Clinical pharmacokinetics and drug metabolism of tazarotene: a novel topical treatment for acne and psoriasis.

Tazarotene (AGN 190168) is a new acetylenic retinoid which is effective for the topical treatment of patients with stable plaque psoriasis and mild to moderate acne vulgaris. Topical gel application provides direct delivery of tazarotene into the skin. At 10 hours after a topical application of 0.1% tazarotene gel to the skin of healthy individuals and patients with psoriasis, approximately 4 to 6% of the dose resided in the stratum corneum and 2% of the dose distributed to the viable epidermis and dermis. Tazarotene is rapidly hydrolysed by esterases to its active metabolite, tazarotenic acid. Tazarotenic acid does not accumulate in adipose tissue, but undergoes further metabolism to its sulfoxide and to other polar metabolites and is rapidly eliminated via both urinary and faecal pathways with a terminal half-life of about 18 hours. Percutaneous absorption is similar between healthy individuals and patients with facial acne, leading to plasma concentrations below 1 microg/L. The systemic bioavailability of tazarotene (measured as tazarotenic acid) is low, approximately 1% after single and multiple topical applications to healthy skin. In patients with psoriasis under typical conditions of use, systemic bioavailability increased during the initial 2 weeks of treatment from 1% (single dose) to 5% or less (steady state). The increased bioavailability is probably related to decreases in plaque elevation and scaling due to successful treatment, resulting in a less effective skin penetration barrier to tazarotene. Steady-state concentrations of tazarotenic acid are achieved within 2 weeks of topical treatment in both healthy and psoriatic skin types. The large variability in plasma concentrations observed in patients with psoriasis is probably because of the large differences in lesional skin condition, the amount of drug applied and the surface area of application. There was no significant drug accumulation in the body with long term treatment of patients with psoriasis. Topical administration of tazarotene requires dosages much smaller than those usually required for oral retinoids, such as isotretinoin, acitretin and etretinate, and it delivers the drug directly into the target skin tissues. The low systemic absorption and rapid systemic elimination of tazarotene and tazarotenic acid results in limited systemic exposure. Thus, topical tazarotene has a low potential for systemic adverse effects and is effective in the treatment of patients with acne and psoriasis.     

他扎罗汀乳膏治疗痤疮的临床疗效观察

目的:为痤疮患者提供更好的治疗方案。方法:122例痤疮患者按随机单盲对照原则分为他扎罗汀组(42例)、水氯酊组(38例)和联合治疗组(42例),连续外用8周后观察疗效。结果:3组皮损数均随治疗时间的延长而逐渐减少,与治疗前比较,治疗8周后皮损总分3组差异均有统计学意义(P<0.05或P<0.01)。治疗8周后有效率,他扎罗汀组与水氯酊组比较差异有统计学意义(χ2=17.629,P<0.05);联合治疗组与水氯酊组比较差异也有统计学意义(χ2=15.532,P<0.05);他扎罗汀组与联合治疗组比较差异无统计学意义(χ2=10.130,P>0.05)。结论:对于非炎症性痤疮可单用他扎罗汀治疗;对脓疱型患者水氯酊效果优于他扎罗汀,考虑与氯霉素的抗菌作用有关;而对于炎症性痤疮可选用他扎罗汀加0.5%水氯酊外用。     

Tazarotene versus tazarotene plus clindamycin/benzoyl peroxide in the treatment of acne vulgaris: a multicenter, double-blind, randomized parallel-group trial

Topical retinoids offer highly effective treatment for both inflammatory and non-inflammatory acne, with tazarotene demonstrating greater efficacy than other topical retinoids. A multicenter, double-blind, randomized, parallel-group trial has been performed to evaluate whether the adjunctive use of clindamycin/benzoyl peroxide could enhance the efficacy of tazarotene still further. Patients with moderate to severe inflammatory acne applied tazarotene 0.1% cream each evening and were randomly assigned to morning applications of vehicle gel or a ready-to-dispense formulation of clindamycin 1%/benzoyl peroxide 5 % gel containing 2 emollients. Tazarotene/clindamycin/benzoyl peroxide achieved a significantly greater reduction in comedo count than tazarotene monotherapy and, among patients with a baseline papule plus pustule count of > or =25 (the median value), a significantly greater reduction in inflammatory lesion count. The combination therapy was also at least as well-tolerated as tazarotene monotherapy. The adjunctive use of clindamycin/benzoyl peroxide gel with tazarotene cream promotes greater efficacy and may also enhance tolerability. Any improvements in tolerability could be due to the emollients in the clindamycin/benzoyl peroxide gel formulation.     

他扎罗汀乳膏与阿达帕林凝胶随机对照治疗寻常型痤疮多中心临床试验

目的 评价国产0．1％他扎罗汀乳膏治疗面部轻中度寻常型痤疮的疗效及安全性。方法 用多中心、随机单盲对照试验方法，0．1％他扎罗汀乳膏或0．1％阿达帕林凝胶局部外用每日1次，疗程8周。在治疗前、治疗2，4和8周进行观察。入选病例142例，其中0．1％他扎罗汀乳膏组71例，完成8周观察64例。0．1％阿达帕林凝胶组71例，完成8周观察67例。结果他扎罗汀乳膏组有效率72．3％，阿达帕林凝胶组有效率62．7％。两组之间无显著统计学差异。两组的不良反应均表现为轻度到中度的局部刺激，发生率分别为28．70％和23．50％。结论 他扎罗汀乳膏治疗寻常型痤疮安全有效。     

The efficacy of topical tazarotene monotherapy and combination therapies in psoriasis

Tazarotene (Tazorac, Allergan, Inc.) is the first topical retinoid approved for the treatment of plaque psoriasis. It has a similar onset of action compared to potent topical steroids and has the advantage of a longer remission. The common side effects associated with the drug include skin irritation (including pruritus), erythema and a burning sensation. To overcome some of these shortcomings, it has been used in combination with steroids, calcipotriene and phototherapy. Combination therapy not only results in a decrease in adverse side effects, but also enhanced efficacy. Clinical study data have shown that combination therapy is just as important as tazarotene monotherapy, if not more.     

The efficacy of topical tazarotene monotherapy and combination therapies in psoriasis

Tazarotene (Tazorac^®, Allergan, Inc.) is the first topical retinoid approved for the treatment of plaque psoriasis. It has a similar onset of action compared to potent topical steroids and has the advantage of a longer remission. The common side effects associated with the drug include skin irritation (including pruritus), erythema and a burning sensation. To overcome some of these shortcomings, it has been used in combination with steroids, calcipotriene and phototherapy. Combination therapy not only results in a decrease in adverse side effects, but also enhanced efficacy. Clinical study data have shown that combination therapy is just as important as tazarotene monotherapy, if not more.     

Evidence-based review: fixed-combination therapy and topical retinoids in the treatment of acne

Topical fixed-combination products and topical retinoid monotherapy are established first-line treatments for mild-to-moderate acne vulgaris, yet adequate comparative data are lacking. The following evidence-based review addresses the question: "In patients with mild-to-moderate acne, are topical fixed-combination products or topical retinoids a more efficacious choice in reducing noninflammatory, inflammatory and total lesions after 12 weeks of treatment?" To identify relevant studies, a PubMed search was performed using "acne" and search terms for adapalene, tretinoin, tazarotene, benzoyl peroxide, clindamycin, or erythromycin. Forty-two studies from January 1991 to November 2009 were included. The studies were evaluated using the Strength of Recommendation Taxonomy, and all but seven received the highest level of evidence grade. To evaluate efficacy, a side-by-side comparison was made using reduction in acne lesion counts at week 12 for study groups treated with fixed-combination therapy or retinoid monotherapy. Twenty-nine studies containing relevant efficacy data for fixed-combination therapy and retinoid monotherapy are summarized here. Nine studies compared fixed-combination therapy with retinoid monotherapy; in eight of these studies, fixed-combination therapy was significantly more efficacious in reducing acne lesion counts. This evidence-based review analyzes clinical evidence to date for these therapies to provide guidance in determining appropriate treatment for patients with mild-to-moderate acne.     

Tazarotene foam, 0.1%, for the treatment of acne

Introduction: Acne is a common skin condition of the pilosebaceous units that affects the young and old, ranges from moderate to severe and can be treated with an array of options. Topical retinoids are the initial treatment for acne due to their ability to treat comedones, the starting point of acne.

Areas covered: Tazarotene is a topical retinoid available as a cream, gel and foam. Tazarotene 0.1% foam was FDA approved in 2012 for the treatment of acne in patients ages ≥12 and is the first foam topical retinoid on the market. Phase I and III trials support the efficacy and safety of tazarotene foam for acne.

Expert opinion: The foam vehicles may increase compliance and satisfaction in some patients and as retinoids are commonly first line acne treatments, this new topical retinoid foam may be a useful option for some acne patients.     

Adverse events related to topical drug treatments for acne vulgaris

ABSTRACT

Introduction: Acne vulgaris is a widespread skin disease. Topical therapy is a standard treatment for mild to moderate acne. Given the complex pathophysiology of acne, various agents with complementary action are nowadays frequently combined to increase the efficacy of therapy.

Area covered: This review focus on safety profile of topical agents used for the treatment of acne vulgaris, including topical retinoids, benzyl peroxide, azelaic acid, topical antibiotic, and combined agents. Data from clinical trials but also metanalyses, systematic reviews, and other secondary analyses are presented.

Expert opinion: In general, topical agents used for acne vulgaris have a favorable safety profile. The most commonly reported AEs were associated with local skin irritation, usually mild to moderate in intensity, intermittent, and rarely led to the cessation of therapy. Irritative potential seems to be highest for BPO and topical retinoids. Due to the possibility of development of Cutibacterium acnes resistance, topical antibiotics should not be used in monotherapy but as a part of combination therapy. In female adolescent and adults of childbearing potential, topical retinoids should be used with caution, because they are contraindicated in pregnant females (FDA Pregnancy category) C (adapalene, tretinoin) and X (tazarotene).     

维A酸在银屑病患者中的应用

银屑病为常见的慢性复发性皮肤病,维A酸已成功应用于该疾病的治疗。本文重点介绍两种代表性药物——阿维A酸与他扎罗汀在银屑病临床治疗中的有关情况。口服阿维A酸对脓疱型及红皮病型银屑病最为有效,与光疗联合对中、重度斑块性银屑病疗效显著;而他扎罗汀作为第一个受体选择性外用维A酸,不论单用或联合治疗,对寻常型银屑病均有显著疗效。     

Adapalene: a review of its use in the treatment of acne vulgaris

Adapalene (Differin) is a retinoid agent indicated for the topical treatment of acne vulgaris. In clinical trials, 0.1% adapalene gel has proved to be effective in this indication and was as effective as 0.025% tretinoin gel, 0.1% tretinoin microsphere gel, 0.05% tretinoin cream and 0.1% tazarotene gel once every two days; however, the drug was less effective than once-daily 0.1% tazarotene gel. It can be used alone in mild acne or in combination with antimicrobials in inflammatory acne and has proved efficacious as maintenance treatment. Adapalene has a rapid onset of action and a particularly favourable tolerability profile compared with other retinoids. These attributes can potentially promote patient compliance, an important factor in treatment success. Adapalene is, therefore, assured of a role in the first-line treatment of acne vulgaris.     

Pharmacokinetics of tazarotene and acitretin in psoriasis

Introduction: Psoriasis is a prevalent cutaneous condition with severe physical and psychological manifestations. Since the advent of biologics, clinical outcomes in psoriasis have improved. However, retinoids are useful in the correct clinical context. Tazarotene and acitretin are currently the only US Food and Drug Administration approved retinoids for treatment of psoriasis. Both topical tazarotene and oral acitretin act on retinoic acid receptors and retinoid-X-receptors, resulting in altered gene expression of inflammatory cytokines and inhibition of keratinocyte proliferation.

Areas covered: This article provides an in-depth pharmacologic and clinical review on the use of tazarotene and acitretin in psoriasis. The PubMed database was searched using combinations of keywords: acitretin, bioavailability, dosing, efficacy, etretinate, interactions, mechanism, pharmacodynamics, pharmacokinetics, pharmacogenetics, psoriasis, safety, tazarotene, tolerability, and toxicity.

Expert opinion: Tazarotene and acitretin are effective treatments for psoriasis. Benefits include lack of immunosuppression and success treating inflammatory psoriasis. When combined with other topical and systemic agents, both retinoids improve clinical efficacy while lowering the treatment threshold. However, topical adherence and bothersome side effects can limit retinoid use. Acitretin and tazarotene both improve outcomes through a unique mechanism that especially benefits subsets of patients, despite side effects and limitations.     

Tazarotene cream versus adapalene cream in the treatment of facial acne vulgaris: a multicenter, double-blind, randomized, parallel-group study

A multicenter, double-blind, randomized, parallel-group trial compared tazarotene 0.1% cream with adapalene 0.1% cream, once daily for 12 weeks, in 173 patients with facial acne vulgaris. Tazarotene was associated with a significantly greater incidence of patients achieving 50% or greater global improvement (77% vs. 55%, P < or = .01), and a significantly greater reduction in comedo count (median of 68% vs. 36%, P < or =.001, compared with adapalene. A significant between-group difference in baseline inflammatory lesion count precluded a comparison of efficacy against inflammatory acne. The most common adverse events were dryness, peeling/flaking, itching, redness/erythema, burning, and facial irritation with comparable incidences of each between groups. Mean peeling and burning levels were milder with adapalene, though were trace or less in both groups throughout. There were no significant between-group differences in the incidence of patients discontinuing due to lack of efficacy or adverse events. Tazarotene cream offers significantly greater efficacy and comparable tolerability to adapalene cream.     

他扎罗汀凝胶与卡泊三醇软膏治疗斑块型银屑病的比较

目的 :观察他扎罗汀凝胶治疗斑块型银屑病的疗效与安全性 ,并与卡泊三醇软膏比较。方法 :71例斑块型银屑病病人分为 2组 ,他扎罗汀组 36例 ,每晚外涂 1次 ;卡泊三醇组 35例 ,早、晚各外涂1次 ,2组疗程均为 12wk。结果 :2组的总有效率分别为 83%和 79% ,差异无显著意义 (P >0 .0 5 )。结论 :他扎罗汀凝胶治疗斑块型银屑病安全有效 ,与卡泊三醇相仿     

Pharmacokinetics of tazarotene cream 0.1% after a single dose and after repeat topical applications at clinical or exaggerated application rates in patients with acne vulgaris or photodamaged skin

OBJECTIVE: To evaluate the safety and pharmacokinetics of tazarotene cream 0.1% under standard (face only) or exaggerated (15% body surface area, including the face) application conditions after a single dose and after repeat topical applications once daily to patients with acne vulgaris or photodamaged skin. METHODS: Two separate, randomised, single-centre, nonblinded, parallel-group pharmacokinetic studies were conducted. In one study, tazarotene cream 0.1% was applied either to the face of eight female patients with moderate acne or to 15% body surface area of ten female patients with severe acne. In the other study, tazarotene cream 0.1% was applied either to the face (six females, two males) or to 15% body surface area (8 females, 8 males) of patients with photodamaged skin. In both studies, tazarotene cream 0.1% was applied once daily (except on days 1 and 2) for 30 days. Blood was drawn for measurement of plasma concentrations of tazarotenic acid at defined time intervals after application of the cream. Plasma tazarotenic acid concentrations were determined by a validated gas chromatography-tandem mass spectrometry method with a lower limit of quantification of 0.005 microg/L. RESULTS: At exaggerated application rates in patients with acne vulgaris, the maximum average peak concentration (C(max)) and 24-hour area under the concentration-time curve (AUC) values of tazarotenic acid were (mean +/- SD) 1.20 +/- 0.41 microg/L (n = 10) and 17.0 +/- 6.1 microg. h/L (n = 10), respectively, and occurred on day 15. The single highest C(max) was 1.91 microg/L. At standard application rates in patients with acne vulgaris, the maximum average C(max) and AUC values of tazarotenic acid were 0.10 +/- 0.06 microg/L (n = 8) and 1.54 +/- 1.01 microg. h/L (n = 8), respectively, and occurred on day 15. At exaggerated application rates in patients with photodamaged skin, the maximum average C(max) and AUC values of tazarotenic acid were (mean +/- SD) 1.75 +/- 0.53 microg/L (n = 16) and 23.8 +/- 7.0 microg. h/L (n = 16), respectively, and occurred on day 22. The single highest C(max) was 3.43 microg/L on day 29. At standard application rates in patients with photodamaged skin, the maximum average C(max) and AUC values of tazarotenic acid were 0.236 +/- 0.255 microg/L (n = 8) and 2.44 +/- 1.38 microg. h/L (n = 8), respectively, and occurred on day 15. Gender had no influence on the systemic exposure of tazarotenic acid. The most common treatment-related adverse events were signs and symptoms of local irritation, of mild or moderate severity. CONCLUSIONS: The pharmacokinetics of tazarotene cream 0.1% in patients with acne vulgaris or photodamaged skin are similar. The maximum average plasma concentrations of tazarotenic acid after topical application of tazarotene cream 0.1% to the face were less than 0.25 microg/L. The maximum average plasma concentrations of tazarotenic acid following application to an exaggerated body surface area (15%) were less than 1.8 microg/L.     

7种药物治疗寻常型银屑病的成本-效果分析

目的:评价7种药物治疗寻常型银屑病的经济学效果。方法:221例寻常型银屑病患者随机接受平消胶囊(A组)、吡硫翁锌气雾剂(B组)、他扎罗汀乳膏(C组)、复方青黛胶囊(D组)、百癣夏塔热片(E组)、阿维A胶囊(F组)、卡泊三醇乳膏(G组)治疗,以药物经济学方法进行成本-效果分析。结果:A、B、C、D、E、F、G组的总成本(C)分别为959.83、894.00、1343.50、892.03、832.66、592.02、4664.11元,有效率(E1)分别为65.63%、84.38%、62.50%、66.67%、70.97%、72.73%、80.65%;患者皮损面积及严重程度指数(PASI评分)总分减少量(E2)分别为8.44、11.72、8.25、8.85、9.18、9.74、10.73;平均成本-效果比C/E1分别为1462.49、1059.49、2149.60、1337.98、1173.26、814.00、5783.15,C/E2分别为113.72、76.28、162.85、100.79、90.70、60.78、434.68;与F组比较,A、B、C、D、E、G组增量成本-效果比ΔC/ΔE1分别为-5180.42、2592.10、-7345.85、-4950.66、-13672.73、51415.28,ΔC/ΔE2分别为-282.93、152.52、-504.35、-337.09、-429.71、4113.22。结论:7种药物中,阿维A胶囊治疗寻常型银屑病是较好的治疗方案。