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
Androderm Pharmacology, Pharmacokinetics, Studies, Metabolism - Testosterone Transdermal System
Androderm Pharmacology, Pharmacokinetics, Studies, Metabolism - Testosterone Transdermal System
Androderm (testosterone transdermal system) delivers physiologic amounts
of testosterone producing
circulating testosterone
concentrations that approximate the normal
circadian rhythm
of healthy young men.
Testosterone
Androderm (testosterone transdermal system) delivers testosterone, the
primary androgenic hormone.
Testosterone is responsible for the normal growth and development
of the male sex
organs and for maintenance of secondary sex characteristics. These effects
include the growth and maturation
of the prostate, seminal
vesicles, penis, and scrotum; development
of male hair distribution, s.c.
as facial, pubic, chest,
and axillary hair; laryngeal
enlargement; vocal cord
thickening; and alterations in b.d.
musculature and fat distribution.
Male hypogonadism results
from insufficient secretion
of testosterone and is characterized by low serum
testosterone concentrations.
Symptoms associated with male
hypogonadism include
the following: impotence
and decreased sexual desire;
fatigue and loss
of energy; mood depression; and
regression of secondary
sexual characteristics.
General Androgen Effects
Androgens promote retention
of nitrogen, sodium, potassium,
and phosphorus, and decreased urinary
excretion of calcium. Androgens
have been reported to increase protein
anabolism and decrease protein
catabolism. Nitrogen balance is improved only when there is sufficient
intake of calories and protein.
Androgens are also responsible for the growth
spurt of adolescence and for the eventual termination
of linear growth
that is brought about by the fusion
of the epiphyseal growth centers.
In children, exogenous androgens
accelerate linear growth
rates but may cause disproportionate
advancement in bone maturation.
Use over long periods may result in fusion of the epiphyseal growth
centers and termination
of the growth process. Androgens
have been reported to stimulate
the production of red
blood cells by enhancing erythropoietin
production.
During exogenous administration
of androgens, endogenous
testosterone release is inhibited through feedback
inhibition of pituitary
LH secretion. With large doses
of exogenous androgens,
spermatogenesis may
also be suppressed through feedback
inhibition of pituitary
follicle stimulating hormone
(FSH) secretion. There is a lack of substantial evidence
that androgens are effective in accelerating fracture
healing or in shortening
post-surgical convalescence.
Pharmacokinetics
Absorption Following Androderm (testosterone transdermal system) application
to nonscrotal skin, testosterone
is continuously absorbed during the 24.hour dosing period. Daily application
of Androderm at approximately 10 PM results in a serum
testosterone concentration
profile that mimics the normal
circadian variation observed in healthy
young men (Fig. 2 below). Maximum concentrations occur in the early morning
hours with minimum concentrations
in the evening (Table 1 below),
Table 1
Steady-state serum testosterone
pharmacokinetic parameters in hypogonadal men measured during continuous
Androderm (testosterone transdermal system) treatment.
| Parameter
|
Units
|
n
|
Mean
|
SD
|
| Cmax |
ng/ dL
|
56
|
753
|
276
|
| Cavg |
ng/ dL
|
56
|
498
|
169
|
| Cmin |
ng/ dL
|
56
|
246
|
120
|
| Tmax |
hr
|
56
|
7.9
|
2.2
|
| T 1/2 |
min
|
29
|
71
|
32
|
| CL |
L/ day
|
49
|
1304
|
464
|
Cmax = maximum serum
concentration
Cavg = average serum
concentration (AUC/24
hr)
Cmin = minimum serum
concentration
Tmax = time of maximum
serum concentration
T1/2 = Elimination half-life
CL = Clearance
In a group of 34 hypogonadal
men, application of two Androderm 2.5 mg systems to the abdomen,
back, thighs, or upper arms resulted in average testosterone absorption
of 4 to 5 mg over 24 hours. The
serum testosterone concentration
profiles during application were similar for these sites (Table 2). Applications
to the chest and shins resulted
in greater interindividual variability and average
24 hour absorption of 3
to 4 mg.
Table 2
Mean serum testosterone
concentrations (ng/dL) measured during single-dose applications of two
Androderm 2.5 mg systems applied
at night to different sites in 34 hypogonadal men.
| Sample
|
Abdomen
|
Back
|
Thigh
|
Upper Arm
|
|
Time (hr)
|
Mean
|
SD
|
Mean
|
SD
|
Mean
|
SD
|
Mean
|
SD
|
|
0
|
90
|
82
|
80
|
74
|
85
|
76
|
81
|
69
|
|
3
|
286
|
201
|
429
|
252
|
271
|
201
|
308
|
226
|
|
6
|
476
|
236
|
606
|
250
|
489
|
254
|
468
|
245
|
|
9
|
570
|
234
|
613
|
214
|
592
|
251
|
534
|
204
|
|
12
|
575
|
244
|
586
|
233
|
594
|
247
|
527
|
199
|
|
24
|
352
|
164
|
403
|
174
|
367
|
161
|
332
|
124
|
In a steady-state study of 12 hypogonadal men, nightly application of
1. 2, or 3 Androderm 2.5 mg systems
resulted in increases in the mean
morning serum testosterone
concentrations. These concentrations averaged 424, 584, and 766 ng/dL
with the application of 1, 2, and 3 systems, respectively. The mean
baseline serum
testosterone concentration
was 76 ng/db.
Normal range morning serum
testosterone concentrations
are reached during the first day of dosing. There is no
accumulation of testosterone
during continuous treatment.
In a study of 20 hypogonadal patients, two Androderm 2.5 mg
systems and a single Androderm 5 mg
system produced equivalent
serum testosterone concentration
profiles. Average steady state
concentrations over 24 hours (Cssavg) were 613±169 and 621±176
ng/dL for the two 2.5 mg and single 5 mg
systems, respectively. Cmax values were 925±340 ng/dL for the two
2.5 mg systems and 905±254
ng/dL for the single 5 mg system.
Distribution
In serum, testosterone
is bound with high affinity
to sex hormone
binding globulin (SHBG) and with low affinity
to albumin. The albumin bound
portion easily dissociates and is presumed to be bioactive. The SHBG-bound
portion is not considered to be bioactive. The amount of SHBG in serum
and the total testosterone
concentration determine
the distribution of bioactive
and nonbioactive androgen. Bioactive serum
testosterone concentrations
(BT) measured during Androderm (testosterone transdermal system) treatment
paralleled the serum testosterone
profile (Figure 2) and remained
within the normal reference
range.
Metabolism
Inactivation of testosterone
occurs primarily in the liver. Testosterone (T) is metabolized to various
17.keto steroids through two different pathways, and the major active
metabolites are estradiol
(E2) and dihydrotestosterone (DHT). DHT binds with greater affinity
to SHBG than does testosterone. In reproductive
tissues, DHT is further metabolized to 3-alpha and 3-beta androstanediol.
In many tissues, the activity
of testosterone appears
to depend on reduction to DHT, which binds to cytosol
receptor proteins. The steroid-receptor
complex is transported to the nucleus, where it initiates transcription
events and cellular changes
related to androgen action.
During steady-state pharmacokinetic studies in hypogonadal men treated
with Androderm, the average
DHT:T and E2:T ratios were comparable to those in normal
men, approximately 1:10 and 1:200, respectively. Upon removal of the Androderm
systems, serum testosterone
concentrations decrease with an apparent
half-life of approximately
70 minutes. Hypogonadal concentrations are reached within 24 hours following
system removal.
Androderm therapy suppresses
endogenous testosterone
secretion via
the pituitary/gonadal axis, resulting in a reduction
in baseline serum
testosterone concentrations compared to the untreated state.
Excretion
Approximately 90% of a testosterone
dose given intramuscularly is
excreted in the urine as glucuronide
and sulfate conjugates of
testosterone and its
metabolites; about 6% is excreted in the feces, mostly in unconjugated
form.
Special Populations
Geriatric
No age related effects on testosterone
pharmacokinetics
were observed in clinical
trials of Androderm in men up to 65 years of age. In
a group of 9 elderly testosterone
deficient men (65-79 years of age, average
baseline testosterone level 184±50 ng/dL). a single application
of two Androderm 2.5 mg systems
to the back resulted in an average
testosterone level of
591±121 ng/dL with a Tmax of 14.2±4.2 hours. The total testosterone
delivered over the 24-hour application time
was 3.8±0.6 mg, approximately 20% less than the average
amount delivered in younger patients.
Race
There is insufficient information available from Androderm trials to
compare testosterone
pharmacokinetics
in different racial groups.
Renal Insufficiency
There is no experience
with use of Androderm in patients with renal insufficiency.
Hepatic Insufficiency
There is no experience
with use of Androderm in patients with hepatic insufficiency.
Drug-Drug Interactions
See PRECAUTIONS
Clinical Studies
In clinical studies using
the Androderm 2.5 mg system, 93%
of patients were treated with two systems daily, 6% used three systems
daily, and 1% used one system
daily. The hormonal effects of Androderm (testosterone transdermal system)
as a treatment for male
hypogonadism were demonstrated
in four open-label trials that included 94 hypogonadal men, ages 15 to
65 years. In these trials, Androderm
produced average morning serum
testosterone concentrations within the normal
reference range in 92% of patients.
The mean (SD) serum hormone
concentrations and percentage of patients who achieved average concentrations
within the normal ranges are
shown in Table 3 below.
Table 3
Individual morning serum
hormone concentrations (ng/dL)
and percent of patients with mean
concentrations within the normal
range during continuous Androderm
treatment (n=94).
| |
T
|
BT
|
DHT
|
E2
|
| Normal
Range |
(306-1081)
|
(93-420)
|
(28-85)
|
(0.9-3.6)
|
| Mean
|
589
|
312
|
47
|
2.7
|
| SD |
209
|
127
|
18
|
1.2
|
| % Normal
|
92
|
88
|
a5
|
77
|
| % High
|
1
|
12
|
2
|
22
|
| % Low
|
7
|
0
|
13
|
1
|
A physiological suppression
of the pituitary/gonadal axis
occurs during continuous Androderm treatment
leading to reduced serum LH
concentrations. In clinical
trials, 10 of 21 (48%) of men with primary
(hypergonadotropic) hypogonadism achieved normal
range LH
concentrations within 6 to 12 months of treatment. LH
concentrations may remain elevated in some patients despite serum testosterone
concentrations within the normal
range. Twenty-nine patients, previously treated with testosterone, completed
12 months of Androderm treatment. Following an 8-week androgen
withdrawal period, Androderm
treatment produced positive
effects on fatigue, mood
and sexual function. The percent
of patients complaining of fatigue
decreased from 79% to 10% during treatment
(p<0.001). The average
patient depression
score (Beck Depression Inventory)
decreased from 6.9 to 3.9 (p<0.001). Nocturnal penile tumescence
and rigidity monitoring showed
an increase in mean duration
of erections 0.23 to 0.39 hours per
night (p=0.01) and an increase in penile tip rigidity
from 18% to 50% (p<0.001). The total number
of self-reported erections reported increased from 2.3 to 7.8 per
week (p<0.001). Comparison with intramuscular
testosterone: Sixty-six patients, previously treated with testosterone
injections, received Androderm or intramuscular
testosterone enanthate (200 mg
every 2 weeks) treatment
for 6 months. The percent
of time that serum concentrations
measured throughout the dosing interval remained within the normal
range were as follows:
| |
Androderm
|
IM |
p
value |
| T |
82% |
72% |
0.05 |
| BT |
87% |
39% |
<0.001 |
| DHT
|
76 % |
70% |
0.06 |
| E2 |
81 % |
35% |
<0.001 |
Effect on plasma lipids:
In 67 men treated for 6 to 12 months,
the average (SE) serum
total cholesterol and
HDL concentrations were 199 (7.6)
ng/dL and 46 (2.3) ng/dL.
Compared to baseline values
during a hypogonadal state actfieved
by 8 weeks of androgen withdrawal
in 29 patients, the following changes in lipids were observed during 1
year of Androderm treatment: Cholesterol decreased 1.2%; HDL
decreased 8%; Cholesterol/ HDL
ratio increased 9%. In these
patients, lipids measured during Androderm treatment
were not significantly different from those measured during prior IM injection
treatment.
Effects on the prostate: Prostate size and serum
prostate specific antigen
(PSA) concentrations during treatment
were comparable to values reported for eugonadal men. One case
of prostate carcinoma
occurred during Androderm treatment; two cases were detected during IM
treatment.
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