Ganfort PF Mechanism of Action

Pharmacotherapeutic group: Ophthalmological beta-blocking agents: Timolol, combinations. ATC code: S01ED51.
Pharmacology: Pharmacodynamics: Mechanism of action: Ganfort PF consists of two active substances: Bimatoprost and timolol maleate. These two components decrease elevated intraocular pressure (IOP) by complementary mechanisms of action and the combined effect results in additional IOP reduction compared to either compound administered alone. Ganfort PF has a rapid onset of action.
Bimatoprost is a potent ocular hypotensive agent. It is a synthetic prostamide, structurally related to prostaglandin F_2α (PGF_2α) that acts through an identified prostamide receptor. The efficacy of bimatoprost may be related to a dual mechanism of action on aqueous humor outflow that involves uveoscleral and trabecular meshwork Schlemm's canal pathways. Bimatoprost reduces IOP in humans by increasing aqueous humor outflow through the trabecular meshwork and enhancing uveoscleral outflow.
Timolol is a beta₁ and beta₂ (non-selective) adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic (membrane-stabilising) activity. Timolol lowers IOP by reducing aqueous humor formation.
Clinical effects: Bimatoprost lowers IOP with a peak ocular hypotensive effect at approximately 12 hours; timolol reaches peak ocular hypotensive effect at approximately 1 to 2 hours. Both bimatoprost and timolol significantly lower IOP following the first dose. The IOP-lowering effect of Ganfort PF is non-inferior to that achieved by adjunctive therapy of bimatoprost (once daily) and timolol (twice daily).
Based on published clinical study data, the use of Ganfort PF in evening in patients with OAG or OHT demonstrated comparable safety and efficacy profiles to patients who dosed Ganfort PF in the morning.
Pharmacokinetics: Ganfort medicinal product: Plasma bimatoprost and timolol concentrations were determined in a crossover study comparing the monotherapy treatments to Ganfort treatment in healthy subjects. Systemic absorption of the individual components was minimal and not affected by co-administration in a single formulation.
In two 12-month studies where systemic absorption was measured, no accumulation was observed with either of the individual components.
Bimatoprost: Bimatoprost penetrates the human cornea and sclera well in vitro. After ocular administration, the systemic exposure of bimatoprost is very low with no accumulation over time. After once daily ocular administration of one drop of 0.03% bimatoprost to both eyes for two weeks, blood concentrations peaked within 10 minutes after dosing and declined to below the lower limits 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.
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 metabolism.
Bimatoprost is eliminated primarily by renal excretion, up to 67% of an intravenous dose administered to healthy 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, the mean AUC_0-24hrs values 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.
Timolol: After ocular administration of a 0.5% eye drops solution in humans undergoing cataract surgery, peak timolol concentration was 898 ng/mL in the aqueous humor at one hour post-dose. Part of the dose is absorbed systemically where it is extensively metabolized in the liver. The half-life of timolol in plasma is about 4 to 6 hours. Timolol is partially metabolized by the liver with timolol and its metabolites excreted by the kidney. Timolol is not extensively bound to plasma.
Toxicology: Preclinical Safety Data: Ocular Toxicology: Preclinical repeated dose ocular toxicity studies of the bimatoprost 0.03%/timolol 0.5% combination demonstrated an ocular safety profile similar to that of bimatoprost (alone) or timolol (alone).
Bimatoprost: The toxicity of bimatoprost (alone) has been assessed in ocular instillation studies up to 1 month duration in New Zealand White rabbits (NZW), up to 6 months duration in Dutch belted (DB) rabbits, up to 1 month duration in dogs, and up to 1 year duration in monkeys.
Slight, transient ocular discomfort and conjunctival hyperemia were noted in NZW rabbits in both 3-day and 1-month studies at bimatoprost concentrations as low as 0.001%. However, rabbits administered placebo solutions exhibited the same response. Dogs exhibited ocular discomfort and transient slight conjunctival erythema at concentrations as low as 0.001% bimatoprost, and in placebo controls. Administration of bimatoprost or placebo to DB rabbits did not cause ocular irritation in any study. Since slight, transient ocular irritation was observed in NZW rabbits and dogs QID, but not in DB rabbits given the same formulation of bimatoprost and placebo BID, these effects may be due to the higher frequency of dosing. No systemic effects were noted in the 6-month ocular rabbit study which achieved a maximal AUC_de that was approximately 360-fold higher than the human value resulting from the 0.03% bimatoprost/0.5% timolol combination clinical regimen.
Monkeys given ocular administration of 1 drop of bimatoprost 0.03% QD or BID or bimatoprost 0.1% BID for 52 weeks exhibited a dose-related increase in the prominence of the periocular sulci, resulting in a widening of the palpebral fissure of the treated eye. The severity and incidence of this effect was temporally related to dose. No functional or microscopic change related to the periocular change was observed. An increase in iris pigmentation was noted in some animals in all treated groups. No associated increase in melanocyte number was observed with the pigmentation. It appears that the mechanism of increased iris pigmentation is due to increased stimulation of melanin production in melanocytes and not to an increase in melanocyte number. The highest dose (0.1% twice daily) produced a maximal AUC_de that was approximately 440-fold higher than the human value resulting from the 0.03% bimatoprost/0.5% timolol combination clinical regimen.
Timolol: Timolol 1.5% (alone) administered to rabbits and dogs into one eye, 3 times daily for up to 12 months (5 days/week) resulted in only minor, treatment-related, ocular irritation.
Systemic Toxicology: Systemic toxicity studies were not carried out with the combination 0.03% bimatoprost/0.5% timolol because of the distinct and well-understood mechanisms of action of the individual compounds and the extensive systemic toxicology evaluation of the individual compounds in the following studies.
Bimatoprost: 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.
No effects were observed in mice given 4 mg/kg/day bimatoprost orally for 3 months. This dose produced a maximal AUC_de that was approximately 1,000-fold higher than the human value resulting from the 0.03% bimatoprost/0.5% timolol combination clinical regimen. Female mice given oral doses of 8 mg/kg/day showed a reversible thymic lymphoid proliferation. This finding was only observed in mice and a maximal AUC_de that was approximately 3,000-fold higher than the human value resulting from the 0.03% bimatoprost/0.5% timolol combination clinical regimen.
A decrease in food consumption and an increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed in male rats given ≥8 mg/kg/day for 13 weeks. Reversible decreases in body weight and body weight gain were observed in both genders at ≥4 mg/kg/day. A reversible increase in ovarian weight accompanied by delayed regression of corpora lutea was noted in females ≥4 mg/kg/day. The ovarian effects were observed only in studies with nulliparous rats and since these effects were not seen in other species or pregnant rats suggesting that bimatoprost may uniquely affect the luteal cycle in nulliparous rats. These findings were observed at an AUC_de that was at least 11,000-fold higher than the human value resulting from the 0.03% bimatoprost/0.5% timolol combination clinical regimen. The species-specificity and considerable exposure margins indicate that risk of ovarian effects is negligible in humans. There were no drug related effects in either gender at 0.1 mg/kg/day. A slight decrease (9%) in body weight in females (2 mg/kg/day) versus control was observed in the 1-year study in rats. There was a slight increase in transaminase activity (~3-fold) in males of all dose groups but these changes were not associated with any histopathological lesions and reversibility was apparent. Ovarian and hepatic effects were reversible, and considered species specific since these changes had not been observed in mice and monkeys at systemic exposures up to 8,500 to 99,000-fold higher, respectively, than the human value resulting from the 0.03% bimatoprost/0.5% timolol combination clinical regimen.
Periocular effects were also observed with IV administration of 0.01 mg/kg/day in monkeys for 17 weeks. IV administration of 0.01 mg/kg/day produced an AUC_de of 1,600-fold greater than the human value resulting from the 0.03% bimatoprost/0.5% timolol combination clinical regimen. The periocular effects were resolved following cessation of treatment. No functional or anatomic abnormalities of the eye were detected. The underlying cause of the prominence of the sulci and widening of the palpebral fissures observed with ocular and IV administration in monkeys is unknown. Since periocular changes were observed with both ocular and IV administration of bimatoprost, these studies suggest there are local receptor-specific effects underlying the periocular effects in monkeys.
Timolol: Timolol maleate administered orally to rats or dogs at doses up to 50 mg/kg/day for upto 4 months produced no drug-related toxicity.
Carcinogenicity and Genotoxicity Studies: Bimatoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses up to 2 mg/kg/day and 1 mg/kg/day, respectively, for 104 weeks, giving AUC values approximately 1,300 and 2,000-times greater than the human value resulting from the 0.03% bimatoprost/0.5% timolol combination clinical regimen.
In a 2-year study of timolol maleate administered orally to rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day. This dose was approximately 510,000-times the daily dose of bimatoprost 0.03%/timolol 0.5% in humans.
Neither bimatoprost nor timolol maleate are considered genotoxic hazards, based on results of comprehensive genotoxicity test batteries. Bimatoprost was not mutagenic or clastogenic in the Ames test, in the mouse lymphoma test, or in the in vivo mouse micronucleus tests. Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 μg/mL). In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000 μg/plate, were associated with statistically significant elevations of revertants observed with tester strain TA 100 (in seven replicate assays), but not in the remaining three strains. In the assays with tester strain TA 100, no consistent dose response relationship was observed, and the ratio of test to control revertants did not reach 2. A ratio of 2 is usually considered the criterion for a positive Ames test.
Fertility Studies: In the fertility and early embryonic development study in rats, there were no drug-related effects of bimatoprost at up to 0.6 mg/kg/day on male or female reproductive performance, paternal or maternal toxicity, sperm analysis parameters, uterine implantation parameters, or embryo viability. The highest dose produced a C_max 160 times higher than in humans given the 0.03% bimatoprost/0.5% timolol combination clinical regimen. Although an AUC_de for 0.6 mg/kg/day was not determined in this particular study for this study, it can be inferred as 710 times the value in humans given the clinical regimen from the exposure data in an embryofetal developmental study.
Reproduction and fertility studies of timolol in rats demonstrated no adverse effect on male or female fertility at doses up to 5,100 times the daily dose of 0.03% bimatoprost/0.5% timolol combination in humans.
Embryo Fetal Development Studies: In an embryofetal developmental study in CD-1 mice given 0.3 and 0.6 mg/kg/day bimatoprost orally, maternal toxicity was apparent as a small percentage of late gestational abortions (days 16-17) and early delivery. No maternal toxicity occurred at 0.1 mg/kg/day bimatoprost (C_max was 28-fold higher than humans given the 0.03% bimatoprost/0.5% timolol combination clinical regimen). The lowest dose showing maternal toxicity (0.3 mg/kg/day bimatoprost) had an AUC_de that was 220 times higher than humans given the clinical regimen. The embryofetal no-observed-adverse-effect level (NOAEL) was 0.6 mg/kg/day bimatoprost, which produced an AUC_de that was 490 times higher than humans given the clinical regimen.
Teratogenicity studies with timolol in mice, rats, and rabbits at oral doses up to 50 mg/kg/day (8,600-times the daily dose of bimatoprost 0.03%/timolol 0.5% in humans) demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1,000 mg/kg/day (170,000-times the daily dose of bimatoprost 0.03%/timolol 0.5% in humans) were maternally toxic in mice and resulted in an increased number of fetal resorptions.
Prenatal and Postnatal Studies: In the prenatal and postnatal developmental study, treatment of F₀ rats with ≥0.3 mg/kg/day of bimatoprost affected gestation and prenatal development, manifest as reduced gestation length, late resorption and fetal death, postnatal mortality, and reduced pup body weight. At 0.6 mg/kg/day bimatoprost, reductions in the number of dams delivering litters, gestation index, and number of nursed litters were observed. No effects on postnatal development and mating performance of the F₁ offspring were observed at 0.1 mg/kg/day bimatoprost, which produced 94-times the human exposure (AUC_de). These parameters were affected slightly at 0.3 mg/kg/day which produced 280-times the human exposure to 0.03% bimatoprost/0.5% timolol combination. Neurobehavioral function, Caesarean-sections, and litters in F₁ rats were unaffected by dosages as high as 0.3 mg/kg/day of bimatoprost.