Tretinoin microsphere gel in facial acne vulgaris: a meta-analysis

Journal of Drugs in Dermatology, August, 2008 by Marge Nighland, Rachel Grossman

ABSTRACT: Background: Acne vulgaris can persist beyond adolescence into the fourth decade of life or later; most patients have a combination of inflammatory and noninflammatory lesions.

Objective: To determine whether tretinoin microsphere gel (TMG) 0.04% applied once nightly is well tolerated and effective in reducing inflammatory and noninflammatory lesions in adolescents and adults with mild to moderate facial acne.

Methods: The results of 3 randomized, double-blind, vehicle-controlled studies of TMG 0.04% applied once nightly for 12 consecutive weeks in a total of 629 patients, ages 11 to 49 years, were combined. Reductions in acne lesion counts were assessed twice monthly, and an investigator's global evaluation (IGE) was performed at the study endpoint (week 12).

Results: Tretinoin microsphere gel 0.04% was significantly superior to the vehicle gel in reducing both inflammatory and noninflammatory lesions over the 12-week treatment period, and produced a higher successful treatment rate than the vehicle gel, as judged by IGE ratings at week 12. The most frequent adverse events were erythema, peeling, and dryness, which were mostly mild and occurred in 59.7% to 63.3% of patients with TMG 0.04%, as compared with 26.9% to 51.0% of patients with the vehicle gel (placebo).

Conclusion: The TMG 0.04% formulation is significantly superior when compared to its vehicle gel in reducing inflammatory and noninflammatory acne lesions over a period of 12 weeks and is well tolerated.

INTRODUCTION

Acne vulgaris is a common inflammatory dermatosis estimated to affect more than 80% of adolescents. (1), (2) Its incidence peaks at around 18 years of age, but it can persist to the fourth decade of life or later. (3), (5) Most acne patients have a combination of noninflammatory and inflammatory lesions; the former (comedones) predominate in mild cases, whereas moderate cases exhibit more inflammatory lesions (papules and pustules), and severe cases exhibit nodular lesions. (4) The pathogenesis of acne is multifactorial, and involves sebaceous follicle obstruction, excessive sebum production due to hormonal stimulation of sebaceous glands, proliferation of Propionibacterium acnes, which produces chemotactic factors and, via, activation of toll-like receptor-2 (TLR-2), proinflammatory mediators that generate an inflammatory response, and follicular rupture and extension of the inflammation into the dermis, resulting in the formation of inflammatory lesions. (3), (7)

A variety of topical medications are available for treating mild to moderate acne, including retinoids such as tretinoin (all-transretinoic acid), the clinical efficacy of which is well established. (8-12) Tretinoin acts by both comedolysis and the normalizing maturation of the follicular epithelium such that comedone formation is decreased and progression to larger or inflammatory lesions is prevented. (12), (13) These effects are mediated by binding to and activating all subtypes of nuclear retinoic acid receptors (RARs). (14), (15) In addition, tretinoin also produces an anti-inflammatory effect, possibly by downregulating TLR-2 expression and function. (16) Clinical improvement of mild to moderate acne is usually seen within 6 weeks of instituting topical tretinoin therapy. (12)

Despite its benefits, tretinoin, as with other topical retinoids, has the potential to cause localized irritation, which may manifest as a pustular flare after 1 to 2 weeks of use. (12), (13) To minimize this response while maintaining clinical efficacy, tretinoin has been formulated in sponge-like polymeric microspheres that encapsulate the active ingredient and deliver it gradually and relatively selectively to the follicle. (17) In comparison with a standard 0.025% cream, a tretinoin microsphere gel (TMG) 0.1% formulation has been shown to be less irritant to normal skin (18) and to cause significantly less erythema and dryness. (19)

This study, which combined data from 3 randomized, double-blind, vehicle (placebo)-controlled clinical studies (2 phase 3 studies and 1 phase 4 study), compared the efficacy and tolerability of the lowest concentration of TMG available (0.04%) with its vehicle gel in patients with mild or moderate facial acne over a 12-week period. This study also assessed the relationship between reductions in inflammatory and noninflammatory lesion counts with TMG 0.04% administration and the investigator's global evaluation (IGE) of the treatment response.

TABLE 1. Demographic characteristics and baseline disease
severities of patients enrolled in the 3 studies.

                             Study 1 *               Study 2 **

Baseline              TMG 0.04%  Vehicle gel  TMG 0.04%  Vehicle gel

characteristics       (n = 108)  (n = 110)    (n = 117)  (n = 116)

Age, years (mean)     20.2       19.2          18.3       18.9

Gender (%)

Male                  39 (36%)   55 (50%)      53 (45%)   46 (40%)

Female                69 (64%)   55 (50%)      64 (55%)   70 (60%)

Ethnicity (%)

Caucasian             76 (70%)   80 (73%)      90 (77%)   86 (74%)

Black                 13 (12%)   15 (13%)      16 (14%)   19 (16%)

Other                 19 (18%)   15 (13%)      11 (9%)    11 (9%)

Acne lesion counts
(mean)

Total [range]         59.2        59.7         65.6       65.3

                     [20-137]    [20-141]     [31-139]   [30-146]

Inflammatory          21.2        19.7         21.4       20.5

Noninflammatory       38.0        40.1         44.2       44.7

                               Study 3 ***              Total

Baseline
characteristics      TMG 0.04%  Vehicle gel  TMG 0.04%  Vehicle gel
                     (n = 88)    (n = 90)    (n = 313)    (n = 316)

Age, years (mean)     26.7       29.0         21.3        21.9

Gender (%)

Male                  15 (17%)   18 (20%)    107 (34%)    119(38%)

Female                73 (83%)   72 (80%)    206 (66%)    197(62%)

Ethnicity (%)

Caucasian             57 (65%)    49 (54%)   223 (71%)    15 (68%)

Black                 16 (18%)    29 (32%)    45 (14%)    63 (20%)

Other                 15 (17%)    12 (13%)    45 (14%)    38 (12%)

Acne lesion counts
(mean)

Total [range]         42.4       41.1         56.9        56.5

                     [15-108]   [16-87]      [15-139]    [16-146]

Inflammatory          16.9       16.2         20.1        19.0

Noninflammatory       25.6       24.9         36.8        37.5

* Study 23333.11 DR (adolescents and adults; phase 3); **Study 24100.11
(adolescents and adults; phase 3). *** Study 27720.11 (adults only;
phase 4); TMG = tretinoin microsphere gel.