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Pharmacology: Pharmacodynamics: Mode of Action: Ethinyl estradiol: Estrogens are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estrogens modulate the pituitary secretion of gonadotropins, luteinizing hormone, and follicle-stimulating hormone through a negative feedback system. Estrogen increases levels of sex hormone-binding globulin (SHBG) and may reduce unbound androgen levels. Ethinyl estradiol is a synthetic derivative of estradiol. The addition of the ethinyl group prevents rapid degradation by the liver.
Cyproterone: Steroidal compound with antiandrogenic, antigonadotropic and progestin-like activity.
Pharmacokinetics: Cyproterone acetate: Following oral administration cyproterone acetate is completely absorbed in a wide dose range. The ingestion of GIANE-35 effects a maximum serum level of 15 ng cyproterone acetate/ml at 1.6 hours. Thereafter, drug serum levels decrease in two disposition phases characterized by half-lives of 0.8 hours and 2.3 days. The total clearance of cyproterone acetate from serum was determined to 3.6 ml/min/kg. Cyproterone acetate is metabolized by various pathways including hydroxylations and conjugations. The main metabolite in human plasma is the 15ß-hydroxy derivative.
Some dose parts are excreted unchanged with bile fluid. Most of the dose is excreted in form of metabolites at a urinary to biliary ratio of 3:7. The renal and biliary excretion was determined to proceed with a half-life of 1.9 days. Metabolites from plasma were eliminated at a similar rate (half-life of 1.7 days).
Cyproterone acetate is almost exclusively bound to plasma albumins. About 3.5 - 4.0 % of total drug levels are present unbound. Because protein binding is non-specific, changes in SHBG (sex hormone binding globulin) levels do not affect the pharmacokinetics of cyproterone acetate.
Due to the long half-life of the terminal disposition phase from plasma (serum) and the daily intake, cyproterone acetate accumulates during one treatment cycle. Mean maximum drug serum levels increased from 15 ng/ml (day 1) to 21 ng/ml and 24 ng/ml, at the end of treatment cycles 1 and 3, respectively. The area under the concentration versus time profile increased 2.2 fold (end of cycle 1) and 2.4 fold (end of cycle 3). Steady-state conditions were reached after about 10 days. During long-term treatment cyproterone acetate accumulates over treatment cycles by a factor of 2.
The absolute bioavailability of cyproterone acetate is almost complete (88 % of dose). The relative bioavailability of cyproterone acetate from GIANE-35 was 109 % when compared to an aqueous microcrystalline suspension.
Ethinylestradiol: Orally administered ethinylestradiol is rapidly and completely absorbed. Following ingestion of GIANE-35, maximum drug serum levels of about 80 pg/ml are reached at 1.7 hours. Thereafter, ethinylestradiol plasma levels decrease in two phases characterized by half-lives of 1 - 2 hours and about 20 hours. For analytical reasons these parameters can only be calculated for higher dosages.
For ethinylestradiol an apparent volume of distribution of about 5 l/kg and a metabolic clearance rate from plasma of about 5 ml/min/kg were determined.
Ethinylestradiol is highly but non-specifically bound to serum albumin. 2% of drug levels are at present unbound. During absorption and first-liver passage ethinylestradiol is metabolized resulting in a reduced absolute and variable oral bioavailability. Unchanged drug is not excreted. Ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6 with a half-life of about one day.
Due to the half-life of the terminal disposition phase from plasma and the daily ingestion, steady-state plasma levels are reached after 3 - 4 days and are higher by 30 - 40 % as compared to a single dose. The relative bioavailability (reference: aqueous microcrystalline suspension) of ethinylestradiol from GIANE-35 was almost complete.
The systemic availability of ethinylestradiol might be influenced in both directions by other drugs. There is, however, no interaction with high doses of vitamin C. Ethinylestradiol induces the hepatic synthesis of SHBG (sex hormone binding globulin) and CBG (corticoid binding globulin) during continuous use. The extent of SHBG induction, however, is dependent upon the chemical structure and dose of the coadministered progestin. During treatment with GIANE-35 SHBG concentrations in serum increased from about 100 nmol/l to 300 nmol/l and the serum concentrations of CBG increased from about 50 mcg/ml to 95 mcg/ml.
