CLINICAL PHARMACOLOGY
ECPs are not effective if the woman is pregnant; they
act primarily by inhibiting ovulation. They may also act
by altering tubal transport of sperm and/or ova (thereby
inhibiting fertilization), and/or possibly altering the
endometrium (thereby inhibiting implantation).
Pharmacokinetics
Absorption
No specific investigation of the absolute bioavailability
of the ECPs in humans have been conducted. However, literature
indicates that levonorgestrel is rapidly and completely
absorbed after oral administration (bioavailability about
100%) and it is not subject to first-pass metabolism.
Ethinyl estradiol is rapidly absorbed from the gastrointestinal
tract but due to marked metabolism in the gut mucosa and
during passage through the liver, ethinyl estradiol absolute
bioavailability after oral administration is about 40%
to 50%.
After a single oral dose of two ECPs to 35 postmenopausal
women under fasting conditions, the bioavailabilities
of levonorgestrel and ethinyl estradiol were about 94%
and 97%, respectively, relative to the same two active
drugs given in an oral reference tablet. The obtained
pharmacokinetic parameters for levonorgestrel and ethinyl
estradiol are presented in TABLE 1. The effect of food
on the bioavailability of the ECPs following oral administration
has not been evaluated.
| TABLE 1
Mean (SD) Pharmacokinetic Parameters After Oral
Dose of 2 ECPs |
| Levonorgestrel
(n=35) |
| Cmax ng/ml |
Tmax h |
AUC ng/ml*h |
T½ h |
| 10.9 (4.0) |
1.7 (1.0) |
167 (92) |
40.8 (19.2) |
| Ethinyl Estradiol
(n=35) |
| Cmax pg/ml |
Tmax h |
AUC pg/ml*h |
T½ h |
| 248.2 (67) |
1.7 (0.4) |
2747 (701) |
21.2 (9.3) |
Distribution
Levonorgestrel in serum is primarily bound to SHBG. Ethinyl
estradiol is about 97% bound to plasma albumin. Ethinyl
estradiol does not bind to SHBG but induces SHBG synthesis.
Metabolism
Levonorgestrel: The most important metabolic
pathways occur in the reduction of the 4-3-oxo group and
hydroxylation at positions 2a, 10b, 16b, followed by conjugation.
Most of the metabolites that circulate in the blood are
sulfates of 3a, 5b-tetrahydro-levonorgestrel, while excretion
occurs predominantly in the form of glucuronides. Some
of the parent levonorgestrel also circulates as 17b-sulfate.
Metabolic clearance rates may differ among individuals
by several fold, and this may account in party for the
high variability observed in levonorgestrel concentrations
among users.
Ethinyl Estradiol: The cytochrome P450
enzyme (CYP3A4) is responsible for the 2-hydroxylation
that is the major oxidative reaction. The 2-hydroxy metabolite
is further transformed by methylation and glucuronidation
prior to urinary and fecal excretion. Levels of Cytochrome
P450 (CYP3A) vary widely among individuals and can explain
the variation in rates of ethinyl estradiol 2-hydroxylation.
Ethinyl estradiol is excreted in the urine and feces as
glucoronides and sulfates and undergoes enterohepatic
circulation.
Elimination
The elimination half-life for levonorgestrel after a
single dose of two ECPs is 40.8 ± 19 hours. Levonorgestrel
and its metabolites are primarily excreted in the urine.
The elimination half-life of ethinyl estradiol is 21.2
± 9.3 hours.
Special Populations
This product is not intended for use in geriatric (age
65 or older) or pediatric (premenarchal) populations and
pharmacokinetic data are unavailable for these populations.
Steroid hormones may be poorly metabolized in patients
with impaired liver function.
Race, Hepatic Insuffiency, and Renal Insuffiency: No
formal studies have evaluated the effect of race, hepatic
disease and renal disease on the disposition of the ECPs.
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