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
Testoderm Pharmacology, Pharmacokinetics, Studies, Metabolism - Testosterone (transdermal)
Testoderm Pharmacology, Pharmacokinetics, Studies, Metabolism - Testosterone (transdermal)
CLINICAL PHARMACOLOGY
Testosterone
The TESTODERM® products deliver
physiologic amounts of testosterone, the primary
endogenous androgenic
hormone. Endogenous testosterone serum
concentrations in normal
males follow a circadian
pattern. Daily morning application of any of the TESTODERM®
products results in a serum
testosterone profile
that approximates the natural
endogenous pattern of normal
men.
General Androgen Effects
Endogenous androgens, including testosterone
and dihydrotesterone (DHT), are 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
prostate, seminal
vesicles, penis, and scrotum; the development
of male hair
distribution, such as facial,
pubic, chest, and axillary
hair; laryngeal enlargement,
vocal chord thickening,
alterations in body musculature,
and fat distribution. DHT
is necessary for the normal
development of secondary
sex characteristics.
Male hypogonadism
results from insufficient secretion
of testosterone and is characterized by low serum
testosterone concentrations.
Symptoms associated with male
hypogonadism include
impotence and decreased
sexual desire, fatigue
and loss of energy, mood
depression, and regression
of secondary sexual characteristics.
Drugs in the androgen
class also cause
retention of nitrogen,
sodium, potassium, 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 responsible for the growth
spurt of adolescence
and for the eventual termination
of linear growth
brought about by fusion
of the epiphyseal growth
centers. In children, exogenous
androgens accelerate linear growth
rates but may cause a
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 the production of erythropoietin.
During exogenous
administration
of androgens, endogenous
testosterone release may be inhibited through feedback
inhibition of pituitary
luteinizing hormone (LH). At
large does of exogenous
androgens, spermatogenesis
may also be suppressed through feedback
inhibition of pituitary
follicle-stimulating hormone (FSH).
There is a lack of substantial evidence
that androgens are effective in accelerating fracture
healing or in shortening
post-surgical convalescence.
Pharmacokinetics
Absorption
Daily morning application of any of the TESTODERM®
products approximates the natural
endogenous pattern
of serum testosterone
of normal males. Following
application, testosterone
is continuously absorbed during the 24-hour dosing period. The serum
testosterone concentration
rises to a maximum at
2 to 4 hours and return toward baseline
within approximately 2 hours after system
removal. The testosterone
levels achieved with TESTODERM® products generally
are within the range for
normal men. Patients
vary in their ability
to absorb testosterone
transdermally (see Clinical Studies).
TESTODERM® TTS
For TESTODERM® TTS three skin
sites (arm, back, and upper buttocks), representing recommended
application sites, are interchangeable based on equivalent
testosterone
AUC (0-27) (area
under serum concentration curve) values.
In clinical
trials, 94% of patients on TESTODERMâ
TTS treatment achieved
maximum and average
serum testosterone
concentrations (Cmax and Cavg, respectively)
within the normal range;
the average Cmax
and Cavg serum
testosterone concentrations
were 531 ng/dL and 366 ng/dL, respectively. Within-subject coefficient
of variation in testosterone
Cavg for subjects on TESTODERMâ
TTS therapy was 17%.
The typical
steady state serum
testosterone concentration
pattern achieved with a nominal testosterone
dose of 5 mg/day from TESTODERMâ
TTS is shown in Figure 1.
Figure 1. Serum concentrations of testosterone
(mean ± SD) during pretreatment
baseline or while wearing a TESTODERMâ
TTS system on the upper
buttocks (n=32). Systems
were applied at 0 hours (8 AM) and removed 24 hours later.
Normal range serum
testosterone concentrations
are reached during the first day of dosing.
There is no accumulation
of testosterone
following repeated application of TESTODERMâ
TTS.
Two TESTODERMâ TTS systems
deliver a testosterone
dose which is twice that
delivered by a single system.
There is no first-pass skin
metabolism of testosterone
to DHT when applied to arm, back
or upper buttocks skin
sites as recommended.
TESTODERMâ
Scrotal skin
is at least five times more permeable
to testosterone
than other skin sites.
TESTODERMâ or TESTODERMâ
WITH ADHESIVE will not produce adequate serum
testosterone concentrations
if applied to non-scrotal skin.
Hypogonadal men using TESTODERMâ
therapy have trough serum
testosterone concentrations
that are about 15% of peak levels. Serum levels reach a plateau
at 3 to 4 weeks.
TESTODERMâ
WITH ADHESIVE
Data from a pharmacokinetic trial in
50 normal male subjects show
that TESTODERMâ WITH
ADHESIVE applied to scrotal skin
is equivalent to
TESTODERMâ with respect
to rate (Cmax)
and extent (AUC) of testosterone delivery.
Distribution
Circulating testosterone
is chiefly bound in the
serum to sex
hormone-binding globulin (SHBG) and albumin. The albumin-bound fraction
of testosterone easily dissociates from albumin
and is presumed to be bioactive. The portion of testosterone
bound to SHBG is not considered
biologically active. The amount of SHBG in the serum
and the total testosterone
level will determine the
distribution of
bioactive and nonbioactive
androgen. SHBG-binding capacity is high in prepubertal children,
declines during puberty
and adulthood, and increases again during the later decades of life.
Metabolism
There is considerable variation
in the half-life of
testosterone as
reported in the literature, ranging from 10 to 100 minutes. Testosterone
is a substrate for
conversion to an
active metabolite,
dihydrotestosterone (DHT). Testosterone is metabolized to various
17-keto steroids through two different pathways, and the major active
metabolites are estradiol and DHT. Concentrations of estradiol
in normal men are 1.0
to 5.0 ng/dL. DHT concentrations in normal
male serum
are 30 to 85 ng/dL. DHT binds with greater affinity
to SHBG than does testosterone. 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
and cellular changes
related to androgen action. In
reproductive tissues,
DHT is further metabolized to 3-alpha and 3-beta androstanediol.
Composite results of all studies with TESTODERMâ
show elevated DHT concentrations and a change in the ratio
of testosterone to DHT (T/DHT) during treatment. The range
in this ratio was 0.7
- 12.5, as compared with a ratio
of 3.6 - 15.2 in normal
untreated men. The long-term effects of the change in this ratio
are not known.
The T/DHT ratio
during TESTODERMâ TTS
treatment was not
statistically significantly different from placebo treatment.
Excretion
About 90% of a dose
of testosterone
given intramuscularly is excreted in the urine
as glucuronic and sulfuric acid
conjugates of testosterone and its metabolites; about 6% of a dose
is excreted in the feces, mostly in the unconjugated form. Inactivation
of testosterone
occurs primarily in the liver.
Special Populations
Geriatric
In clinical
trials with TESTODERMâ
TTS, Cavg testosterone
concentrations were not different between men aged
65 and older and younger adult
males.
Race
There is insufficient information available from
trials with the TESTODERMâ
products to compare testosterone pharmacokinetics
in different racial groups.
Renal Insufficiency
There is no
experience with the
use of the TESTODERMâ
products in patients with renal
insufficiency.
Hepatic Insufficiency
There is no
experience with the
use of the TESTODERMâ
products in patients with hepatic
insufficiency.
Drug-Drug Interactions
See PRECAUTIONS:
Drug Interactions.
Clinical Studies
TESTODERMâ
TTS
Of 32 hypogonadal men receiving daily
application of a single TESTODERMâ
TTS system, 94% achieved normal
serum concentrations of
testosterone as
determined by Cmax and Cavg (200-1000 ng/dL).
Mean free testosterone, estradiol, and dihydrotestosterone concentrations
were also in the normal
range after application
of TESTODERMâ
TTS.
TESTODERMâ
and TESTODERMâ WITH
ADHESIVE
After at least 3 weeks of TESTODERMâ
therapy when steady-state is obtained, 30 hypogonadal men treated
with 6 mg/d systems for 22 hours daily achieved mean
maximum serum
testosterone concentrations of 593 ng/dL at 2 to 4 hours post
application. Sixty percent of the patients achieved individual maximal
testosterone concentrations
>500 ng/dL. The mean
24 hour steady-state AUC
(area under the curve) value was 9132 ng/dL. The mean
DHT serum concentrations
ranged from 134 to 162 ng/dL. Normal levels of testosterone
have been maintained in patients who have worn the systems for up
to six years. DHT levels also remain stable. The increase in serum
testosterone concentration
is proportional to the size of the system.
The variability
of total testosterone
concentrations among patients receiving TESTODERMâ
treatment was 35% to 49%. The coefficient
of variation of total
testosterone concentrations within individual patients was 30% to
41%. This variability is comparable to the values reported in the
literature for both normal and hypogonadal men.
In two 12-week clinical
studies in 72 hypogonadal men, TESTODERMâ
therapy produced positive
effects on mood and sexual
behavior. By five weeks, 45 patients not previously treated with
TESTODERMâ showed statistically
significant increases
in sexual activity. Compared
to baseline, mean
sexual events per
week increased for sexual
intercourse (0.3 to 0.8), orgasm
(0.4 to 1.2), waking erections (1.0 to 3.5), and spontaneous erections
(0.4 to 2.8).
Changes in nonfasting serum
lipid concentrations were observed during TESTODERMâ
therapy. By three months total cholesterol
and high-density lipoprotein cholesterol decreased an average
of 8% and 13%, respectively. High-density lipoprotein cholesterol
remained stable thereafter.
Total cholesterol
continued to decrease through two years. At
the end of two years, the
total cholesterol/high-density lipoprotein cholesterol
ratio was not different
from pretreatment
values.
Estradiol levels increased to the normal
range with treatment.
Sporadic elevations of estradiol
above the normal range
for men were observed in 3 of 72 patients and these were not associated
with feminizing side effects.
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