Combination oral contraceptives primarily 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 the endometrium (which reduce the likelihood of implantation).
Levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability about 100%). Levonorgestrel is not subject to first-pass metabolism or enterohepatic circulation and therefore does not undergo variations in absorption after oral administration. 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 between 38% and 48%.
There have been no formal multiple-dose studies conducted using levonorgestrel and ethinyl estradiol tablets triphasic regimen. However, a multiple-dose study was done in 22 women using a monophasic, low dose combination of 0.10 mg levonorgestrel and 0.02 mg ethinyl estradiol. Maximum serum concentrations of levonorgestrel were found to be 2.8 ± 0.9 ng/mL (mean ± SD) at 1.6 ± 0.9 hours after a single dose, reaching a steady state at day 19. Observed levonorgestrel concentrations increased from day 1 to days 6 and 21 by 34% and 96%, respectively. Unbound levonorgestrel concentrations subsequently increased from day 1 to days 6 and 21 by 25% and 83%, respectively, however, the accumulation of unbound levonorgestrel was approximately 14% less than total levonorgestrel accumulation. The kinetics of total levonorgestrel were non-linear due to an increase in binding of levonorgestrel to SHBG, which is attributed to increased SHBG levels that are induced by the daily administration of ethinyl estradiol. Ethinyl estradiol reached maximum serum concentrations of 62 ± 21 pg/mL at 1.5 ± 0.5 hours after a single dose, reaching steady state at day 6. Ethinyl estradiol concentrations increased by 19% from days 1 to 21 consistent with an elimination half-life of 18 hours.
Single-dose studies with levonorgestrel and ethinyl estradiol tablets triphasic regimen have been conducted with the following data reported below in Table I. Plasma concentrations have been corrected below to reflect single tablet dosing/day.
|TABLE I: MEAN (SE) PHARMACOKINETIC PARAMETERS OF LEVONORGESTREL AND ETHINYL ESTRADIOL TABLETS TRIPHASIC REGIMEN IN SINGLE-DOSE STUDIES|
| Levonorgestrel (LNG) |
|50/30||1.7 (0.1)||1.3 (0.1)||23 (2.2)||17 (1.5)|
|75/40||2.1 (0.2)||1.5 (0.2)||15 (1.2)||21 (2.0)|
|125/30||2.5 (0.2)||1.6 (0.1)||23 (1.4)||34 (3.0)|
| Ethinyl Estradiol (EE) |
|50/30||141 (9)||1.4 (0.1)||8.1 (1.0)||1126 (113)|
|75/40||179 (13)||1.6 (0.2)||14 (1.7)||2177 (244)|
|125/30||115 (10)||1.5 (0.1)||8.8 (1.6)||1072 (170)|
Levonorgestrel is bound to SHBG and albumin. Levonorgestrel has high binding affinity for SHBG that is 60% of that of testosterone. Ethinyl estradiol is about 97% bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but will induce SHBG synthesis.
Levonorgestrel: The most important metabolic pathway occurs in the reduction of the Δ4-3-oxo group and hydroxylation at positions 2α, 1β and 16β, followed by conjugation. Most of the metabolites that circulate in the blood are sulfates of 3α, 5β-tetrahydro-levonorgestrel, while excretion occurs predominately in the form of glucuronides. Some of the parent levonorgestrel also circulates as 17β-sulfate. 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.
Ethinyl estradiol: Cytochrome P450 enzymes (CYP3A4) in the liver are 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 glucuronide and sulfate conjugates, and undergoes enterohepatic circulation.
The elimination half-life for levonorgestrel is approximately 36 ± 13 hours at steady state. Levonorgestrel and its metabolites are primarily excreted in the urine (40% to 68%) and about 16% to 48% are excreted in the feces. The elimination half-life of ethinyl estradiol is 18 ± 4.7 hours at steady state.
No formal studies have evaluated the effect of hepatic disease on the disposition of levonorgestrel and ethinyl estradiol tablets triphasic regimen. However, steroid hormones may be poorly metabolized in patients with impaired liver function.
No formal studies have evaluated the effect of renal disease on the disposition of levonorgestrel and ethinyl estradiol tablets triphasic regimen.
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