Erin Mechanism of Action

Pharmacotherapeutic group: Progestogens and estrogens, fixed combinations. ATC code: G03AA12.
Pharmacology: Pharmacodynamics: The contraceptive effect of COCs is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the cervical secretion.
Pharmacokinetics: Drospirenone: Absorption: Orally administered drospirenone has been reported to be rapidly and almost completely absorbed. Peak serum concentrations of approximately 37 ng/ml are reached at about 1-2 h after single ingestion. Bioavailability is reported to be about 76-85%.
Concomitant ingestion of food has no influence on bioavailability.
Distribution: Drospirenone is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBC). Only 3-5% of the total serum drug concentrations have been reported to be present as free steroid, 95-97% are nonspecifically bound to albumin. The ethinylestradiol-induced increase in SHBG does not influence the serum protein binding of drospirenone. The apparent volume of distribution of drospirenone has been reported to be about 3.7-4.2 l/kg.
Metabolism: Drospirenone is completely metabolized. The major metabolites in the plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-sulfate, both of which are formed without involvement of the P450 system. Drospirenone is metabolized to a minor extent by cytochrome P450 3A4 based on in vitro data. The clearance rate from serum is about 1.2-1.5 ml/min/kg. When drospirenone was acutely co-administered with ethinylestradiol, no direct interaction was found.
Elimination: Drospirenone serum levels decrease in two phases. The terminal disposition phase is characterized by a half-life of approximately 31 h. Drospirenone is not excreted in unchanged form. Its metabolites are excreted at a biliary to urinary ratio of about 1.2 to 1.4. The half-life of metabolite excretion with the urine and feces is reported to be about 1.7 days.
Steady-state conditions: Drospirenone pharmacokinetics are not influenced by SHBG levels. Following daily ingestion drug serum levels increase about two- to three-fold reaching steady-state conditions during the second half of a treatment cycle.
Special Populations: Effect of renal impairment: Steady-state serum drospirenone levels in women with mild renal impairment (creatinine clearance CrCL, 50-80 ml/min) were comparable to those of women with normal renal function (CrCL, >80 ml/min). The serum drospirenone levels were on average 37% higher in women with moderate renal impairment (CrCL, 30-50 ml/min) compared to those in women with normal renal function. Drospirenone treatment was reported to be well tolerated by all groups. Drospirenone treatment did not report any clinically significant effect on serum potassium concentration.
Effect of hepatic impairment: In women with moderate hepatic function, (Child-Pugh B) mean serum drospirenone concentration-time profiles were comparable to those of women with normal hepatic function during the absorption/distribution phases with similar C values. The mean max terminal half-life of drospirenone for volunteers with moderate hepatic impairment was 1.8 times greater than for volunteers with normal hepatic function.
An about 50% decrease in apparent oral clearance (CL/f) was reported in volunteers with moderate hepatic impairment as compared to those with normal liver function. The reported decline in drospirenone clearance in volunteers with moderate hepatic impairment compared to normal volunteers did not translate into any apparent difference in terms of serum potassium concentrations between the two groups of volunteers. Even in the presence of diabetes and concomitant treatment with spironolactone (two factors that can predispose a patient to hyperkalemia) an increase in serum potassium concentrations above the upper limit of the normal range was not reported. It can be concluded that drospirenone is well tolerated in patients with mild or moderate hepatic impairment (Child-Pugh B).
Ethnic groups: The impact of ethnic factors on the pharmacokinetics of drospirenone and ethinylestradiol was reported after single and repeated daily oral administration to young, healthy Caucasian and Japanese women. The results showed that ethnic differences between Japanese and Caucasian women had no clinically relevant influence on the pharmacokinetics of drospirenone and ethinylestradiol.
Ethinylestradiol: Absorption: Orally administered ethinylestradiol is reported to be rapidly and completely absorbed. Peak serum concentrations of about 54-100 ng/ml are reached within 1-2 hours. During absorption and first-liver passage, ethinylestradiol is reported to be metabolized extensively, resulting in a mean oral bioavailability of about 45% with a large interindividual variation of about 20-65%.
Concomitant intake of food has been reported to reduce the bioavailability of ethinylestradiol in about 25% of the investigated subjects while no change was observed in the others.
Distribution: Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98%), and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 2.8-8.6 l/kg has been reported.
Metabolism: Ethinylestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolized by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucuronides and sulfate. The clearance rate was reported to about 2.3-7 ml/min/kg.
Elimination: Ethinylestradiol serum levels decrease in two disposition phases characterized by half-lives of about 1 hour and 10-20 hours, respectively. Unchanged drug is not excreted, ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is reported to be about 1 day.
Steady-state conditions: Steady-state conditions are reached during the second half of a treatment cycle when serum drug levels are higher by 40-110% as compared to single dose.
Toxicology: Preclinical Safety: Preclinical data reported no special risks for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. However, it should be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.