Retin-A Micro

CLINICAL PHARMACOLOGY

Tretinoin is a retinoid metabolite of Vitamin A that binds to intracellular receptors in the cytosol and nucleus, but cutaneous levels of tretinoin in excess of physiologic concentrations occur following application of a tretinoin-containing topical drug product. Although tretinoin activates three members of the retinoid acid (RAR) nuclear receptors (RARα, RARβ, and RARγ) which may act to modify gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation, it has not been established whether the clinical effects of tretinoin are mediated through activation of retinoic acid receptors, other mechanisms, or both.

Mode of Action

Although the exact mode of action of tretinoin is unknown, current evidence suggests that the effectiveness of tretinoin in acne is due primarily to its ability to modify abnormal follicular keratinization. Comedones form in follicles with an excess of keratinized epithelial cells. Tretinoin promotes detachment of cornified cells and the enhanced shedding of corneocytes from the follicle. By increasing the mitotic activity of follicular epithelia, tretinoin also increases the turnover rate of thin, loosely-adherent corneocytes. Through these actions, the comedo contents are extruded and the formation of the microcomedo, the precursor lesion of acne vulgaris, is reduced.

Additionally, tretinoin acts by modulating the proliferation and differentiation of epidermal cells. These effects are mediated by tretinoin's interaction with a family of nuclear retinoic receptors. Activation of these nuclear receptors causes changes in gene expression. The exact mechanisms whereby tretinoin-induced changes in gene expression regulate skin function are not understood.

Pharmacokinetics

Tretinoin is a metabolite of Vitamin A metabolism in man. Percutaneous absorption, as determined by the cumulative excretion of radiolabeled drug into urine and feces, was assessed in 44 healthy men and women. Estimates of in vivo bioavailability, mean (SD)%, following both single and multiple daily applications, for a period of 28 days with the 0.1% gel, were 0.82 (0.11)% and 1.41 (0.54)%, respectively. The plasma concentrations of tretinoin and its metabolites, 13-cis-retinoic acid, all-trans-4-oxo-retinoic acid, and 13-cis-4-oxo-retinoic acid, generally ranged from 1 to 3 ng/mL and were essentially unaltered after either single or multiple daily applications of Retin-A Micro (tretinoin gel) microsphere, 0.1%, relative to baseline levels. Clinical pharmacokinetic studies have not been performed with Retin-A Micro (tretinoin gel) microsphere, 0.04%.

Clinical Studies

Retin-A Micro (tretinoin gel) microsphere, 0.1%

In two vehicle-controlled studies, Retin-A Micro (tretinoin gel) microsphere, 0.1%, applied once daily was significantly more effective than vehicle in reducing the severity of acne lesion counts. The mean reductions in lesion counts from baseline after treatment for 12 weeks are shown in the following table:

Mean Percent Reduction in Lesion Counts Retin-A Micro (tretinoin gel) microsphere, 0.1%

  Retin-A Micro (tretinoin gel) microsphere, 0.1% Vehicle Gel
Study #1
72 pts
Study #2
71 pts
Study #1
72 pts
Study #2
67 pts
Non-inflammatory lesion counts 49% 32% 22% 3%
Inflammatory lesion counts 37% 29% 18% 24%
Total lesion counts 45% 32% 23% 16%

Retin-A Micro (tretinoin gel) microsphere, 0.1% was also significantly superior to the vehicle in the investigator's global evaluation of the clinical response. In Study #1, thirty-five percent (35%) of patients using Retin-A Micro (tretinoin gel) microsphere, 0.1%, achieved an excellent result, as compared to eleven percent (11%) of patients on the vehicle control. In Study #2, twenty-eight percent (28%) of patients using Retin-A Micro (tretinoin gel) microsphere, 0.1%, achieved an excellent result, as compared to nine percent (9%) of the patients on the vehicle control.

Retin-A Micro (tretinoin gel) microsphere, 0.04%

In two vehicle-controlled clinical studies, Retin-A Micro (tretinoin gel) microsphere, 0.04%, applied once daily, was more effective (p < 0.05) than vehicle in reducing the acne lesion counts. The mean reductions in lesion counts from baseline after treatment for 12 weeks are shown in the following table:

Mean Percent Reduction in Lesion Counts Retin-A Micro (tretinoin gel) microsphere, 0.04%

  Retin-A Micro (tretinoin gel) microsphere, 0.04% Vehicle Gel
Study #1
108 pts
Study #2
111 pts
Study #1
110 pts
Study #2
103 pts
Non-inflammatory lesion counts 37% 29% -2%* 14%
Inflammatory lesion counts 44% 41% 13% 30%
Total lesion counts 40% 35% 8% 20%
* - That is, a mean percent increase of 2%

Retin-A Micro (tretinoin gel) microsphere, 0.04%, was also superior (p < 0.05) to the vehicle in the investigator's global evaluation of the clinical response. In Study #1, fourteen percent (14%) of patients using Retin-A Micro (tretinoin gel) microsphere, 0.04%, achieved an excellent result compared to five percent (5%) of patients on vehicle control. In Study #2, nineteen percent (19%) of patients using Retin-A Micro (tretinoin gel) microsphere, 0.04%, achieved an excellent result compared to nine percent (9%) of patients on vehicle control.

No studies were conducted comparing the efficacy of Retin-A Micro (tretinoin gel) , 0.04% to Retin-A, Micro 0.1%. There is no evidence that Retin-A Micro (tretinoin gel) , 0.1% is more efficacious than Retin-A Micro (tretinoin gel) , 0.04% or that Retin-A Micro (tretinoin gel) , 0.04% is safer than Retin-A Micro, 0.1%.

Last reviewed on RxList: 12/2/2009
This monograph has been modified to include the generic and brand name in many instances.

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