Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Ophthalmologicals, prostaglandin analogues, ATC code: S01EE03.
Mechanism of action
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.
Clinical efficacy
A 12 week (double-masked, randomized, parallel group ) clinical study compared the efficacy and safety of bimatoprost 0.3 mg/mL single-dose with bimatoprost 0.3 mg/mL (multi-dose formulation). bimatoprost 0.3 mg/mL single-dose achieved non-inferior IOP-lowering efficacy to bimatoprost 0.3 mg/mL (multi-dose formulation) for worse eye IOP change from baseline in patients with glaucoma or ocular hypertension. bimatoprost 0.3 mg/mL single-dose also achieved equivalent IOP lowering efficacy with bimatoprost 0.3 mg/mL (multi-dose 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 (multi-dose 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 (multi-dose 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 (multi- dose 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.
Paediatric population
The safety and efficacy of BIMATOPROST S.K in children aged 0 to 18 years has not been established.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
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 AUC 0-24hrs 


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.
Distribution
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%.
Biotransformation
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.
Elimination
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.
Characteristics in elderly patients
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.