure-insensitive pathway).

Bimatoprost does not have a miotic effect in primates. Furthermore, bimatoprost did not alter retinal arteriolar tone in human xenografted retinal tissue in vitro.

Pharmacokinetic Profile

An in vitro study indicates that ocular absorption of bimatoprost occurs mainly through the sclera. After topical administration to the eye, systemic absorption occurs rapidly and peak blood concentrations of bimatoprost are reached within 10 minutes. Concentrations then rapidly decline to below the detection limit within 1.5 hours. Approximately 12% of bimatoprost remains unbound and is mainly distributed in the plasma (steady-state volume of distribution = 0.67 L/kg).

Metabolism of bimatoprost occurs mainly via oxidation, N-de-ethylation and glucuronidation; however, the major circulating species after intravenous administration is the parent compound. The elimination half-life of an intravenously administered radiolabelled 3.12 µg/kg dose of bimatoprost was approximately 45 minutes in six healthy volunteers. Up to 67% of the dose was excreted in the urine and 25% in the faeces. Total body clearance of bimatoprost was 1.5 L/h/kg.

The effect of age on the pharmacokinetics of bimatoprost have not been examined. Pharmacokinetic studies in patients with renal or hepatic impairment have also not been performed.

Therapeutic Efficacy

Clinical trials of bimatoprost have demonstrated that the drug has significant IOP-lowering efficacy. Dose-response and dose-frequency studies in patients with elevated IOP have demonstrated that the most effective regimen is a once-daily dosage of bimatoprost 0.03%. Twice-daily administration was found to confer no additional efficacy and in some studies was less effective than once-daily administration.

Mean reductions in IOP 12 hours after administration of bimatoprost 0.03% ranged from 6.8 to 9.2mm Hg in randomised clinical trials. Once-daily administration of bimatoprost 0.03% produced significantly greater reductions in IOP than timolol 0.5% given twice daily in large, randomised comparative trials involving 1128 patients with ocular hypertension or glaucoma (between-treatment difference in reduction ≈2 to 4mm Hg). Furthermore, reductions in IOP were maintained throughout the 24-hour dosage interval in bimatoprost-treated patients and this effect was maintained for up to 1 year. After 3 or 6 months’ treatment the percentage of patients achieving a target IOP of ≤17mm Hg was significantly greater in bimatoprost — (71 and 64%) than timolol — (46 and 37%) treated groups.

The clinical efficacy of bimatoprost 0.03% ophthalmic solution has also been compared with topical latanoprost 0.005% administered once daily in one small double-blind phase II study (n = 64) and a 3-month investigator-masked trial involving 232 patients with glaucoma or ocular hypertension. Both trials demonstrated no significant difference in the IOP-lowering efficacy of the drugs 12 hours postdose at the end of the treatment periods; however, diurnal control of IOP was more consistent with bimatoprost. The mean reduction in IOP at 12pm and 4pm (16 and 20 hours after drug administration) was significantly in favour of bimatoprost-treated patients after 3 months’ treatment (between-treatment difference ≈1mm Hg). Although the percentage of patients achieving a target IOP of ≤17mm Hg was not significantly different between treatment groups, a significantly greater proportion of the bimatoprost-treated patients reached a target IOP of ≤15mm Hg (29 vs 14%).

The combination of dorzolamide 2%/timolol 0.5% was compared with bimatoprost 0.03% in a 3-month randomised, single-blind trial involving 177 patients with ocular hypertension or glaucoma inadequately controlled with β-blocker therapy. Treatment with bimatoprost 0.03% produced significantly greater mean reductions in IOP at 8am than treatment with dorzolamide 2%/timolol 0.5% at every visit throughout the study. Furthermore, approximately twice as many patients had an IOP of ≤16mm Hg after 3 months treatment with bimatoprost than with dorzolamide/timolol (31 vs 14%).

Tolerability

Once-daily treatment with bimatoprost 0.03% was well tolerated during clinical trials in patients with ocular hypertension or glaucoma. The most common adverse event was conjunctival hyperaemia which was reported in 42 to 46% of patients treated with the drug and was more frequent than in patients receiving timolol 0.5% or latanoprost 0.005%. Most cases of conjunctival hyperaemia occurring in bimatoprost-treated patients were mild (greater than mild conjunctival hyperaemia occurred in 5.4 to 10.6% of patients). Approximately 1 to 4% of patients discontinued treatment with bimatoprost due to conjunctival hyperaemia. Overall withdrawal rates as a result of adverse events ranged from 2.6 to 7% during clinical trials of bimatoprost 0.03%.

Changes in the pigmentation of the iris have been reported in approximately 1% of patients receiving treatment with bimatoprost 0.03% for 6 months. Pigmentation of the periocular skin, eyelash darkening and eyelash growth have also been reported with the use of bimatoprost 0.03%. The long-term consequences of these effects are currently unknown.

Ocular adverse effects reported in 1 to 10% of patients included ocular dryness, visual disturbance, ocular burning, foreign body sensation, eye pain, blepharitis, cataract, superficial punctate keratitis, eyelid erythema, ocular irritation, eye discharge, tearing, photophobia, allergic conjunctivitis, asthenopia and conjunctival oedema. Ocular burning or stinging was less frequent in bimatoprost-treated patients than in patients receiving timolol 0.5%. Bimatoprost had no effect on visual acuity or cup to disc ratio in patients receiving the drug for up to 3 months during clinical trials.

Bimatoprost 0.03% had no clinically significant effect on heart rate or blood pressure in patients with glaucoma or ocular hypertension receiving the drug during clinical trials.

Dosage and Administration

Treatment with bimatoprost 0.03% ophthalmic solution is indicated for the reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension who have failed to reach target IOP with another IOP-lowering medication or are intolerant of other IOP-lowering medications.

One drop of bimatoprost 0.03% should be instilled once daily in the affected eye or eyes. Bimatoprost is approved for use concomitantly with other topical ophthalmic drugs; however, as with all concomitant ocular drug applications, the drugs should be applied at least 5 minutes apart.

Bimatoprost should be used with caution in patients with active intraocular inflammation, aphakia, a torn posterior lens capsule or patients with known risk factors for macular oedema.

Treatment with bimatoprost has not been studied in patients with renal or hepatic impairment and therefore caution is recommended before administering the drug in patients with these conditions. Careful consideration is recommended before administering bimatoprost to breast-feeding mothers or pregnant women as well designed clinical trials have not been performed in these patients.