Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2022 Publisher: Aspire Pharma Ltd, Unit 4, Rotherbrook Court, Bedford Road, Petersfield, Hampshire, GU32 3QG, UK
Pharmacotherapeutic group: Ophthalmologicals, prostaglandin analogues
ATC code: S01EE03
The mechanism of action by which bimatoprost reduces intraocular pressure in humans is by increasing aqueous humour outflow through the trabecular meshwork and enhancing uveoscleral outflow. Reduction of the intraocular pressure starts approximately 4 hours after the first administration and maximum effect is reached within approximately 8 to 12 hours. The duration of effect is maintained for at least 24 hours.
Bimatoprost is a potent ocular hypotensive agent. It is a synthetic prostamide, structurally related to prostaglandin F2α (PGF2α), that does not act through any known prostaglandin receptors. Bimatoprost selectively mimics the effects of newly discovered biosynthesised substances called prostamides. The prostamide receptor, however, has not yet been structurally identified.
A 12 week (double-masked, randomized, parallel group) clinical study compared the efficacy and safety of bimatoprost 0.3 mg/ml (preservative free formulation) with bimatoprost 0.3 mg/ml (preserved formulation). bimatoprost 0.3 mg/ml (preservative free formulation) achieved non-inferior IOP-lowering efficacy to bimatoprost 0.3 mg/ml (preserved formulation) for worse eye IOP change from baseline in patients with glaucoma or ocular hypertension. bimatoprost 0.3 mg/ml (preservative free formulation) also achieved equivalent IOP lowering efficacy with bimatoprost 0.3 mg/ml (preserved formulation) in average eye IOP at each follow-up timepoint at weeks 2, 6 and 12.
During 12 months' monotherapy treatment with bimatoprost 0.3 mg/ml (preserved formulation) in adults, versus timolol, mean change from baseline in morning (08:00) intraocular pressure ranged from -7.9 to -8.8 mmHg. At any visit, the mean diurnal IOP values measured over the 12-month study period differed by no more than 1.3 mmHg throughout the day and were never greater than 18.0 mmHg.
In a 6-month clinical study with bimatoprost 0.3 mg/ml (preserved formulation), versus latanoprost, a statistically superior reduction in morning mean IOP (ranging from -7.6 to -8.2 mmHg for bimatoprost versus –6.0 to -7.2 mmHg for latanoprost) was observed at all visits throughout the study. Conjunctival hyperaemia, growth of eyelashes, and eye pruritus were statistically significantly higher with bimatoprost than with latanoprost, however, the discontinuation rates due to adverse events were low with no statistically significant difference.
Compared to treatment with beta-blocker alone, adjunctive therapy with beta-blocker and bimatoprost 0.3 mg/ml (preserved formulation) lowered mean morning (08:00) intraocular pressure by -6.5 to -8.1 mmHg.
Limited experience is available in patients with open-angle glaucoma with pseudoexfoliative and pigmentary glaucoma, and chronic angle-closure glaucoma with patent iridotomy.
No clinically relevant effects on heart rate and blood pressure have been observed in clinical trials.
The safety and efficacy of Eyreida in children aged 0 to 18 years has not been established.
Bimatoprost penetrates the human cornea and sclera well in vitro. After ocular administration in adults, the systemic exposure of bimatoprost is very low with no accumulation over time. After once daily ocular administration of one drop of bimatoprost 0.3 mg/ml to both eyes for two weeks, blood concentrations peaked within 10 minutes after dosing and declined to below the lower limit of detection (0.025 ng/ml) within 1.5 hours after dosing. Mean Cmax and AUC0-24hrs values were similar on days 7 and 14 at approximately 0.08 ng/ml and 0.09 ng•hr/ml respectively, indicating that a steady bimatoprost concentration was reached during the first week of ocular dosing.
Bimatoprost is moderately distributed into body tissues and the systemic volume of distribution in humans at steady-state was 0.67 l/kg. In human blood, bimatoprost resides mainly in the plasma. The plasma protein binding of bimatoprost is approximately 88%.
Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation following ocular dosing. Bimatoprost then undergoes oxidation, N-deethylation and glucuronidation to form a diverse variety of metabolites.
Bimatoprost is eliminated primarily by renal excretion, up to 67% of an intravenous dose administered to healthy adult volunteers was excreted in the urine, 25% of the dose was excreted via the faeces. The elimination half-life, determined after intravenous administration, was approximately 45 minutes; the total blood clearance was 1.5 l/hr/kg.
After twice daily dosing of bimatoprost 0.3 mg/ml, the mean AUC0-24hr value of 0.0634 ng•hr/ml bimatoprost in the elderly (subjects 65 years or older) were significantly higher than 0.0218 ng•hr/ml in young healthy adults. However, this finding is not clinically relevant as systemic exposure for both elderly and young subjects remained very low from ocular dosing. There was no accumulation of bimatoprost in the blood over time and the safety profile was similar in elderly and young patients.
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Monkeys administered ocular bimatoprost concentrations of ≥0.3 mg/ml daily for 1 year had an increase in iris pigmentation and reversible dose-related periocular effects characterised by a prominent upper and/or lower sulcus and widening of the palpebral fissure. The increased iris pigmentation appears to be caused by increased stimulation of melanin production in melanocytes and not by an increase in melanocyte number. No functional or microscopic changes related to the periocular effects were observed, and the mechanism of action for the periocular changes is unknown.
Bimatoprost was not mutagenic or carcinogenic in a series of in vitro and in vivo studies.
Bimatoprost did not impair fertility in rats up to doses of 0.6 mg/kg/day (at least 103-times the intended human exposure). In embryo/foetal developmental studies abortion, but no developmental effects were seen in mice and rats at doses that were at least 860-times or 1700-times higher than the dose in humans, respectively. These doses resulted in systemic exposures of at least 33- or 97-times higher, respectively, than the intended human exposure. In rat peri/postnatal studies, maternal toxicity caused reduced gestation time, foetal death, and decreased pup body weights at ≥0.3 mg/kg/day (at least 41-times the intended human exposure). Neurobehavioural functions of offspring were not affected.
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