Lumigan 0.01% Mechanism of Action

Pharmacotherapeutic group: Other antiglaucoma preparations. ATC code: S01EE03.
Pharmacology: Mechanism of Action: Bimatoprost is a synthetic prostamide structurally related to prostaglandin F_2α (PGF_2α).
Bimatoprost is a potent ocular hypotensive agent.
Bimatoprost efficacy may be related to a dual mechanism of action on aqueous humour outflow that involves uveoscleral and trabecular meshwork Schlemm's canal pathways. Studies in human models of the trabecular meshwork/Schlemm's canal outflow pathways have demonstrated that bimatoprost produces marked increases in hydraulic conductivity that are prostamide receptor mediated.
Pharmacokinetics: Absorption and Systemic Drug Exposure: Bimatoprost penetrates the human cornea and sclera well in vitro. The mean corneal permeability coefficient was 3.24 x 10^-6 cm/sec. Bimatoprost penetrated human scleral tissue better than corneal tissue with a mean scleral permeability coefficient of 14.5 x 10^-6 cm/sec. After ocular administration, the systemic exposure of bimatoprost is very low with no accumulation over time. After once daily ocular administration of 1 drop of 0.03% bimatoprost to both eyes of healthy subjects for 2 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 C_max 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 drug concentration was reached during the first week of ocular dosing.
The blood concentrations of bimatoprost from patients with glaucoma or ocular hypertension in 2 Phase 3 safety and efficacy studies were measured (N=88 on once-daily treatment and N=89 on twice-daily treatment). The samples were collected at approximately 5 minutes after the evening dose on day 0 and at 3, 6 and 12 months. Bimatoprost blood concentrations were similar to those observed in normal, healthy subjects and there was no significant systemic drug accumulation over time. The C-1 acid metabolite (AGN 191522) was typically not measurable in blood samples from these studies.
Distribution: Bimatoprost is moderately distributed into body tissues and the systemic volume of distribution in human at steady-state was 0.67 L/kg. In human blood, bimatoprost resides mainly in the plasma. Bimatoprost was approximately 88% bound to human plasma proteins at concentrations ranging from 1 to 250 ng/mL that was concentration independent. Up to 20% of bimatoprost was bound reversibly to synthetic melanin at concentrations ranging from 0.2-100 μg/mL which was also concentration independent.
Metabolism: Bimatoprost is not extensively metabolized in human eye and it is the major circulating species in the blood once it reaches the systemic circulation following ocular dosing. Bimatoprost then undergoes glucuronidation, hydroxylation, N-deethylation and deamidation to form a diverse variety of metabolites. The glucuronide conjugates of bimatoprost are the most abundant metabolite excreted in urine and faeces. There is evidence that hydrolysis of bimatoprost to the free acid is not a prerequisite for its ocular hypotensive activity.
The effects of bimatoprost treatment on hepatic drug metabolizing enzymes was investigated in rats and monkeys following one month of daily intravenous administration. Systemic drug exposures were at least 4,000 times greater than those seen in humans following QD ophthalmic administration. Bimatoprost was found to have no significant effect on any of the hepatic microsomal enzyme activities in cynomolgus monkeys. In female rats, an increase in the activity of UDP-glucuronosyl transferase was observed. In the male rats, a marginal reduction in the rate of testosterone 16β-hydroxylation were the only findings. Neither of these observations is expected to have any clinically significant consequences in humans.
Elimination: Following an intravenous dose of radiolabeled bimatoprost (3.12 μg/kg) to six healthy subjects, the mean maximum blood concentration of total radioactivity was 14.5 ng·eq/mL. Total radioactivity was eliminated from the body with a short half-life of 1.74 hours. The blood concentration of intact bimatoprost was 12.2 ng/mL at maximum and declined rapidly with an elimination half-life of 0.771 hour (approximately 45 minutes). Blood concentrations of AGN 191522, the C-1 acid metabolite, were much lower than those of bimatoprost as peak concentration was 0.12 ng/mL. The total blood clearance (Clb) of unchanged bimatoprost was 1.50 L/hr/kg.
Sixty-seven percent of the administered dose of bimatoprost was excreted in the urine with only a small fraction excreted as unchanged drug. Twenty-five percent of the dose was recovered in feces of which 15-40% was eliminated as unchanged drug.
Pharmacokinetic in Special Clinical Situations: Characteristic in Elderly Patients: There was no significant systemic accumulation of bimatoprost following twice-daily dosing for 7 days in either young (18-44 years, mean=28.5) or elderly patients (65-80 years, mean=71.0). Bimatoprost appeared rapidly in the blood in both age groups, and was below the LLOQ by 1.5 hours in most patients. Systemic exposure was higher in the elderly than the young following both single and multiple dosing (124% and 213%, respectively). The mean AUC_0-24hrs value of 0.0634 ng·hr/mL in elderly subjects was statistically significantly higher than that of 0.0218 ng·hr/mL in young subjects, suggesting the existence of an age effect. However, this finding is not considered clinically relevant as bimatoprost exhibits similar efficacy and safety profiles in both the young and elderly populations.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Bimatoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to 2 mg/kg/day and 1 mg/kg/day respectively (at least 192 and 291 times the recommended human exposure based on blood AUC levels respectively) for 104 weeks.
Bimatoprost was not mutagenic or clastogenic in the Ames test, in the mouse lymphoma test, or in the in vivo mouse micronucleus tests.
No impairment of fertility occurred in rats when males were treated for 70 days prior to cohabitation and females were treated for 15 days prior to mating. Treatment was continued in males until copulation was observed and in females through gestation day 7.
The highest doses (0.6 mg/kg/day) achieved systemic exposure that was 103 times that observed in humans treated with 1 drop of 0.03% bimatoprost in each eye once daily for 2 weeks.
Clinical Studies: In a 3 month clinical study of patients with open angle glaucoma or ocular hypertension with an average baseline IOP of 23.5 mmHg, the IOP-lowering effect of LUMIGAN 0.01% once daily (in the evening) was up to 7.5 mmHg. In this same study, LUMIGAN 0.01% also had a similar overall safety profile compared with LUMIGAN 0.03%. After 12 months of treatment, discontinuations were 8.1% for LUMIGAN 0.01%.