Onreltea - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
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Onreltea - Scientific Information

Manufacture: Galderma Laboratories
Country: Canada
Condition: Rosacea
Class: Miscellaneous agents
Form: Cream, gel, liniment or balm, lotion, ointment, etc
Ingredients: brimonidine tartrate, carbomer, glycerol, methylparahydroxybenzoate, phenoxyethanol, propylene glycol, purified water, titanium dioxide, sodium hydroxide

Pharmaceutical Information

Drug Substance

Proper name: Brimonidine tartrate
Chemical name: 5-Bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine L-tartrate
5-Bromo-6-(2-imidazolin-2-ylamino)quinoxaline tartrate
Molecular formula and molecular mass: C11H10BrN5C4H6O6, molecular mass: 442.2 g/mol
Structural formula:



Physicochemical properties: Brimonidine tartrate is a white to slightly yellowish crystalline substance that is freely soluble in water and insoluble in almost all organic solvents.

Clinical Trials

Study Demographics and Trial Design

The efficacy of ONRELTEA (brimonidine) Gel, 0.33% in the treatment of moderate to severe facial erythema of rosacea has been demonstrated in two randomized, vehicle controlled clinical trials, which were identical in design. The studies were conducted in 553 subjects aged 18 years and older who were treated once daily for 4 weeks with either ONRELTEA or vehicle. Of these, 539 were included in the efficacy analysis at Day 29.

Study Results

The results from both clinical studies demonstrated that ONRELTEA was significantly more effective (p<0.001) in the reduction of facial erythema of rosacea than vehicle gel when applied once daily for 29 days. With respect to the primary endpoint of both pivotal studies (2-grade composite Success defined as 2-grade improvement on both the Clinician Erythema Assessment (CEA) and Patient Self Assessment (PSA) at hours 3, 6, 9, and 12 on Day 29) success rates were significantly higher (17.6% to 31.5%; p-val <0.001) for subjects on once-daily ONRELTEA treatment compared to those on vehicle treatment (8.6% to 10.9%; see Table 2). In addition, ONRELTEA demonstrated statistical superiority (p<0.001) over vehicle gel with respect to rapid initial onset of a clinically meaningful effect (1 -Grade Composite Success for CEA and PSA) after the first application at 30 minutes on Day 1, and to achievement of a clinically meaningful effect (1-Grade Composite Success for CEA and PSA) at hours 3, 6, 9, and 12 on Day 29 (see Table 2).

Table 1: Summary of 2-grade Composite Success on Day 29
Success Study 1 Study 2
ONRELTE
(N=127)
n/N (%)
Vehicle Gel
(N=128)
n/N (%)
ONRELTEA
(N=142)
n/N (%)
Vehicle Gel
(N=142)
n/N (%)
Hour 3 40/127 (31.5%) 14/128 (10.9%) 36/142 (25.4%) 13/142 (9.2%)
Hour 6 39/127 (30.7%) 12/128 (9.4%) 36/142 (25.4%) 13/142 (9.2%)
Hour 9 33/127 (26.0%) 13/128 (10.2%) 25/142 (17.6%) 15/142 (10.6%)
Hour 12 29/127 (22.8%) 11/128 (8.6%) 30/142 (21.1%) 14/142 (9.9%)
Day 29 p-value <0.001 - <0.001 -
Day 29 odds
ratio (95% CI)
3.75 (2.10, 6.70) - 2.95 (1.69, 5.15) -

2-grade Composite Success: 2-grade improvement on CEA and 2-grade improvement on PSA.

Table 2: Summary of 1-grade Composite Success on Day 29
Success Study 1 Study 2
ONRELTEA
(N=127)
n/N (%)
Vehicle Gel
(N=128)
n/N (%)
ONRELTEA
(N=142)
n/N (%)
Vehicle Gel
(N=142)
n/N (%)
Hour 3 90/127 (70.9%) 42/128 (32.8%) 101/142 (71.1%) 57/142 (40.1%)
Hour 6 88/127 (69.3%) 41/128 (32.0%) 92/142 (64.8%) 61/142 (43.0%)
Hour 9 81/128 (63.3%) 38/128 (29.7%) 95/142 (66.9%) 56/141 (39.7%)
Hour 12 72/127 (56.7%) 39/128 (30.5%) 76/142 (53.5%) 57/142 (40.1%)
Day 29 p-value <0.001 - <0.001 -

1-grade Composite Success: 1-grade improvement on CEA and 1-grade improvement on PSA.

No clinically meaningful trends with respect to tachyphylaxis or rebound effects (worsening of baseline erythema after cessation of treatment) were observed with use of ONRELTEA for 29 days. In addition, subjects using ONRELTEA concomitantly with other medications for the treatment of rosacea did not experience an increase of treatment-emergent adverse events beyond that anticipated for each drug individually.

Detailed Pharmacology

Pharmacodynamics

Brimonidine is a potent and highly selective alpha-2 adrenoreceptor agonist that is approximately 00-fold more selective for the alpha-2 adrenoreceptor than for the alpha-1 adrenoreceptor. Compared with clonidine and apraclonidine, brimonidine’s alpha-2 adrenoreceptor selectivity is up to 12- and 32-fold greater, respectively (Burke and Schwartz 1996; Adkins and Balfour 1998).

Vasoconstriction and Mechanism of Action

Alpha2-adrenoceptors are predominantly coupled to the inhibitory heterotrimeric GTP-binding protein (G-protein) inhibiting the activity of adenylyl cyclase and the opening of voltage-gated Ca2+ channels and activating K+ channels (Guimaräes and Moura 2001; Goodman and Gillman, 2001). The alpha-2 adrenoceptors may also be coupled to other intracellular pathways involving Na+/H+ exchange and the activation of phospholipase A2, C and D (Guimaräes and Moura 2001; Goodman and Gillman 2001). In neurons, alpha-2 adrenoceptors inhibit N-, P- and Q-type voltage- gated Ca2+ channels (Guimaräes and Moura 2001; Goodman and Gillman 2001). Finally, alpha-2A and alpha-2B but not alpha-2C adrenoceptors are down-regulated following exposure to agonists apparently due to an increase in the rate of receptor disappearance (Guimaräes and Moura 2001).

Alpha-1 adrenoceptors are present on most arteries and veins whereas alpha-2 adrenoceptor localization is more limited to small arteries and veins at the prejunctional sympathetic innervation level and at the postjunctional vessel level (Guimaräes and Moura 2001). In subcutaneous tissue, vasoconstriction of small, distal resistance arteries depends mainly on postjunctional (postsynaptic) smooth muscle alpha-2 adrenergic receptor stimulation (Chotani et al 2000; Nielsen et al 1989). This is in agreement with alpha-2 adrenergic receptor playing a major role in the regulation of cutaneous vascular tone (Flavahan et al 2000) and especially for alpha-2A adrenoceptors, which also appear to be involved in the vasoconstrictor effect of alpha-2 adrenoceptor stimulants – at least in part (MacMillan et al. 1996). This supports the pharmacological effect of brimonidine tartrate in the local treatment of erythema by a local vasoconstriction effect.

The subcutaneous vasoconstrictive effect of alpha-2 adrenergic receptor stimulation is considered to be the basis of the clinical efficacy of brimonidine for once daily cutaneous treatment of facial erythema of rosacea adult patients.

Pharmacodynamic Evaluation

The primary pharmacology studies reported in the literature strongly support that brimonidine is a potent alpha-2 adrenoceptor agonist, most specifically for alpha-2A subtype, with a mechanism of action similar to the other alpha-2 agonists. Brimonidine showed a markedly greater affinity for α2 adrenoceptors than apraclonidine and clonidine, the reference alpha-2 adrenoceptor agonists.

Pharmacokinetics

No specific pharmacokinetic study after cutaneous application of brimonidine gel was performed in animal species. Only toxicokinetic profiles in repeat-dose dermal toxicity studies are available in rats and minipigs.

Toxicokinetic (TK) measurements in the 13-week, 57-week and 2-year dermal toxicity studies in rats demonstrated high exposure multiples at the NOAEL when compared to the exposure achieved in clinical maximized conditions (Study RD.06.SRE.18143). After dermal administration of brimonidine gel to rats or minipigs, lower systemic exposures were observed in minipigs, possibly related to differences in skin penetration or metabolism.

Brimonidine was extensively metabolized primarily in the liver by an alpha-C-oxidation to quinoxalinone and quinoxalin-2,3-dione derivatives, and cleavage of the imidazoline ring to the aryl guanidine. Metabolic profiles of brimonidine were similar in humans and in all species used in toxicology investigations, except in dogs for which the major metabolites were determined to be the 4’,5’-dehydrobrimonidine (IIc) and the 5-bromo-6-guanidinoquinoxaline (VI) metabolites.

A maximal use systemic relative bioavailability study (Study RD.06.SPR.18143) was conducted in subjects with rosacea to determine the extent of systemic absorption of brimonidine tartrate in comparison to brimonidine tartrate 0.2% ophthalmic solution. On Day 1, all subjects were to receive brimonidine tartrate 0.2% ophthalmic solution (TID dose regimen, with 8-hour dosing interval). After a 2-day washout period, subjects were distributed among 4 treatment groups (randomized on Day 1) to receive Brimonidine Tartrate 0.07% Gel twice daily (BID), 0.18% Gel QD or BID, or 0.5% Gel QD during Days 4 to 32. Of note Brimonidine Tartrate Gel 0.5 % (equivalent to brimonidine 0.33% w/w) was the to- be-marketed formulation. Brimonidine plasma concentrations were determined by using a validated LC-MS/MS method with a lower limit of quantification (LOQ) of 10 pg/mL.

The PK parameters for brimonidine were calculated using standard non-compartmental methods In addition , the C max and AUC 0-24h data were analyzed statistically using log-transformed data in order to compare the route of administration (Ocular versus topical routes) and to assess the treatment groups and the treatment duration effects.

In Study RD.06.SPR.18143, ophthalmic instillation of brimonidine tartrate 0.2% ophthalmic solution resulted in quantifiable exposure (≥10 pg/mL) in all 96 subjects who received all 3 doses. The mean Cmax (±SD) was 54±28 pg/mL and the mean AUC0-24h (±SD) was 568±277 pg.hr/mL. Of note, the individual PK profiles displayed demonstrate that the dose regimen used in the current study (TID) does not impact on the Cmax values as there is no accumulation over the 24-hour ocular treatment period Conversely, daily topical application of Brimonidine Tartrate Gel for 29 days in the study demonstrated quantifiable (≥10 pg/mL) systemic exposure in 22%, 48%, 71% and 79% of subjects receiving Brimonidine Tartrate 0.07% Gel BID, 0.18% Gel QD, 0.18% Gel BID, and 0.5% Gel QD, respectively.

For the marketed formulation, Brimonidine Tartrate 0.5% Gel (equivalent to brimonidine 0.33% w/w), the mean Cmax (±SD) at the end of the treatment period was 25±24 pg/mL and the mean AUC0-24h (±SD) was 290±242 pg.hr/mL. Of note, the highest mean exposures in the Brimonidine Tartrate 0.5% Gel group were observed after 15 days of treatment (Cmax=46 ± 62 pg/mL, AUC0-24h=417 ± 264 pg.h/mL) due to isolated fluctuations in brimonidine plasma concentrations, which were not observed at the end of the treatment period.

The systemic exposures for 1 day of topical application were comparable to systemic exposures after 29 days of topical application in all treatment groups; thus, suggesting no drug accumulation throughout the 4-week treatment duration, irrespective of the dose and the dose regimen.

Furthermore, intra-individual comparisons of systemic exposure following topical and ophthalmic application were analyzed for all tested concentration/regimen combinations. The Topical/Ocular ratios calculated over the entire 29-day topical treatment period duration were significantly lower than 1, confirming lower systemic exposures for Brimonidine Tartrate Gel relative to the ophthalmic solution.

For the marketed formulation, Brimonidine Tartrate 0.5% Gel (equivalent to brimonidine 0.33% w/w), the Cmax mean Topical/Ocular ratios were 0.3 (first topical application), 0.6 (15 days of topical application), and 0.4 (29 days of topical application). For Cmax, the Topical/Ocular ratios calculated over the entire duration of the Brimonidine Tartrate 0.5% Gel treatment period were significantly lower than 1, irrespective of the study period, with significance based on the 90% CIs and because the upper limit of the CIs was below 0.8. Of note, the highest ratio was observed in the Brimonidine Tartrate 0.5% Gel QD group (mean ratio 0.6, 90% CI [0.5-0.7]) after 15 days of application. The ratio was lower at the end of the 29-day topical treatment period (mean ratio 0.4, 90% CI: 0.3-0.4); therefore, the higher ratio of 0.6 could be attributed to high isolated plasma levels observed at Day 18. The same tendency was observed for the quantifiable AUC 0-24h data. Systemic exposure after topical application of Brimonidine Tartrate 0.5% Gel was 2- to 3-times lower (based on Cmax) or 2- to 5-times lower (based on AUC0-24h) in comparison to a single day of TID ocular instillation of brimonidine tartrate 0.2% ophthalmic solution.

The results of Study 18143 demonstrated that the systemic exposures after topical treatment for all tested concentrations and regimens were significantly lower (based on the 90% CIs) compared to the systemic exposure for the ophthalmic route. Systemic exposure with brimonidine tartrate was low after topical application and was not affected by the number of product applications.

Toxicology

Repeat-Dose Toxicity

In hairless mice, the application of 200 µL/mouse of brimonidine tartrate gel increased mortality (Study RDS.03.SRE.12627). Brimonidine tartrate gel applied at 100 µL/animal appeared well tolerated in hairless mice in concentrations up to 2%.

In rats, following the application of 0.18%, 1% and 2% gel at 0.6 and 3 mL/kg, sporadic clinical signs such as decreased activity were observed. Abdominal distension was seen in the 13-week rat studies (Studies MB 07-15233.03 and RDS.03.SRE.12648) in females receiving 1% brimonidine and in male and females receiving 2% brimonidine and a higher incidence was seen in the 57-week rat study (RDS.03.SRE.12626) in males receiving 2% and in females receiving ≥0.18%. Females showed a higher incidence than males. The main effect in rats after 13 weeks of application was a body weight gain reduction in males at all dose levels (-17% at 0.18%, -33% at 1%, and 44% at 2%); a similar although not statistically significant effect was seen in females ( 12% at 1% and 8% at 2%). In females, food consumption was reduced at 1% and 2% concentrations. Body weight gains were similarly decreased in the 57- week study in male rats (-24% at 1% and 32% at 2%) and in female rats at all dose levels (-19% at 0.18%, -14% at 1%, and -15% at 2%) with associated decreased food consumption in all treated groups. In the 57-week study, decreased survival was observed in females treated with brimonidine tartrate 2% gel (-26% compared to the vehicle control group). In the 13-week study, some minimal changes in hematology and clinical chemistry were not considered adverse, as the changes were not associated with histopathological findings and furthermore were not observed in the 57-week study. No histopathology changes were observed in the rat.

In minipigs, no meaningful local or systemic effects were reported after 9 months of treatment at up to 1% brimonidine tartrate gel given at 2 mL/kg (Study RDS.03.SRE.12694).

Overall, brimonidine tartrate gel appeared well tolerated topically at concentrations of up to 2% (100 µL/animal) in mice, 1% in female rats (3 mL/kg) and minipigs (2 mL/kg), and 0.18% (0.6 mL/animal) in male rats. When given topically at these maximum tolerable dose volumes and concentrations, no target organs were identified at histopathology.

In chronic/carcinogenicity studies in rodents (Angelov et al. 1996a), brimonidine tartrate was given orally at 0.1, 0.5, and 2.5 mg/kg/day in mice and at 0.05, 0.25 and 1 mg/kg/day in rats mixed in the diet. After 52 and 21 months in mice or 24 months in rats, hypertrophy of the tunica muscularis and hyperplasia of the epithelial mucosa of the small and large intestine was seen in mice at 2.5 mg/kg/day and in rats at 0.25 and 1 mg/kg/day. Intestinal findings were considered as exaggerated pharmacological effects and generally reverted after treatment removal. Following 1 year of oral administration in monkeys at 0.1, 0.5, 2.5 mg/kg/day, sinus bradycardia, sinus arrhythmias and hypotensive effects were noted at 2.5 mg/kg/day. They were considered as exaggerated pharmacological effects. Overall, brimonidine appeared well tolerated up to oral dose levels around 1 mg/kg/day in rodents and 2.5 mg/kg/day in monkeys.

Genotoxicity

Brimonidine was reported to be not genotoxic in the following test systems: a bacterial mutation assay (Ames test), in vitro and in vivo cytogenetic assays and a dominant lethal mutation assay (Snyder and Green 2001).

Carcinogenicity

A 1-year photo(co)carcinogenicity study was performed in hairless mice with Brimonidine Tartrate Gel (Study RDS.03.SRE.12629). Exposure to UV- radiation did not result in enhancement of photocarcinogenesis at concentration of up to 2% Brimonidine Tartrate Gel.

A 2-year dermal carcinogenic study was performed in rats with a Brimonidine Tartrate Gel formulation (Study RDS.03.SRE.12667). There was no indication of carcinogenic potential at concentrations up to 0.18% in males and up to 2%/0.72% in females (dose reduced after 343 days of treatment), corresponding to AUC0-24h on Day 457 of 215 ng.h/mL and 1070 ng.h/mL in males and females, respectively.

In a 21-month dietary carcinogenicity study in mice, no carcinogenic effects were observed up to the dose level of 2.5 mg brimonidine /kg/day. In a 24-month dietary carcinogenicity study in rats, no carcinogenic effects were observed up to the dose level of 1.0 mg/kg/day (Angelov et al. 1996a).

Reproductive and Developmental Toxicity

In studies conducted following oral administration of brimonidine tartrate, no treatment-related effects were observed on male and female fertility up to 1 mg/kg/day in rats, no teratogenic effect was reported up to 2.5 mg/kg/day in rats and 5 mg/kg/day in rabbits and no pre- and post-natal development toxicity was found at doses of up to 1 mg/kg/day in rats (Angelov et al. 1996b).

Local Tolerance Studies

A primary skin irritation and phototoxicity study in hairless female mice, an eye irritation study in rabbits, and a skin sensitization study in guinea pigs did not show significant treatment-related adverse reactions. In addition, no skin irritation was seen with topical application in rats after 57 weeks of dosing with brimonidine gel concentrations of up to 2%, after 2 years of dosing in rats with concentrations of 0.6% in males and 0.75% in females, and after 9 months of dosing in minipigs with concentrations of up to 1%.