Angeliq Mechanism of Action

Pharmacokinetics: Estradiol: Based on data obtained with estradiol/drospirenone combination tablets containing estradiol 1 mg and drospirenone 1 or 4 mg, maximum serum estradiol concentrations of about 22 pg/mL are expected 6-8 hrs after administering a single oral dose. Estradiol undergoes extensive hepatic first-pass metabolism, reducing the oral bioavailability of the estrogen to about 5%. Following repeated oral administration of estradiol/drospirenone combination tablets, serum estradiol levels show little variation over 24-hr dosing interval. Because of the large circulating pool of estrogen sulfates and glucuronides and the enterohepatic recirculation, the terminal half-life of estradiol is a composite parameter, and is in the range of about 13-20 hrs for oral administration. Within the circulation, estradiol is bound nonspecifically to serum albumin and specifically to sex hormone-binding globulin (SHBG; 38%); only about 2-3% of circulating estradiol is present as free steroid. Orally administered Angeliq induces SHBG formation, and the ~20% increase in SHBG influences the distribution of estradiol with respect to the plasma proteins. The apparent volume of distribution of estradiol after a single IV dose is about 1 L/kg. Estradiol is rapidly metabolized, and besides estrone and estrone sulfate, a large number of other metabolites and conjugates are formed. Estrone and estriol are pharmacologically active; however, only estrone occurs at relevant concentrations in plasma. Estrone reaches about 6-fold higher serum levels than estradiol. The serum level of the estrone conjugates are about 26-fold higher than the corresponding levels of free estrone. The metabolite clearance of estradiol is 10-30 mL/min/kg. The metabolites are excreted via the urine and bile with a half-life of about 1 day. Following once-daily oral administration of estradiol/drospirenone combination tablets, estradiol and estrone concentrations reach steady state after 5 days. Serum estradiol levels accumulate approximately 2-fold between the 1st dose and steady state.
Drospirenone: The absorption of drospirenone is rapid and almost complete after oral administration. Maximum serum concentrations occur about 1 hr after oral administration of Angeliq. The absolute bioavailability of drospirenone is 76-85%, and is not influenced by food. After oral administration, serum drospirenone levels decrease with a mean terminal half-life of about 35-39 hrs. Drospirenone does not bind to SHBG or corticoid-binding globulin, but binds to other plasma proteins. The free fraction of drospirenone in the plasma is approximately 3-5%. Drospirenone is extensively metabolized after oral or IV administration. At least 20 different metabolites have been observed in the urine and feces, but only trace amounts are excreted unchanged. The renally excreted drospirenone metabolites do not exhibit pharmacological activity. The total clearance of drospirenone is 1.2-1.5 mL/min/kg. Excretion is nearly complete 10 days after a single dose, and the feces to urine excretion ratio is 1.2-1.4. The excretion half-life in urine and feces is ~40 hrs, which is similar to the terminal half-life of the drug in plasma. In patients with impaired renal function, serum drospirenone concentrations increase slightly as creatinine clearance decreases. This is not expected to be of clinical relevance because of the excellent tolerability of drospirenone. Following repeated once-daily oral administration of estradiol/drospirenone combination tablets, serum drospirenone concentrations increase within the 1st 10 days of treatment and then reach steady state. The mean accumulation factor for drospirenone between the 1st dose and steady state is 2.4-2.9, which is to be expected from the daily dosing interval and the terminal half-life of the drug. The pharmacokinetics of drospirenone were clearly dose-proportional after repeated daily administration of drospirenone 1-4 mg in combination with estradiol 1 mg to postmenopausal women.