Atralin

CLINICAL PHARMACOLOGY

Mechanism Of Action

Tretinoin is a metabolite of Vitamin A that binds with high affinity to specific retinoic acid receptors located in both 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 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.

Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones.

Pharmacokinetics

In two (2) studies, the plasma levels of tretinoin and its major metabolites (13-cis-retinoic acid and 4-oxo-13-cisretinoic acid) were investigated in a total of 14 patients (age: 13 – 25 years) with severe acne, who applied 4 g ± 0.5 g (range 3.5 g – 4.5 g) of Atralin Gel once daily to face, back and chest, as compared to a mean of 0.71 g (range of 0.07 – 3.71 g) applied in the controlled clinical trials. Blood samples were taken at baseline and immediately prior to treatment on days 1, 5, 10 and 14. On Day 14, the final study day, samples also were taken 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours, post-treatment.

The plasma concentrations of tretinoin and its metabolites could be measured (LOQ = 0.5 ng/mL for all three analytes) in all patients at all time points. The range of plasma concentrations of tretinoin and its metabolites, 13-cisretinoic acid and all-trans-4-oxo-retinoic acid at baseline and after multiple once daily applications of Atralin Gel, 0.05% for 14 days are given in Table 2 (below). Although some patients had increased concentrations of tretinoin or its metabolites over baseline values, no consistent increase in these concentrations were observed across patients.

Table 2: Concentrations of active and metabolites at Baseline and at Day 14 after exposure to Atralin Gel, 0.05%

Compound Baseline Concentration Range (ng/ml) Day 14 Concentration Range (ng/ml)
Tretinoin 0.68-1.62 0.69-2.88
13-cis-retinoic acid 0.67-1.79 0.51-2.26
4-oxo-13-cis-retinoic acid 0.82-5.92 0.59-6.96

Clinical Studies

Clinical Trials

The safety and efficacy of Atralin Gel used once daily before bedtime for the treatment of mild to moderate acne vulgaris were assessed in two 12-week prospective, multi-center, randomized, controlled trials. Subjects in these two trials ranged from 10 to 65 years of age, were approximately 52% female, 48% male, and were 74% Caucasian, 15% Black or African American, 3% Asian, and 8% Other.

Efficacy results at Week 12 are presented in Table 3. Success on the 6-point Global Severity Score is defined as a score of 0 (clear) or 1 (very mild). In Trial 2, subjects were also required to have at least two grades reduction from baseline for success. 'Very mild' acne is defined as: skin almost clear; rare non-inflammatory lesions present, with rare non-inflamed papules (papules may be hyperpigmented, though not pink-red, less than 4 lesions). The database was not large enough to assess whether there were differences in effects in age, gender, or race subgroups.

Table 3: Efficacy Results at Week 12 in Trials 1 and 2

Trial 1 Atralin Gel
N=375
Vehicle
N=185
Global Severity Score Success* 78 (21%) 23 (12%)
Non-Inflammatory Facial Lesions
  Mean Baseline Count 50.7 52.4
  Mean Absolute Reduction 21.8 10.3
  Mean Percent Reduction 43% 21%
Inflammatory Facial Lesions
  Mean Baseline Count 23.4 23.9
  Mean Absolute Reduction 9.7 5.8
  Mean Percent Reduction 41% 26%
Total Facial Lesions
  Mean Baseline Count 74.1 76.3
  Mean Absolute Reduction 31.4 16.1
  Mean Percent Reduction 43% 22%
Trial 2 Atralin Gel
N=299
Vehicle
N=302
Global Severity Score Success** 69 (23%) 42 (14%)
Non-Inflammatory Facial Lesions
  Mean Baseline Count 51.9 52.7
  Mean Absolute Reduction 18.7 10.8
  Mean Percent Reduction 37% 20%
Inflammatory Facial Lesions
  Mean Baseline Count 22.9 23.4
  Mean Absolute Reduction 7.0 4.0
  Mean Percent Reduction 30% 17%
Total Facial Lesions
  Mean Baseline Count 74.8 76.1
  Mean Absolute Reduction 25.7 14.7
  Mean Percent Reduction 35% 19%
* Success was defined as 0 (clear) or 1 (very mild)
** Success was defined as 0 (clear) or 1 (very mild) with at least 2 grades reduction from baseline

Last reviewed on RxList: 9/10/2014
This monograph has been modified to include the generic and brand name in many instances.

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