A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Retin A Pharmacology, Pharmacokinetics, Studies, Metabolism - Tretinoin (topical)
Retin A Pharmacology, Pharmacokinetics, Studies, Metabolism - Tretinoin (topical)
CLINICAL PHARMACOLOGY
Cream, Gel and Liquid
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.
Gel with Microspheres
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 acid 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.
Irritation Potential
Acne Clinical Trial Results: In
clinical trials with
acne patients treated with gel
with microspheres, analysis
over the twelve week treatment period
showed that cutaneous
irritation scores
for erytherna, peeling, burning/stinging, or itching peaked during
the initial 2 weeks
of therapy, decreasing thereafter. Throughout, no more than 3% of
patients had scores indicative of a severe irritation
rating; although, 6% (14/224) of patients treated with gel
with microspheres discontinued treatment
due to irritation. Of these 14 patients, four had severe irritation
after 3 to 5 days of treatment, with blistering in one patient.
Results in Studies of Subjects Without Acne: In
a half-face comparison trial conducted for up to 14 days in women
with sensitive skin,
but without acne, gel with
microspheres was statistically less irritating than tretinoin
cream, 0.1%. In addition,
a cumulative 21 day
irritation evaluation in subjects with normal
skin showed that gel
with microspheres had a lower irritation
profile than tretinoin
cream, 0.1%. The clinical significance of these irritation
studies for patients with acne
is not established. Comparable effectiveness
of gel with microspheres
and tretinoin cream, 0.1%, has not been established. The lower irritancy
of gel with microspheres
in subjects without acne
may be attributable to the properties of its vehicle. The contribution
to decreased irritancy by the MICROSPONGE System has not been established.
Pharmacokinetics
Tretinoin is an endogenous
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, 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 relative to baseline
levels.
In vitro and in vivo pharmacokinetic studies with
tretinoin indicate that less than 0.3% of the topically applied
dose is bioavailable. Circulating
plasma levels of both
tretinoin and isotretinoin
are only slightly elevated above those found in healthy normal
controls.
Emollient Cream
The exact mechanism
of action of tretinoin
is unknown although retinoids are believed to exert an effect
on the growth and differentiation
of various epithelial cells. When applied topically, however, there
was no noted increase in desmosine, hydroxproline, or elastin
mRNA in human
skin. In addition, the role
of the irritative
nature of this product
in effecting the positive effects attributed to this product
for its indication
has not yet been fully determined.
The transdermal absorption
of tretinoin from
various topical formulations
ranged from 1% to 31% of applied dose, depending on whether it was
applied to healthy skin
or dermatitic skin. When percutaneous
absorption of tretinoin
emollient cream was assessed
in healthy male subjects
(n = 14) after a single application, as well as after repeated daily
applications for 28 days, the absorption
of tretinoin was less
than 2% and endogenous
concentrations of tretinoin
and its major metabolites were unaltered.
CLINICAL STUDIES
Tretinoin Cream
In one large vehicle-controlled clinical
trial, tetinoin cream
0.025%, applied once daily was more effective than vehicle
in the treatment of
facial acne vulgaris
of mild to moderate severity. Percent reductions in lesion count
after treatment for
12 weeks in this study are shown in TABLE 1.
| TABLE 1 |
| |
Tretinoin Cream 0.025% |
Vehicle Cream |
| |
N=75 |
N=58 |
| Non-inflammatory lesions |
45% |
27% |
| Inflammatory lesions |
46% |
32% |
| Total lesions |
46% |
28% |
| N Number of subjects. |
Tretinoin Gel
In two large vehile-controlled clinical
trials, tretinoin
gel 0.025%, applied once
daily was more effective than vehicle
in the treatment of
facial acne vulgaris
of mild to moderate severity. Percent reduction in lesion
counts after treatment
for 12 weeks in these studies are shown in TABLE 2.
| TABLE 2 |
| |
Tretinoin Gel 0.025% |
Vehicle Gel |
| |
N=198 |
N=204 |
| Study 1 |
|
|
-36% |
-27% |
|
|
-35% |
-25% |
|
|
-36% |
-27% |
| |
N=58 |
N=58 |
| Study 2 |
|
|
-42% |
-26% |
|
|
-38% |
-23% |
|
|
-41% |
-26% |
| N = Number of subjects |
Gel with Microspheres
In two vehicle-controlled clinical
studies, gel with microspheres
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:
| TABLE 3 Mean Percent Reduction
in Lesion Counts |
| |
Gel with microspheres |
Vehicle gel |
| |
Study #1, 72 pts |
Study #2, 71 pts |
Study #1, 72 pts |
Study #2, 67 pts |
|
|
49% |
32% |
22% |
3% |
|
|
37% |
29% |
18% |
24% |
|
|
45% |
32% |
23% |
16% |
Gel with microspheres was also significantly superior
to the vehicle in the
investigator's global evaluation
of the clinical response.
In study #1, 35% of patients
using gel with microspheres
achieved an excellent result compared to 11% of patients on vehicle
control. In study #2, 28%
of patients using gel with
microspheres achieved an excellent result compared to 9% of patients
on vehicle control.
Emollient Cream
Two adequate and well-controlled trials were conducted involving
a total of 161 evaluable patients (under 50 years of age) treated
with tretinoin emollient cream
and 154 evaluable patients treated with the vehicle
emollient cream on the face
for 24 weeks as an adjunct
to a comprehensive skin
care and sun avoidance
program, to assess the effects on fine wrinkling, mottled hyperpigmentation,
and tactile skin
roughness. Patients were evaluated at baseline
on a 10 point scale
and changes from that baseline
rating were categorized as follows:
- No Improvement = No change or an increase of 1 unit
or more.
- Minimal Improvement = Reduction of 1 unit.
- Moderate Improvement = Reduction of 2 units or more.
In these trials, the fine wrinkles, mottled hyperpigmentation,
and tactile roughness of the facial
skin were thought to be
caused by multiple
factors which included intrinsic
aging or environmental
factors, such as chronic sun exposure. The results of these assessments
are found in TABLE 4.
| TABLE 4 Fine Wrinkling, Mottled
Hyperpigmentation and Tactile Skin Roughness |
| Fine Wrinkling |
| |
No improvement |
Minimal improvement |
Moderate Improvement |
| Emollient cream
+ CSP* |
36% |
40% |
24% |
| Vehicle + CSP |
62% |
30% |
8% |
| Mottled Hyperpigmentation |
| |
No Improvement |
Minimal Improvement |
Moderate Improvement |
| Emollient cream
+ CSP |
35% |
27% |
38% |
| Vehicle + CSP |
53% |
21% |
27% |
| Tactile Skin Roughness |
| |
No Improvement |
Minimal Improvement |
Moderate Improvement |
| Emollient cream
+ CSP |
49% |
35% |
16% |
| Vehicle + CSP |
67% |
23% |
10% |
| * CSP = Comprehensive skin
protection and sun avoidance
programs including use of sunscreens, protective
clothing, and emollient
cream. |
Most of the improvement in these signs was noted during the first
24 weeks of therapy. Thereafter, therapy primarily maintained the
improvement realized during the first 24 weeks.
A majority of patients will
lose most mitigating effects of tretinoin emollient cream
on fine wrinkles, mottled hyperpigmentation, and tactile roughness
of facial skin
with discontinuation of a comprehensive skin
care and sun avoidance
program including tretinoin
emollient cream; however,
the safety and effectiveness
of using tretinoin
emollient cream
daily for greater than 48 weeks have not been established.
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