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
Seasonale Pharmacology, Pharmacokinetics, Studies, Metabolism - Levonorgestrel/ethinyl estradiol
Seasonale Pharmacology, Pharmacokinetics, Studies, Metabolism - Levonorgestrel/ethinyl estradiol
CLINICAL PHARMACOLOGY
Mode of action
Combination oral contraceptives act by suppression of gonadotropins.
Although the primary mechanism of this action is inhibition of ovulation, other
alterations include changes in the cervical mucus (which increase the difficulty
of sperm entry into the uterus) and changes in the endometrium (which reduce
the likelihood of implantation).
Pharmacokinetics
Absorption
No specific investigation of the absolute bioavailability of
Seasonale in humans has been conducted. However, literature indicates that levonorgestrel
is rapidly and completely absorbed after oral administration (bioavailability
nearly 100%) and is not subject to first-pass metabolism. Ethinyl estradiol
is rapidly and almost completely absorbed from the gastrointestinal tract but,
due to first-pass metabolism in gut mucosa and liver, the bioavailability of
ethinyl estradiol is approximately 43%.
|
Table 1: Mean ±SD
Pharmacokinetic Parameters Following A Single Dose Administration of Two
Tablets of Seasonale in Healthy Female Subjects Under Fasting Conditions
|
|
Analyte
|
AUCt
|
Cmax
|
Tmax
|
T1/2
|
| |
(mean±SD)
|
(mean±SD)
|
(mean ±
SD)
|
(mean ±SD)
|
|
Levonorgestrel
|
60.8 ± 25.6
|
5.6 ± 1.5
|
1.4 ± 0.3 hours
|
29.8 ± 8.3
|
| |
ng*hr/mL
|
ng/mL
|
|
hours
|
|
Ethinyl estradiol
|
1307 ± 361
|
145 ± 45
|
1.6 ± 0.5 hours
|
15.4 ± 3.2
|
| |
pg*hr/mL
|
pg/mL
|
|
hours
|
The effect of food on the rate and the extent of levonorgestrel
and ethinyl estradiol absorption following oral administration of Seasonale
has not been evaluated.
Distribution
The apparent volume of distribution of levonorgestrel and ethinyl
estradiol are reported to be approximately 1.8 L/kg and 4.3 L/kg, respectively.
Levonorgestrel is about 97.5 - 99% protein-bound, principally to sex hormone
binding globulin (SHBG) and, to a lesser extent, serum albumin. Ethinyl estradiol
is about 95 - 97% bound to serum albumin. Ethinyl estradiol does not bind to
SHBG, but induces SHBG synthesis, which leads to decreased levonorgestrel clearance.
Following repeated daily dosing of combination levonorgestrel/ethinyl estradiol
oral contraceptives, levonorgestrel plasma concentrations accumulate more than
predicted based on single-dose kinetics, due in part, to increased SHBG levels
that are induced by ethinyl estradiol, and a possible reduction in hepatic metabolic
capacity.
Metabolism
Following absorption, levonorgestrel is conjugated at the 17ß-OH
position to form sulfate and to a lesser extent, glucuronide conjugates in plasma.
Significant amounts of conjugated and unconjugated 3a,5ß-tetrahydrolevonorgestrel
are also present in plasma, along with much smaller amounts of 3a,5a-tetrahydrolevonorgestrel
and 16ß-hydroxylevonorgestrel. Levonorgestrel and its phase I metabolites
are excreted primarily as glucuronide conjugates. Metabolic clearance rates
may differ among individuals by several-fold, and this may account in part for
the wide variation observed in levonorgestrel concentrations among users.
First-pass metabolism of ethinyl estradiol involves formation
of ethinyl estradiol-3-sulfate in the gut wall , followed by 2-hydroxylation
of a portion of the remaining untransformed ethinyl estradiol by hepatic cytochrome
P-450 3A4 (CYP3A4). Levels of CYP3A4 vary widely among individuals and can explain
the variation in rates of ethinyl estradiol hydroxylation. Hydroxylation at
the 4-, 6-, and 16- positions may also occur, although to a much lesser extent
than 2-hydroxylation. The various hydroxylated metabolites are subject to further
methylation and/or conjugation.
Excretion
About 45% of levonorgestrel and its metabolites are excreted
in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates.
The terminal elimination half-life for levonorgestrel after a single dose of
Seasonale was about 30 hours. Ethinyl estradiol is excreted in the urine and
feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic
recirculation. The terminal elimination half-life of ethinyl estradiol after
a single dose of Seasonale was found to be about 15 hours.
SPECIAL POPULATIONS
Race
No formal studies on the effect of race on the pharmacokinetics
of Seasonale were conducted.
Hepatic Insufficiency
No formal studies have been conducted to evaluate the effect
of hepatic disease on the pharmacokinetics of Seasonale . However, steroid hormones
may be poorly metabolized in patients with impaired liver function.
Renal Insufficiency
No formal studies have been conducted to evaluate the effect
of renal disease on the pharmacokinetics of Seasonale .
Drug-Drug Interactions
See PRECAUTIONS section – Drug
Interactions.
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