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
Activella Pharmacology, Pharmacokinetics, Studies, Metabolism - Estradiol/Norethindroneacetate
Activella Pharmacology, Pharmacokinetics, Studies, Metabolism - Estradiol/Norethindroneacetate
CLINICAL PHARMACOLOGY
Estrogen drug products act by regulating the transcription
of a limited number of genes. Estrogens diffuse through cell membranes and bind
to and activate the nuclear estrogen receptor, a DNA-binding protein that is
found in estrogen-responsive tissues. The activated estrogen receptor binds
to specific DNA sequences, or hormone-response elements, that enhance the transcription
of adjacent genes and in turn lead to the observed effects. Estrogen receptors
have been identified in tissues of the reproductive tract, breast, pituitary,
hypothalamus, liver, and bone in women.
Estrogens are largely responsible for the development and maintenance
of the female reproductive system and secondary sexual characteristics. Although
circulating estrogens exist in a dynamic equilibrium of metabolic interconversions,
estradiol is the principal intracellular human estrogen and is substantially
more potent than its metabolites, estrone and estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian
follicle, which secretes 70 to 500 µg of estradiol daily, depending on the phase
of the menstrual cycle. After menopause, most endogenous estrogen is produced
by conversion in peripheral tissues of androstenedione which is secreted by
the adrenal cortex, to estrone. Thus, estrone and the sulfate conjugated form,
estrone sulfate, are the most abundant circulating estrogens in postmenopausal
women.
Circulating estrogens modulate the pituitary secretion of the
go-nadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH)
through a negative feedback mechanism, and estrogen replacement therapy acts
to reduce the elevated levels of these hormones seen in postmenopausal women.
Progestin compounds enhance cellular differentiation and generally oppose the
actions of estrogens by decreasing estrogen receptor levels, increasing local
metabolism of estro-gens to less active metabolites, or inducing gene products
that blunt cellular responses to estrogen. Progestins exert their effects in
target cells by binding to specific progesterone receptors that interact with
progesterone response elements in target genes. Progesterone receptors have
been identified in the female reproductive tract, breast, pituitary, hypothalamus,
and central nervous system. Progestins produce similar endometrial changes to
those of the naturally occurring hormone progesterone.
The use of unopposed estrogen therapy has been associated with
an increased risk of endometrial hyperplasia, a possible precursor of endometrial
adenocarcinoma. The addition of a progestin, in adequate doses and appropriate
duration, to an estrogen replacement regimen reduces the incidence of endometrial
hyperplasia, and the attendant risk of carcinoma in women with intact uterus.
PHARMACOKINETICS
ABSORPTION
Estradiol is well absorbed through the gastrointestinal tract.
Following oral administration of Activella ™ (estradiol/norethindrone
acetate tablets), peak plasma estradiol concentrations are reached slowly within
5-8 hours. When given orally, estra-diol is extensively metabolized (first-pass
effect) to estrone sulfate, with smaller amounts of other conjugated and unconjugated
estrogens. After oral administration, norethindrone acetate is rapidly absorbed
and transformed to norethindrone. It undergoes first-pass metabolism in the
liver and other enteric organs, and reaches a peak plasma concentration within
0.5-1.5 hours. The oral bioavailability of estradiol and norethindrone following
administration of Activella ™ when compared to a combination
oral solution is 53% and 100%, respectively. The pharma-cokinetic parameters
of estradiol (E2), estrone (E1), and norethindrone (NET)
following single oral administration of Activella ™ in 25 volunteers
are summarized in TABLE 1.
TABLE 1:PHARMACOKINETIC PARAMETERS AFTER A SINGLE DOSE OF
ACTIVELLA™ IN HEALTHY POSTMENOPAUSAL WOMEN
|
Activella™ (n=25) Meanc ±
SD
|
|
Estradiol a (E2)
|
|
|
AUC (0-72h)(pg/ml*h)
Cmax (pg/ml)
Tmax (h)
T½ (h) d
|
1053 ± 310
34.6 ± 10.8
6.8 ± 2.9
13.2 ± 4.7
|
|
Estrone a (E1)
|
|
|
AUC (0-72h)(pg/ml*h)
Cmax (pg/ml)
Tmax (h)
T½ (h) d
|
5223 ± 1618
251.1 ± 91.0
5.7 ± 1.4
12.2 ± 4.6
|
|
Norethindrone (NET)
|
|
|
AUC (0-72h)(pg/ml*h)
Cmax (pg/ml)
tmax (h)
t½ (h)
|
23681± 9023
5308 ± 1510
1.0 ± 0.0
11.4 ± 2.7
|
AUC= area under the curve,
Cmax= maximum plasma concentration, tmax=
time at maximum plasma concentration, t½= half-life,
SD= standard deviation a baseline unadjusted data;
b (n=23); C arithmetic mean; d baseline adjusted
data
Following continuous dosing with once-daily administration
of Activella™ (estradiol/norethindrone acetate tablets), serum
levels of estradiol, estrone, and norethindrone reached steady-state within
two weeks with an accumulation of 33-47% above levels following single dose
administration. Unadjusted circulating levels of E2, E1,
and NET during Activella™ treatment at steady state (dosing
at time 0) are provided in Figures 1a and 1b.
DISTRIBUTION
The distribution of exogenous estrogens is similar to that
of endogenous estrogens. Estrogens are widely distributed in the body and are
generally found in higher concentrations in the sex hormone target organs. Estradiol
circulates in the blood bound to sex-hormone-binding globulin (SHBG) (37%) and
to albumin (61%), while only approximately 1-2% is unbound. Norethindrone also
binds to a similar extent to SHBG (36%) and to albumin (61%).
METABOLISM AND EXCRETION
Estradiol: Exogenous estrogens are metabolized in the same
manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium
of metabolic interconversions. These transformations take place mainly in the
liver. Estradiol is converted reversibly to estrone, and both can be converted
to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepat-ic
recirculation via sulfate and glu-curonide conjugation in the liver, bil-iary
secretion of conjugates into the intestine, and hydrolysis in the gut followed
by reabsorption. In postmenopausal women, a significant portion of the circulating
estrogens exist as sulfate conjugates, especially estrone sulfate, which serves
as a circulating reservoir for the formation of more active estrogens. The half-life
of estradiol following single dose administration of Activella ™
(estradiol/norethindrone acetate tablets) is 12-14 hours.
Norethindrone Acetate: The most important metabolites of norethindrone
are isomers of 5a-dihydro-norethin-drone
and tetrahydro-norethindrone, which are excreted mainly in the urine as sulfate
or glucuronide conjugates. The terminal half-life of norethindrone is about
8-11 hours.
DRUG-DRUG INTERACTIONS
Coadministration of estradiol with norethindrone acetate did
not elicit any apparent influence on the phar-macokinetics of norethindrone.
Similarly, no relevant interaction of norethindrone on the pharmacoki-netics
of estradiol was found within the NETA dose range investigated in a single dose
study.
FOOD-DRUG INTERACTIONS A single-dose study in 24 healthy postmenopausal
women was conducted to investigate any potential impact of administration of
Activella™ with and without food. Administration of Activella
™ with food did not modify the bioavailability of estradiol,
although increases in AUC0-72 of 19% and decreases in Cmax
of 36% for norethindrone were seen.
CLINICAL STUDIES
VASOMOTOR SYMPTOMS
Activella™ is effective in reducing the number
of moderate-to-severe vaso-motor symptoms in postmenopausal women. In a 12-week
randomized clinical trial involving 92 subjects, Activella™ was
compared to 1 mg of estradiol and to placebo. The mean number and intensity
of hot flushes were significantly reduced from baseline to week 12 in both the
Activella™ and the 1 mg estradiol group compared to placebo.
ENDOMETRIAL HYPERPLASIA
Activella™ (estradiol/norethindrone acetate
tablets) reduced the incidence of estrogen-induced endometrial hyperplasia at
1 year in a randomized, controlled clinical trial. This trial enrolled 1,176
subjects who were randomized to one of4 arms: 1 mg estradiol unopposed (n=296),
1 mg E2 + 0.1 mg NETA (n=294), 1 mg E2 + 0.25 mg NETA
(n=291), and Activella™ [1 mg E2 + 0.5 mg NETA]
(n=295). At the end of the study, endometrial biopsy results were available
for 988 subjects. The results of the 1 mg estradiol unopposed arm compared to
Activella™ are shown in TABLE 2.
TABLE 2 : INCIDENCE OF ENDOMETRIAL HYPERPLASIA WITH UNOPPOSED
ESTRADIOL AND ACTIVELLA™ IN A 12-MONTH STUDY
| |
1 mg E2 (n=296) |
Activella & trade; (n=295) |
|
No. of subjects with Histological valuation at the end
of the study
|
247
|
241
|
|
No. (%) of subjects with endometrial hyperplasia at the
end of the study
|
36 (14.6%)
|
1 (0.4%)
|
During the initial months of therapy, irregular bleeding or
spotting occurred with Activella™ treatment. However, bleeding
tended to decrease over time, and after 12 months of treatment with Activella
™, fewer than 3% of women reported bleeding.
n=number of women
1 mg E2 (3, 6, 9 and 12 months): n=278, 255, 226, 212 Activella™
(3, 6, 9 and 12 months): n=273, 246, 238, 232
INFORMATION REGARDING LIPID EFFECTS
A 12-month, placebo-controlled clinical trial in 80 postmenopausal
Caucasian women at low risk for cardiovascular disease compared the effects
of Activella™ to placebo on lipid parameters. These results
are shown in TABLE 3.
TABLE 3 : PERCENTAGE CHANGE FROM BASE-LINE IN SELECTED LIPID
PARAMETERS WITH ACTIVELLA™ IN A 12-MONTHPLACEBO CONTROLLED
STUDY
|
Lipid Parameter %
|
Activella™ (n=35)
|
Placebo (n=34)
|
|
Total Cholesterol
|
-10.5%
|
-0.8%
|
|
HDL-C1
|
-12.4%
|
-6.1%
|
|
LDL-C2
|
-10.8%
|
0.8%
|
|
LDL: HDL Ratio
|
0.1%
|
9.2%
|
|
Triglycerides
|
2.2%
|
4.4%
|
|
1 High density lipoprotein-cholesterol
2 Low density lipoprotein-chlolesterol
|
EFFECT ON BONE MINERAL DENSITY The results of two randomized,
mul-ticenter, calcium-supplemented (500-1000 mg/day), placebo-controlled, 2
year clinical trials have shown that Activella™ (estradiol/norethindrone
acetate tablets) is effective in preventing bone loss in postmenopausal women.
A total of462 postmenopausal women with intact uteri and baseline BMD values
for lumbar spine within 2 standard deviations of the mean in healthy young women
were enrolled. In a US trial, 327 postmenopausal women (mean time from menopause
2.5 to 3.1 years) with a mean age of53 years were randomized to 7 groups (0.25
mg, 0.5 mg, and 1 mg of estradiol alone, 1 mg estradiol with 0.25 mg norethindrone
acetate, 1 mg estradi-ol with 0.5 mg norethindrone acetate, and 2 mg estradiol
with 1 mg norethindrone acetate, and placebo. In a European trial, 135 postmenopausal
women (mean time from menopause 8.4 to 9.3 years) with a mean age of58 years
were randomized to 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol
with 0.5 mg norethin-drone acetate, and placebo.
Approximately 58% and 67% of the randomized subjects in the
two clinical trials, respectively, completed the two clinical trials. BMD was
measured using dual-energy x-ray absorptiometry (DEXA).
A summary of the results comparing Activella™ and
placebo from the two prevention trials is shown in Table 4.
TABLE 4 : PERCENTAGE CHANGE (MEAN±SEM) IN BONE MINERAL
DENSITY (BMD) (Intent to Treat Analysis, Last Observation Carried Forward)
|
|
US Trial
|
EU Trial
|
| |
Placebo
|
Activella™
|
Placebo
|
Activella™
|
| |
(n=37)
|
(n=37)
|
(n=40)
|
(n=38)
|
|
Lumbar spine
|
-2.1±0.5
|
3.8±0.5*
|
-0.9±0.6
|
5.4±0.8*
|
|
Femoral neck
|
-2.3±0.6
|
1.8±0.7*
|
-1.0±0.7
|
0.7±0.9
|
|
Femoral trochanter
|
-2.0±0.7
|
3.7±0.7*
|
0.8±1.1
|
6.3±1.2*
|
|
Ward’s triangle
|
–
|
–
|
-1.6±1.3
|
2.7±1.7
|
|
Distal radius
|
–
|
–
|
-0.7±0.5
|
2.1±0.5*
|
|
Total body
|
–
|
–
|
0.4±0.4
|
3.0±0.5*
|
|
US= United States, EU = European
|
|
* Significantly (p<0.001) different from placebo
|
The overall difference in mean percentage change in BMD at
the lumbar spine between Activella™ and placebo was 5.9% in
the US trial (1000 mg/day calcium) and 6.3% in the European trial (500 mg/day
calcium). Activella™ also increased BMD at the femoral neck
and femoral trochanter compared to placebo. The increase in lumbar spine BMD
in the US and European clinical trials is displayed in Figure 4.
EFFECT ON BONE TURNOVER Activella™ (estradiol/norethindrone
acetate tablets) significantly reduced serum and urine markers ofbone turnover
with a marked decrease in bone resorption makers (e.g., urinary pyridinoline
crosslinks Type 1 collagen C-telopeptide, pyridinoline, de-oxypyridinoline)
and to a lesser extent in bone formation markers (e.g., serum osteocalcin, bone-specific
alkaline phosphatase, C-terminal propetide of Type 1 collagen). The suppression
of bone turnover markers was evident by 3 months and persisted throughout the
24-month treatment period.
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