Tazarotene is a retinoid prodrug which is converted to its active form, the cognate carboxylic acid of tazarotene (AGN 190299), by rapid deesterification in animals and man. AGN 190299 (“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.

Psoriasis: The mechanism of tazarotene action in psoriasis is not defined. Topical tazarotene blocks induction of mouse epidermal ornithine decarboxylase (ODC) activity, which is associated with cell proliferation and hyperplasia. In cell culture and in vitro models of skin, tazarotene suppresses expression of MRP8, a marker of inflammation present in the epidermis of psoriasis patients at high levels. In human keratinocyte cultures, it inhibits cornified envelope formation, whose build-up is an element of the psoriatic scale. Tazarotene also induces the expression of a gene which may be a growth suppressor in human keratinocytes and which may inhibit epidermal hyperproliferation in treated plaques. However, the clinical significance of these findings is unknown.

Acne: 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.

Pharmacokinetics

Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. Little parent compound could be detected in the plasma. Tazarotenic acid was highly bound to plasma proteins ( > 99%). Tazarotene and tazarotenic acid were metabolized to sulfoxides, sulfones and other polar metabolites which were eliminated through urinary and fecal pathways. The half-life of tazarotenic acid was approximately 18 hours, following topical application of tazarotene to normal, acne or psoriatic skin.

In a multiple dose study with a once daily dose for 14 consecutive days in 9 psoriatic patients (male=5; female=4), measured doses of tazarotene 0.1% cream were applied by medical staff to involved skin without occlusion (5 to 35% of total body surface area: mean ± SD: 14 ± 11%). The Cmax of tazarotenic acid was 2.31 ± 2.78 ng/mL occurring 8 hours after the final dose, and the AUC_0-24h was 31.2 ± 35.2 ng•hr/mL on day 15 in the five patients who were administered clinical doses of 2 mg cream/cm² .

During clinical trials with 0.05% or 0.1% tazarotene cream treatment for plaque psoriasis, three out of 139 patients with their systemic exposure monitored had detectable plasma tazarotene concentrations, with the highest value at 0.09 ng/mL. Tazarotenic acid was detected in 78 out of 139 patients (LLOQ = 0.05 ng/mL). Three patients using tazarotene cream 0.1% had plasma tazarotenic acid concentrations greater than 1 ng/mL. The highest value was 2.4 ng/mL. However, because of the variations in the time of blood sampling, the area of psoriasis involvement, and the dose of tazarotene applied, actual maximal plasma levels are unknown.

Tazarotene cream 0.1% was applied once daily to either the face (N = 8) or to 15% of body surface area (N = 10) of female patients with moderate to severe acne vulgaris. The mean Cmax and AUC values of tazarotenic acid peaked at day 15 for both dosing groups during a 29 day treatment period. Mean Cmax and AUC_0-24h values of tazarotenic acid from patients in the 15% body surface area dosing group were more than 10 times higher than those from patients in the face-only dosing group. The single highest Cmax throughout the study period was 1.91 ng/mL on day 15 in the exaggerated dosing group. In the face-only group, the mean ± SD values of Cmax and AUC_0-24h of tazarotenic acid on day 15 were 0.10 ± 0.06 ng/mL and 1.54 ± 1.01 ng.hr/mL, respectively, whereas in the 15% body surface area dosing group, the mean ± SD values of Cmax and AUC_0-24h of tazarotenic acid on day 15 were 1.20 ± 0.41 ng/mL and 17.01 ± 6.15 ng.hr/mL, respectively. The steady state pharmacokinetics of tazarotenic acid had been reached by day 8 in the face-only and by day 15 in the 15% body surface area dosing groups.

In a Phase 3 clinical trial, tazarotene 0.1% cream was applied once daily for 12 weeks to each of 48 patients (22 females and 26 males) with facial acne vulgaris. The mean ± SD values of plasma tazarotenic acid at weeks 4 and 8 were 0.078 ± 0.073 ng/mL (N = 47) and 0.052 ± 0.037 ng/mL (N = 42), respectively. The highest observed individual plasma tazarotenic acid concentration was 0.41 ng/mL at week 4 from a female patient. The magnitude of plasma tazarotenic acid concentrations appears to be independent of gender, age, and body weight.

Clinical Studies

In two 12-week vehicle-controlled clinical studies, tazarotene 0.05% and 0.1% creams were significantly more effective than vehicle in reducing the severity of stable plaque psoriasis. Tazarotene cream 0.1% and tazarotene cream 0.05% demonstrated superiority over vehicle cream as early as 1 week and 2 weeks, respectively, after starting treatment.

In these studies, the primary efficacy endpoint was “clinical success,” defined as the proportion of patients with none, minimal, or mild overall lesional assessment at Week 12, and shown in the following Table. “Clinical success” was also significantly greater with tazarotene 0.05% and 0.1% vs vehicle at most follow-up visits.

Patient Numbers and Percentages for Overall Lesional Assessment Scores and “Clinical Success” At Baseline (BL), End of Treatment (Week 12) and 12 Weeks After Stopping Therapy (Week 24)# in Two Controlled Clinical Trials for Psoriasis

At the end of 12 weeks of treatment, tazarotene creams 0.05% and 0.1% were consistently superior to vehicle in reducing the plaque thickness of psoriasis. Improvements in erythema and scaling were generally significantly greater with tazarotene 0.05% and 0.1% than with vehicle. Tazarotene cream 0.1% was also generally more effective than the 0.05% concentration in reducing the severity of the individual signs of disease. However, tazarotene cream 0.1% was associated with a somewhat greater degree of local irritation than the 0.05% cream.

Mean Decreases in Plaque Elevation, Scaling and Erythema in Two Controlled Clinical Trials for Psoriasis

Acne

In two large vehicle-controlled studies, patients (age 12 or over) with facial acne vulgaris of a severity suitable for monotherapy with a topical agent were enrolled. After face cleansing in the evening, tazarotene cream 0.1% was applied once daily to the entire face as a thin layer. Tazarotene was significantly more effective than vehicle in the treatment of facial acne vulgaris. Efficacy results after 12 weeks of treatment are shown in the following Table:

Efficacy Results after Twelve Weeks of Treatment in Two Controlled Clinical Trials for Acne

Last reviewed on RxList: 6/24/2008
This monograph has been modified to include the generic and brand name in many instances.