Mechanism of Action
Tazarotene is a retinoid prodrug that is converted to its active form, the cognate carboxylic acid of tazarotene, by rapid deesterification in animals and man. Tazarotenic acid binds to all three members of the retinoic acid receptor (RAR) family: RARα, RARβ, and RARγ but shows relative selectivity for RARβ, and RARγ and may modify gene expression. The clinical significance of these findings is unknown.
The mechanism of tazarotene action in acne vulgaris is not defined. However, the basis of tazarotene's therapeutic effect in acne may be due to its anti-hyperproliferative, normalizing-of-differentiation and anti-inflammatory effects. Tazarotene inhibited corneocyte accumulation in rhino mouse skin and cross-linked envelope formation in cultured human keratinocytes. The clinical significance of these findings is unknown.
The pharmacodynamics of Fabior Foam are unknown.
Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. Tazarotenic acid was highly bound to plasma proteins (greater than 99%). Tazarotene and tazarotenic acid were metabolized to sulfoxides, sulfones and other polar metabolites which were eliminated through urinary and fecal pathways.
Systemic exposure following topical application of Fabior Foam 0.1% was evaluated in one trial. Patients aged 15 years and older with moderate-to-severe acne applied approximately 3.7 grams of Fabior Foam 0.1% (N=13) to approximately 15% body surface area (face, upper chest, upper back, and shoulders) once daily for 22 days. On day 22, the mean (±SD) tazarotenic acid Cmax was 0.43 (±0.19) ng/mL, the AUC0-24h was 6.98 (±3.56) ng·hr/mL and the half-life was 21.7 (±15.7) hours. The median Tmax was 6 hours (range 4.4 to 12 hours). The AUC0-24hr for tazarotenic acid was approximately 50 fold higher compared with the parent compound tazarotene. The mean (±SD) half-life of tazarotene was 8.1 (±3.7) hours.
Accumulation was observed upon repeated once-daily dosing as the tazarotenic acid predose concentrations were measurable in the majority of subjects. Steady state was attained within 22 days of daily application. Once-daily dosing resulted in little to no accumulation of tazarotene as predose concentrations were mostly below the quantitation limit throughout the study.
In 2 multi-center, randomized, double-blind, vehicle-controlled trials, a total of 1485 patients with moderate-to-severe acne vulgaris were randomized 1:1 to Fabior Foam or vehicle applied once daily for 12 weeks. Acne severity was evaluated using lesion counts and the 6-point Investigator's Global Assessment (IGA) scale (see Table 2). At baseline, 80% of patients were graded as “moderate” or Grade 3 and 20% were graded as “severe” or Grade 4 on the IGA scale. At baseline, subjects had an average of 79.8 total lesions of which the mean number of inflammatory lesions was 31.9 and the mean number of non inflammatory lesions was 47.8. Patients ranged in age from 12 to 45 years, with 860 (58%) patients 12 to 17 years of age; 428 (29%) patients 18 to 25 years old; 143 (10%) patients 26 to 35 years old and 54 (4%) patients 36 to 45 years old. Patients enrolled in the studies by race were white (77%), Black (15%), Asian (4%) and other (4%). Hispanics comprised 18% of the population. An equal number of males (49%) and females (51%) were enrolled. Treatment success was defined as a score of “clear” (Grade 0) or “almost clear” (Grade 1) and at least 2-grade improvement from the baseline score to week 12.
Table 2: Investigator's Global Assessment Scale
|0||Clear||Clear skin with no inflammatory or non-inflammatory lesions.|
|1||Almost clear||Rare non-inflammatory lesions with no more than rare papules.|
|2||Mild||Greater than Grade 1, some non-inflammatory lesions with no more than a few inflammatory lesions (papules/pustules only, no nodular lesions).|
|3||Moderate||Greater than Grade 2, up to many non-inflammatory lesions and may have some inflammatory lesions, but no more than one small nodular lesion.|
|4||Severe||Greater than Grade 3, up to many non-inflammatory and inflammatory lesions, but no more than a few nodular lesions.|
|5||Very severe||Many non-inflammatory and inflammatory lesions and more than a few nodular lesions. May have cystic lesions.|
Absolute and percent reductions in lesion counts and the IGA scale after 12 weeks of treatment in these two trials are shown in Table 3. Each study needed to have a statistically significant reduction in two out of three lesion counts at Week 12.
Table 3: Reductions in Lesion
Counts and Improvements in Investigator's Global Assessment at Week 12
|Study 1||Study 2|
|Mean absolute reduction from Baseline||18.0||14.0||18.0||15.0|
|Mean percent reduction from Baseline||58%||45%||55%||45%|
|Mean absolute reduction from Baseline||28.0||17.0||26.0||18.0|
|Mean percent reduction from Baseline||55%||33%||57%||41%|
|Mean absolute reduction from Baseline||46.0||31.0||43.0||33.0|
|Mean percent reduction from Baseline||56%||39%||56%||43%|
|Investigator's Global Assessment (IGA), n (%)|
|Minimum 2-grade improvement and IGA of 0 or 1||107 (29%)||60 (16%)||103 (28%)||49 (13%)|
Last reviewed on RxList: 5/24/2012
This monograph has been modified to include the generic and brand name in many instances.
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